Next Article in Journal
Potential Effects of Nonadherent on Adherent Human Umbilical Venous Endothelial Cells in Cell Culture
Next Article in Special Issue
Expression of Interferons Lambda 3 and 4 Induces Identical Response in Human Liver Cell Lines Depending Exclusively on Canonical Signaling
Previous Article in Journal
N-palmitoyl-D-glucosamine, A Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice
Previous Article in Special Issue
IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis

Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany
Author to whom correspondence should be addressed.
These authors share first authorship.
These authors share last authorship.
Int. J. Mol. Sci. 2021, 22(3), 1492;
Received: 14 January 2021 / Revised: 23 January 2021 / Accepted: 28 January 2021 / Published: 2 February 2021
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)


In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments.

1. Introduction

The incidence of hepatocellular carcinoma (HCC) has been steadily increasing over the last decades. It was only most recently that a reversal of this trend was observed in Western countries [1]. Nevertheless, HCC ranks number five of the most common cancers worldwide and is one of the leading causes of cancer-related deaths, presenting a major global health problem [2,3]. The majority of HCC develops in the context of chronic liver inflammation and cirrhotic transformation, e.g., due to viral hepatitis, alcohol-related liver damage, and nonalcoholic fatty liver disease [4].
The degree of liver injury and the tumor stage jointly determine the prognosis of patients with HCC, which often remains poor. In early-stage disease, surgery is the curative treatment of choice. Patients with limited tumor burden may also be considered for liver transplantation [5]. However, many patients are diagnosed with advanced tumor stages and left to palliative treatments only. In these patients, pharmacological treatment options for systemic therapy have greatly improved over the past years, but their efficacy is still not satisfying. Thus, there is an unmet need for novel treatment options to further improve patients’ prognosis.
In this context, microRNAs (miRNAs) represent an important tool to gain new insights into the molecular pathogenesis of HCC. In this review, we summarize available data on the role of miRNA in hepatocarcinogenesis. We will briefly recapitulate the current algorithms for systemic treatment and discuss the role of miRNA in tumor biology and whether they could serve as therapeutic targets for disease modulation and predictors of treatment response.

2. Current and Emerging Therapeutic Options for HCC

Continuous viral (e.g., chronic hepatitis B, C, delta co-infection), toxic, or metabolic liver injury leads to chronic liver inflammation and conditions the transformation towards fibrosis and cirrhosis. This slow transition sets the basis for hepatocarcinogenesis and HCC progression. Despite the recommendation of surveillance and periodic imaging of cirrhotic livers, many patients are diagnosed with intermediate or advanced stages of HCC according to the Barcelona Clinic of Liver Cancer (BCLC) staging system [6]. Pharmacological treatment of HCC is particularly challenging as HCCs show important tumor heterogeneity and arise from a distinct microenvironment, with regard to different etiologies of liver injury, and different degrees of inflammation and fibrotic/cirrhotic transition.
Until recently, systemic treatment options of advanced HCC were limited to tyrosine-kinase inhibitors (TKI) [7]. In 2008, the SHARP trial established sorafenib, which simultaneously inhibits tumor growth by targeting the Raf-MEK-ERK cascade as well as angiogenesis by targeting vascular endothelial growth factor (VEGFR) 2, platelet-derived growth factor receptors (PDGFR), and KIT as a novel treatment in patients with advanced HCC [8]. Sorafenib remained the only standard systemic treatment for HCC for almost one decade. In 2018, lenvatinib, a molecule targeting VEGFR 1–3, fibroblast growth factor receptor (FGFR) 1–4, PDGFR, RET, and KIT [9], was tested as non-inferior in the REFLECT trial. Based on data from the RESORCE and CELESTIAL studies, both regorafenib and cabozantinib, targeting VEGFR 1–3, as well as the MET and AXL pathway [10], are approved for use in patients refractory to sorafenib [11,12]. Nevertheless, high toxicity rates and moderate effectivity limit the use of TKIs. Ramucirumab, a novel antibody directed against VEGFR 2, has demonstrated efficacy when used in patients with elevated serum alpha-fetoprotein (AFP) levels [13].
Immunotherapies seemed particularly promising in the setting of HCC, since cirrhosis bears an immunosuppressive environment that may be modulated by checkpoint inhibitors [14]. During the induction of an immune response, tumor-associated antigens are presented by antigen-presenting cells to T-cells, which become activated and induce tumor cell death. This process is negatively regulated by immune checkpoints, such as Programmed Cell Death 1 Protein (PD-1), a receptor mainly expressed on activated lymphocytes. Binding of PD-1 by its ligands PD-L1 and PD-L2 inhibits T cell activation and results in immunosuppression. Therefore, preventing activation of the PD-1/PD-L1 pathway might restore the ability of immune cells to recognize and kill tumor cells. Indeed, phase I/II data suggested that PD-1/PD-L1 inhibitors could be an effective anti-HCC tool, but phase III studies showed limited efficacy when applied as single agents [15]. However, when used as combination therapy including different substance classes, the combination of atezolizumab (PD-L1 antibody) plus bevacizumab (VEGF antibody) showed significantly improved overall survival (OS), progression-free survival (PFS), and excellent tumor response in the phase III IMBRAVE-150 study [16,17]. Current guidelines incorporate this evidence and both sorafenib and lenvatinib might be moved to subsequent therapy lines after immunotherapy failure. Other combinations are currently tested and might lead to further changes of treatment algorithms in the near future. Further progress in immunotherapy for HCC will critically rely on the identification of predictive biomarkers that allow early identification of ‘responders’ in order to personalize treatments as early as possible [18].

3. Role of miRNAs

MicroRNAs (miRNAs) represent a class of small, single-stranded RNAs of approximately 22 nucleotides length that were first described in C. elegans by the group of Ambros [19,20,21,22,23]. MiRNAs do not encode for proteins but repress the expression of their target RNA both on the transcriptional and translational level.
MiRNAs are transcribed by RNA polymerase II and III, leading to 500–3000 nucleotides long pri-miRNAs that are processed in the nucleus by the so-called “microprocessor complex” into precursor miRNAs (pre-miRNA, approximately 70 nucleotides long). Pre-miRNAs reach the cytoplasm via an exportin-5-mediated nuclear export. They are cleaved by the RNase III endonuclease “Dicer” into ~22 nucleotides long, double-stranded miRNAs. The single-stranded, mature miRNA is bound by Argonaute and integrated into the RNA-induced silencing complex (RISC). This complex is able to repress gene expression post-transcriptionally or translationally via binding of the loaded miRNA to the 3′ or 5′ UTR of its target messenger RNAs (mRNAs) (Figure 1). In case of complete complementarity, degradation of the target mRNA occurs, while in case of partial complementarity, translational repression is observed [19,21,24,25].
Up to now, more than 1800 miRNAs have been identified in humans [26]. In silico data predicted that more than 45,000 miRNA target sites are present in human DNA and that expression of more than 60% of all protein-coding genes are regulated by miRNAs [27]. Since one miRNA is able to influence expression of a whole networks of genes, many miRNAs are involved in the regulation of essential cellular processes and were associated with different disease states, such as acute and chronic liver diseases including viral hepatitis, steatohepatitis, liver fibrosis, cirrhosis, and HCC [28,29]. Since miRNAs are extremely stable in body fluids such as serum samples, they have been extensively studied in recent years in order to explore their potential as biomarkers for liver diseases [30].

4. Principal Physiological and Pathogenic Mechanisms of miRNAs

One of the most studied miRNAs is miRNA-122, which accounts for approximately 70% of all miRNAs found in hepatic tissue. When chronic liver injury occurs, decreasing levels of miRNA-122 are observed, leading to the subsequent upregulation of multiple pro-fibrogenic factors such as Kruppel-like factor 6 (KLF6) [31,32]. Downregulation of miRNA-122 also affects a large network of genes involved in systemic iron homeostasis (via upregulation of bone morphogenetic protein receptor type 1A (Bmpr1a), hemochromatosis (Hfe), hemojuvelin (Hjv), and hepcidin antimicrobial peptide (Hamp) [33]), in lipid metabolism [34], cell differentiation [35], and circadian regulation [36]. Other miRNAs playing key roles in hepatocyte proliferation and liver regeneration are miRNA-24 and miRNA-34a [37]. Both negatively regulate hepatocyte nuclear factor 4 alpha (HNF4α) expression in vitro, resulting in the suppression of cytochrome P450 and a reduced amount of HepG2 cells in S-phase [37]. After partial hepatectomy, levels of miRNA-26a and miRNA-217 are decreased in hepatic tissue, stimulating hepatocyte proliferation through regulation of cyclin-D2 (CCND2) and cyclin-E2 (CCNE2) protein expression, B-cell lymphoma protein homolog (Bcl6), and N-lysine methyltransferase SETD8 [38,39]. As major regulators of gene expression, miRNAs also are involved in liver development [40]. The conditional knockout of DICER1, a key element of miRNA biogenesis, led to a significant decrease of miRNA-194, miRNA-192, and miRNA-122 in hepatoblast-derived liver cells. However, while mice with AfpCre;Dicer1flox/flox genotype, i.e., conditional deletion of DICER1 in liver parenchymal cells, displayed no phenotypic anomalies just after birth, at 2–4 months of age, they showed various signs of progressive liver damage, including increased cellular proliferation and apoptosis, elevated circulating alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and overall increased liver mass [41]. This highlights the importance of miRNAs in maintaining liver homeostasis, suggesting a key role in the progression of liver disease.

5. Clinical Application of miRNAs

Increasing insight into the mechanisms of miRNAs in liver disease make them an attractive tool and target for therapeutic approaches. Indeed, several studies have investigated the potential effect of miRNA (ant)agonists for dampening liver disease progression. Scarce data are available regarding the role of miRNAs in hepatocarcinogenesis. Since decreased expression of miRNA-26a in HCC tissue facilitates the rapid proliferation of hepatocytes [38], increasing miRNA-26a levels might be used as a therapeutic approach in HCC. Indeed, systemic administration of miRNA-26a using adeno-associated virus (AAV) vectors in an HCC mouse model resulted in significant inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and an overall protection from disease progression [42]. MiRNA-122, which is downregulated in HCC tissue and targets multiple pathways of HCC pathogenesis, has been proposed as a therapeutic target as well. LNP-DP1, a cationic lipid nanoparticle formulation, was used as a vehicle for miRNA-122 delivery into HCC cells. In vivo intra-tumoral injection resulted in a 50% suppression of HCC growth in xenografts within 30 days, which correlated well with suppression of target genes and impairment of angiogenesis [43]. The expression of various ATP-binding cassette (ABC) transporters, responsible for chemotherapy resistance, is regulated through miRNAs [44]. Therefore, miRNA modulation may also bear a potential to overcome mechanisms of chemotherapy resistance. Miravirsen, an antisense of miRNA-122, that prevents binding to viral RNA and therefore compromising HCV replication, was investigated as a therapeutic approach in viral hepatitis [45]. The potential to reduce hepatitis C RNA levels in a dose-dependent manner was demonstrated in chronic HCV-infected chimpanzees [46] and subsequently in clinical trials [47]. The application of MRX34, a liposomal miRNA-34a mimic, was evaluated as therapy of solid tumors, including HCC, but clinical trials were suspended due to significant immune-related adverse effects [48].

6. Specific miRNAs Involved in Hepatocarcinogenesis

A general overview of specific miRNAs and signaling pathways that are involved in hepatocarcinogenesis is provided in Table 1 and Figure 2.

6.1. miRNA-223

X-chromosome linked miRNA-223 is considered a neutrophil-specific miRNA since it is highly expressed in these cells, playing a pivotal role in attenuation of neutrophil maturation and activation [101]. It is one of the key regulators in homeostasis of the immune system (hematopoietic differentiation), in systemic inflammatory processes, and in various liver diseases [102,103]. MiRNA-223 modulates hepatocellular function by affecting cholesterol levels, drug metabolism, apoptosis, and chromosomal stability of hepatocytes.
In HCC, miRNA-223 is downregulated by sulfatide in association with reduced recruitment of acetylated histone H3 and C/EBPα to the pre-miRNA-223 gene promoter [49]. Wong et al. demonstrated a simultaneous overexpression of the downstream target Stathmin 1 (STMN1), a microtubule-regulatory protein, controlling cellular proliferation and S-phase of the cell cycle [50]. Dong et al. described the miRNA-223-dependent modulation of the mechanistic target of rapamycin (mTOR) signaling pathway by inhibiting cell growth and inducing apoptosis through Ras-related protein 1 (Rab1) [53]. Interestingly, overexpression of miRNA-223 inhibits the development of metastasis by targeting integrin αV [49]. As levels of miRNA-223 are decreased in serum of HCC patients, it might serve as a biomarker [104,105], especially as a monitoring tool in the context of systemic HCC treatment or liver transplantation [106,107].

6.2. miRNA-21

Located on chromosome 17q23.2, miRNA-21 is one of the most abundant miRNAs detected in the circulation and is widely expressed in various types of human tissues (bone marrow, liver, lung, kidney, intestine, colon, and thyroid) [58,108]. On a cellular level, it is located in the cytosol and extracellular exosomes [109,110]. miRNA-21 plays a significant role in inflammation, fibrosis, and especially carcinogenesis. It is overexpressed in multiple solid tumors (e.g., breast, colon, lung, pancreas, prostate, stomach, gall bladder, liver) [55,111].
In HCC, miRNA-21 is significantly upregulated in both tissue and serum [51,56,57,112]. An aberrant expression of miRNA-21 may contribute to HCC progression by modulation of phosphatase and tensing homolog (PTEN) and PTEN-dependent pathways, leading to increased cell invasion, migration, and proliferation. More specifically, upregulation of miRNA-21 decreases PTEN expression, causing increased activity of AKT and the mTOR kinase pathways. As a result, downstream mediators of PTEN such as tyrosine phosphorylation of focal adhesion kinase (FAK) and the expression of matrix metallopeptidase (MMP) 2 and 9 are modulated. Liu et al. described simultaneous silencing in Programmed Cell Death 4 (PDCD4) and reversion-inducing cysteine-rich protein with Kazal motifs (RECKS), leading to reduced apoptosis and increased cell invasion [54]. Exosomal miRNAs such as miRNA-21 are involved in intercellular communication, tumor microenvironment, and tumor metastasis [113]. Several studies revealed a link between increased serum levels of miRNA-21 and tumor progression [51,57,58,114,115]. Tomimaru et al. found miRNA-21 to be a more specific biomarker compared to AFP, when differentiating HCC from chronic hepatitis or healthy controls [57]. Zhou et al. established a plasma miRNA panel containing seven miRNAs, including miRNA-21, which provides high accuracy in the diagnosis of early-stage hepatitis B-related HCC [51].

6.3. miRNA-193a

miRNA-193a is a member of the miRNA-193 family and is located on chromosome 17q11.2 [60]. Pre-miRNA-193a generates two mature miRNAs, miRNA-193a-3p and miRNA-193a-5p, which differ in distinct target sets for each miRNA [116]. Both act as tumor suppressors in liquid and solid malignancies [63,65,66,116,117,118], whereas irregular miRNA-193a expression significantly promotes carcinogenic conditions [117]. When expressed at physiological levels, miRNA-193a-3p mediates tumor-suppressive effects through Epidermal Growth Factor Receptor (EGFR) signaling, enhances apoptosis by inhibition of MCL1, and suppresses tumor cell migration and invasion through small GTPase Rab27B or Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) and S6K2 [63,64,65,66]. The miRNA-193a gene is frequently deleted in several types of human tumors and loss of miRNA-193a-3p’s anti-tumor functions may contribute to neoplastic transformation [64].
In the context of HCC, the expression of miRNA-193a-5p in tumor tissue is controversially discussed as different observations have been reported. In line with most published studies, Roy et al. identified downregulation of miRNA-193a-5p as a common feature of murine and human HCC regardless of the underlying etiology [59]. Downregulation of miRNA-193-a-5p causes cell proliferation and inhibits apoptosis via overexpression of Nucleolar and Spindle-Associated Protein 1 (NUSAP1) and cysteine-rich acidic secreted protein/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), a common target gene of miRNA-139-5p, miRNA-940, and miRNA-193a-5p [59,62]. Conversely, Wang et al. described an overexpression of miRNA-193a-5p in HCC, targeting Bcl2-Modifying Factor (BMF), which modulates cell proliferation, G1/S transition, and apoptosis [60].
Loosen et al. identified miRNA-193a-5p as a potential biomarker in the context of HCC as circulating relative miRNA-193a-5p levels were significantly elevated and predictive for patients’ outcome after tumor resection [61]. In line with this, Liu et al. described a significant difference in miRNA-193-a-5p levels in serum of HCC patients compared to non-HCC patients, without any difference among patients with liver cirrhosis, chronic hepatitis B, and healthy controls [119]. Hydbring at al. demonstrated that targeting miRNA-193a-3p causes cell cycle arrest and apoptosis of cancer cells in different tumor types, such as triple-negative breast cancers and gastric cancers [64]. In the context of HCC, Salvi et al. transfected HCC cells with miRNA-193a, causing increased apoptosis and decreased proliferation. In combination with sorafenib, further inhibition of HCC proliferation could be observed [120].

6.4. miRNA-122

miRNA-122, located on chromosome 18, is the most abundant miRNA in the liver and plays a central role in a large variety of biological processes such as homeostasis, metabolism (regulation of fatty acid metabolism and cholesterol), and liver development (hepatocyte proliferation, differentiation, maturation, and polyploidy) [72,121,122,123]. Transcription of miRNA-122 is regulated by liver-enriched transcription factors, including CCAAT/enhancer-binding protein (C/EBP) α, hepatocyte nuclear factor (HNF) 1α, HNF3β, and HNF4α [72]. miRNA-122 is downregulated in HCC tissue, being associated with hepatocarcinogenesis, metastasis, and poor prognosis [28,67,68]. Accordingly, overexpression of miRNA-122 suppresses HCC cell proliferation and increases chemosensitivity of HCC to antitumoral agents [28,67,70]. Several signaling pathways are involved in miRNA-122-mediated tumor suppression, including cyclin G1, pyruvate kinase isoform M2 (PKM2), Wnt family member 1 (WNT1), and paternally expressed gene 10 (PEG10) [67,68,73,74]. Wu et al. described a correlation between reduced miRNA-122 expression in hepatitis B-related HCC and venous invasion as well as poor prognosis by inhibition of hepatocyte nuclear factor 4α (HNF4α) and UDP-N-acetyl-α-D-galactosamine polypeptide N-acetylglucosaminyltransferase-10 (GALNT10) [75].
miRNA-122 may be a useful biomarker for detecting early liver injury [124,125,126] as it is released in response to various inflammatory processes such as viral infections and hepatocellular malignancies [127]. Nine plasma miRNAs, including miRNA-122, have been identified as biomarkers that predict regorafenib response in patients with HCC [128]. However, recent data challenge the idea of miRNA-122 as a diagnostic biomarker by revealing large interindividual and intraindividual variability of miRNA-122 levels in serum among healthy volunteers [129].
In the context of miRNA-122-based targeted therapy, long non-coding RNA HOTAIR, an oncogene in multiple cancers, might play an important role since it negatively regulates miRNA-122 expression in HCC cells by DNA methyltransferase-mediated DNA methylation and Cyclin 1 activation. Cheng et al. demonstrated that knockdown of HOTAIR was sufficient to inhibit tumorigenicity in vitro and in vivo by upregulation of miRNA-122 expression [130].
A phase 2a, randomized, double-blind study investigated miravirsen, a miRNA-122 inhibitor, as treatment for chronic HCV infection (NCT01200420). Miravirsen showed prolonged dose-dependent reductions in HCV RNA levels without viral resistance in chronic hepatitis C patients [47,131]. Several clinical trials are currently ongoing, e.g., exploring miRNA-122′s role as a marker for detection of drug-induced liver injury following chemotherapy (NCT03039062), its prognostic and predictive value for clinical outcome in patients with acute liver failure (NCT03000621), and the effect of direct-acting antivirals on miRNA-122 and insulin resistance in chronic HCV patients (NCT0300062).

6.5. miRNA-29

The miRNA-29 family consists of miRNA-29a, miRNA-29b-1, miRNA-29b-2, and miRNA-29c and is located on chromosomes 7q32.3 and 1q32.2. miRNA-29 is a critical player in multiple processes, including fibrosis, angiogenesis, epigenetics, proteostasis, metabolism, proliferation, apoptosis, metastasis, and immunomodulation [132,133,134]. It’s role as a tumor suppressor and oncogene is discussed controversially [76,77,133]. miRNA-29a/b/c expression is downregulated in patients with advanced liver fibrosis and mice with fibrosis induced by carbon tetrachloride (CCl4) or bile duct ligation [135]. More specifically, transforming growth factor beta (TGF-β) and nuclear factor kappa B (NF-κB)-dependent downregulation of miRNA-29 promotes the expression of extracellular matrix genes, such as Col1a1, Col4a5, and Col5a3, in hepatic stellate cells [132]. Matsumoto et al. demonstrated improved liver fibrosis in CCl4- and thioacetamide (TAA)-induced fibrosis models after treatment with miRNA-29a, indicating its important role as a potential target and therapeutic tool in liver fibrosis [135]. Downregulation of miR-29 is observed in various types of cancers including HCC and is associated with poor survival [76,77,136]. Parpart et al. described AFP as a functional antagonist of miRNA-29, contributing to global epigenetic alterations and poor prognosis in HCC. AFP inhibits miRNA-29a/b-1 transcription through binding of c-Myc to its transcript [76]. miRNA-29 contributes to the modulation of several genes, such as the upregulation of SET domain bifurcated 1 (SETDB1), an H3K9-specific histone methyltransferase, which is significantly associated with HCC disease progression, cancer aggressiveness, and poorer prognosis [79]. MiRNA-29a/b/c promotes apoptosis of HCC cells by suppressing two cell survival genes, MCL-1 and BCL2 [77]. MiRNA-29 acts as a tumor suppressor miRNA in a Myc- and AKT/Ras-induced HCC mouse model [79,137]. Despite miRNA-29′s potential as a prognostic biomarker, only a few studies have investigated its significance in HCC patients [138].

6.6. miRNA34a/c

The miRNA-34 family consists of miRNA-34a, miRNA-34b, and miRNA-34c and is located on chromosomes 1 and 11. While miRNA-34a is encoded by its own transcript, miRNA-34b and miRNA-34c share a common primary transcript [139,140]. Acting as a tumor-suppressor, miRNA-34 members modulate the p53 pathway by targeting c-MYC, CDK6, and c-MET, and therefore affect proliferation, apoptosis, and invasion in many cancer types, including pancreas, prostate, brain, colon, and breast cancer [80,88,89,90,91]. In hepatic cells treated with ethanol, expression of miRNA-34a was demonstrated to promote proliferation, migration, and transformation by targeting caspase-2 and sirtuin 1, which are involved in tissue remodeling during disease progression from normal liver through cirrhosis to HCC [92].
In the context of HCC, miRNA-34 is downregulated [80,81,82,83,84,85,87]. In early stages of liver regeneration, miRNA-34a is negatively correlated to the expression of Notch receptors [87]. By using miRNA-34a mimics, Wang et al. demonstrated that the Notch signaling pathway led to inhibition of cell growth, cell cycle arrest in G2/M phase, and increased cell apoptosis rate [87]. MiRNA-34a regulates histone deacetylase 1 (HDAC1), which inhibits HCC cell proliferation and induces apoptosis [81]. Moreover, miRNA-34a negatively regulates the expression of lactate dehydrogenase A (LDHA), which inhibits LDHA-dependent glucose uptake in cancer cells, as well as cell proliferation and invasion [80].
miRNA-34c-3p, one of the mature miRNAs of miRNA-34c, directly targets myristoylated alanine-rich protein kinase c substrate (MARCKS), the most prominent cellular substrate for protein kinase C, binding calmodulin, actin, and synapsin. Song et al. demonstrated that knock-out of MARCKS in HepG2 cells reduces cell migration and invasion, but not cell proliferation [84]. Liu et al. showed that miRNA-34c-5p alleviates HCC progression by negatively regulating FAM83A level [85]. FAM83A acts as a cancer-metastasis promoter, which accelerates migration, invasion, and metastasis, by forming a FAM83A/PI3K/AKT/c-JUN positive-feedback loop to activate epithelial-to-mesenchymal transition (EMT) signaling [141]. More specifically, FAM83A activates the PI3K/AKT signaling pathway and its downstream target c-JUN protein, as well as EMT proteins such as E-cadherin (downregulated), Vimentin, and N-cadherin (upregulated) [141].
Several studies provided evidence that miRNA-34a-5p may serve as a potential biomarker for liver cirrhosis since it is elevated in the serum of cirrhotic patients with no further increase in HCC patients and significantly correlates with the expression of AST, a reliable marker for liver damage [119,142]. On the other hand, low expression of miRNA-34c predicts poor prognosis in HCC as it is linked to advanced tumor stage and metastatic disease [84]. A synthetic miRNA-34a mimic is currently investigated for treatment of patients with primary liver cancer and liver metastases (NCT01829971) [143]. miRNA-34a may have potential as a therapeutic tool in metastatic disease, chemoresistance, and tumor recurrence [140,143,144].

6.7. miRNA-199

The miRNA-199 family consists of miRNA-199a and miRNA-199b, located on chromosomes 19 and 1. miRNA-199 is the third most abundant miRNA in liver tissue and is of great interest for cancer therapies since several potential targets of miRNA-199 are involved in carcinogenesis and metastatic progression [100]. Irregular expression of miR199a/b has been observed in various types of cancer, e.g., skin, pancreas, lung, stomach, and lymphoma. In non-small cell lung cancer, for example, the upregulation of miRNA-199a/b inhibits cell proliferation, migration, and invasion by inhibition of Axl expression [95].
Upregulation of miRNA-199 plays a key role in progression of chronic liver injury to liver fibrosis and advanced cirrhosis [145]. Contrarily, miRNA-199 is downregulated in HCC compared to normal liver tissue [93] and linked to the regulation of mTOR, c-Met, hypoxia-inducible-factor 1 (HIF-1)α, and CD44 [96,97,98,99]. MiRNA-199a/b-5p acts as a HCC-specific tumor suppressor, which inhibits Rho-associated protein kinase 1 (ROCK1) and modulates ROCK1/MLC and PI3K/AKT pathways, which are essential for HCC progression [100]. Emerging evidence suggests a potential role of miRNA-199a as a serum biomarker to detect patients with HCC [94,146,147]. Regarding miRNA-199′s therapeutic potential, Callegari et al. developed a miRNA-199-dependent oncolytic adenovirus [148].

7. Conclusion and Perspectives

MiRNAs are involved in hepatocarcinogenesis. This fact makes them interesting biomarkers for reflecting HCC pathogenesis as well as putative targets for preventing or treating HCC. Both in vitro and in vivo data argue for a potential therapeutic use of small RNAs in liver cancer. The principal suitability of miRNAs as a target in liver diseases has been demonstrated for Miravirsen in the context of hepatitis-C virus infection. Nevertheless, several challenges are still to be overcome before RNA-based therapies in the setting of HCC can be translated into clinical routine.
In this review, we summarized current knowledge on non-coding RNA in the transition from liver cirrhosis to HCC. We highlighted opportunities for clinical translation and discussed open issues applicable to future developments.

Author Contributions

Conceptualization: R.M. and C.R. writing—original draft preparation: R.M., B.Ö., and J.L. writing—review and editing: C.R., L.H., M.D., and S.H.L. visualization: L.G., T.H., and J.E. supervision: F.T. and T.L. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors have no conflict of interest to declare.


AAV adeno-associated virus
ALTalanine aminotransferase
ASTaspartate aminotransferase
ABCATP-binding cassette
BCLCBarcelona Clinic of Liver Cancer
BMFBcl2-modifying factor
C/EBP CCAAT/enhancer-binding protein
ds-mi RNADouble-stranded miRNA
FAKfocal adhesion kinase
ERBB4Erb-B2 Receptor Tyrosine Kinase 4
HCChepatocellular carcinoma
HNFhepatocyte nuclear factor
HNF4αhepatocyte nuclear factor 4 alpha
KLF6Kruppel-like factor 6
MMPmatrix metallopeptidase
mTOR mechanistic target of rapamycin
mRNAmessenger RNA
ncRNAnon-coding RNAs
NUSAP1Nucleolar and Spindle-Associated Protein 1
OSoverall survival
PEG10paternally expressed gene 10
PTEN phosphatase and tensing homolog
PDGFRplatelet-derived growth factor receptors
PD-1programmed cell death 1
PDCD4 programmed cell death 4
PFSProgression-free survival
PKM2pyruvate kinase isoform M2
Rab1 Ras-related protein 1
RECKSreversion-inducing cysteine-rich protein with kazal motifs
RISCRNA-induced silencing complex
SPOCK1secreted protein/osteonectin, cwcv, and kazal-like domains proteoglycan 1
SETDB1SET domain bifurcated 1
STMN1Stathmin 1
TKI tyrosine-kinase inhibitors
GALNT10UDP-N-acetyl-α-D-galactosamine polypeptide N-acetylglucosaminyltransferase-10
VEGFRvascular endothelial growth factor
WNT1Wnt family member 1


  1. Shiels, M.S.; O’Brien, T.R. Recent Decline in Hepatocellular Carcinoma Rates in the United States. Gastroenterology 2020, 158, 1503–1505.e2. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. McGlynn, K.A.; Petrick, J.L.; El-Serag, H.B. Epidemiology of Hepatocellular Carcinoma. Hepatology 2020, 73, 4–13. [Google Scholar] [CrossRef] [PubMed]
  3. Arnold, M.; Abnet, C.C.; Neale, R.E.; Vignat, J.; Giovannucci, E.L.; McGlynn, K.A.; Bray, F. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology 2020, 159, 335–349.e15. [Google Scholar] [CrossRef] [PubMed]
  4. Fujiwara, N.; Friedman, S.L.; Goossens, N.; Hoshida, Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J. Hepatol. 2018, 68, 526–549. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Gunasekaran, G.; Bekki, Y.; Lourdusamy, V.; Schwartz, M. Surgical Treatments of Hepatobiliary Cancers. Hepatology 2021, 73, 128–136. [Google Scholar] [CrossRef] [PubMed]
  6. Forner, A.; Reig, M.; Bruix, J. Hepatocellular carcinoma. Lancet 2018, 391, 1301–1314. [Google Scholar] [CrossRef]
  7. Llovet, J.M.; Ducreux, M.; Lencioni, R.; di Bisceglie, A.M.; Galle, P.R.; Dufour, J.F.; Greten, T.F.; Raymond, E.; Roskams, T.; de Baere, T.; et al. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J. Hepatol. 2012, 56, 908–943. [Google Scholar]
  8. Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; De Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; et al. Sorafenib in Advanced Hepatocellular Carcinoma. N. Engl. J. Med. 2008, 359, 378–390. [Google Scholar] [CrossRef]
  9. Kudo, M. Lenvatinib in Advanced Hepatocellular Carcinoma. Liver Cancer 2017, 6, 253–263. [Google Scholar] [CrossRef]
  10. Durante, C.; Russo, D.; Verrienti, A.; Filetti, S. XL184 (cabozantinib) for medullary thyroid carcinoma. Expert Opin. Investig. Drugs 2011, 20, 407–413. [Google Scholar] [CrossRef]
  11. Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.-H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017, 389, 56–66. [Google Scholar] [CrossRef][Green Version]
  12. Abou-Alfa, G.K.; Meyer, T.; Cheng, A.-L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B.-Y.; Cicin, I.; Merle, P.; Chen, Y.; Park, J.-W.; et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N. Engl. J. Med. 2018, 379, 54–63. [Google Scholar] [CrossRef] [PubMed]
  13. Zhu, A.X.; Kang, Y.-K.; Yen, C.-J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 282–296. [Google Scholar] [CrossRef]
  14. Ringelhan, M.; Pfister, D.; O’Connor, T.; Pikarsky, E.; Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 2018, 19, 222–232. [Google Scholar] [CrossRef] [PubMed]
  15. Xu, J.-M.; Li, J.; Bai, C.-M.; Xu, N.; Zhou, Z.; Li, Z.; Zhou, C.; Jia, R.; Lu, M.; Cheng, Y.; et al. Surufatinib in advanced well-differentiated neuroendocrine tumors: A multicenter, single-arm, open-label, phase Ib/II trial. Clin. Cancer Res. 2019, 25, 3486–3494. [Google Scholar] [CrossRef] [PubMed][Green Version]
  16. Cheng, A.-L.; Qin, S.; Ikeda, M.; Galle, P.; Ducreux, M.; Zhu, A.; Kim, T.-Y.; Kudo, M.; Breder, V.; Merle, P.; et al. IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann. Oncol. 2019, 30, ix186–ix187. [Google Scholar] [CrossRef]
  17. Casak, S.J.; Donoghue, M.; Fashoyin-Aje, L.; Jiang, X.; Rodriguez, L.; Shen, Y.-L.; Xu, Y.; Jiang, X.; Liu, J.; Zhao, H.; et al. FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma. Clin. Cancer Res. 2020. [Google Scholar] [CrossRef]
  18. Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019, 380, 1450–1462. [Google Scholar] [CrossRef][Green Version]
  19. Krol, J.; Loedige, I.; Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 2010, 11, 597–610. [Google Scholar] [CrossRef]
  20. Borchert, G.M.; Lanier, W.; Davidson, B.L. RNA polymerase III transcribes human microRNAs. Nat. Struct. Mol. Biol. 2006, 13, 1097–1101. [Google Scholar] [CrossRef]
  21. Macfarlane, L.-A.; Murphy, P.R. MicroRNA: Biogenesis, Function and Role in Cancer. Curr. Genom. 2010, 11, 537–561. [Google Scholar] [CrossRef] [PubMed][Green Version]
  22. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854. [Google Scholar] [CrossRef]
  23. Landgraf, P.; Rusu, M.; Sheridan, R.; Sewer, A.; Iovino, N.; Aravin, A.; Pfeffer, S.; Rice, A.; Kamphorst, A.O.; Landthaler, M.; et al. A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing. Cell 2007, 129, 1401–1414. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Ha, M.; Kim, V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 2014, 15, 509–524. [Google Scholar] [CrossRef]
  25. Ryan, B.M.; Robles, A.I.; Harris, C.C. Genetic variation in microRNA networks: The implications for cancer research. Nat. Rev. Cancer 2010, 10, 389–402. [Google Scholar] [CrossRef]
  26. Benz, F.; Roy, S.; Trautwein, C.; Roderburg, C.; Luedde, T. Circulating MicroRNAs as Biomarkers for Sepsis. Int. J. Mol. Sci. 2016, 17, 78. [Google Scholar] [CrossRef][Green Version]
  27. Friedman, R.C.; Farh, K.K.-H.; Burge, C.B.; Bartel, D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2008, 19, 92–105. [Google Scholar] [CrossRef][Green Version]
  28. Szabo, G.; Bala, S. MicroRNAs in liver disease. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 542–552. [Google Scholar] [CrossRef][Green Version]
  29. Lambrecht, J.; Mannaerts, I.; van Grunsven, L.A. The role of miRNAs in stress-responsive hepatic stellate cells during liver fibrosis. Front. Physiol. 2015, 6, 209. [Google Scholar] [CrossRef][Green Version]
  30. Lambrecht, J.; Verhulst, S.; Mannaerts, I.; Reynaert, H.; van Grunsven, L.A. Prospects in non-invasive assessment of liver fibrosis: Liquid biopsy as the future gold standard? Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864 Pt A, 1024–1036. [Google Scholar] [CrossRef]
  31. Cheung, O.; Puri, P.; Eicken, C.; Contos, M.J.; Mirshahi, F.; Maher, J.W.; Kellum, J.M.; Min, H.; Luketic, V.A.; Sanyal, A.J. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 2008, 48, 1810–1820. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Tsai, W.-C.; Hsu, S.-D.; Hsu, C.-S.; Lai, T.-C.; Chen, S.-J.; Shen, R.; Huang, Y.; Chen, H.-C.; Lee, C.-H.; Tsai, T.-F.; et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J. Clin. Investig. 2012, 122, 2884–2897. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Castoldi, M.; Spasić, M.V.; Altamura, S.; Elmén, J.; Lindow, M.; Kiss, J.; Stolte, J.; Sparla, R.; D’Alessandro, L.A.; Klingmüller, U.; et al. The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J. Clin. Investig. 2011, 121, 1386–1396. [Google Scholar] [CrossRef] [PubMed]
  34. Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R.; et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006, 3, 87–98. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Kim, N.; Kim, H.; Jung, I.; Kim, Y.; Kim, D.; Han, Y.-M. Expression profiles of miRNAs in human embryonic stem cells during hepatocyte differentiation. Hepatol. Res. 2011, 41, 170–183. [Google Scholar] [CrossRef] [PubMed]
  36. Gatfield, D.; Le Martelot, G.; Vejnar, C.E.; Gerlach, D.; Schaad, O.; Fleury-Olela, F.; Ruskeepää, A.-L.; Oresic, M.; Esau, C.C.; Zdobnov, E.M.; et al. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev. 2009, 23, 1313–1326. [Google Scholar] [CrossRef][Green Version]
  37. Takagi, S.; Nakajima, M.; Kida, K.; Yamaura, Y.; Fukami, T.; Yokoi, T. MicroRNAs Regulate Human Hepatocyte Nuclear Factor 4α, Modulating the Expression of Metabolic Enzymes and Cell Cycle. J. Biol. Chem. 2010, 285, 4415–4422. [Google Scholar] [CrossRef][Green Version]
  38. Zhou, J.; Ju, W.; Wang, D.; Wu, L.; Zhu, X.; Guo, Z.; He, X. Down-Regulation of microRNA-26a Promotes Mouse Hepatocyte Proliferation during Liver Regeneration. PLoS ONE 2012, 7, e33577. [Google Scholar] [CrossRef][Green Version]
  39. Pan, C.; Chen, H.; Wang, L.; Yang, S.; Fu, H.; Zheng, Y.; Miao, M.; Jiao, B. Down-Regulation of MiR-127 Facilitates Hepatocyte Proliferation during Rat Liver Regeneration. PLoS ONE 2012, 7, e39151. [Google Scholar] [CrossRef][Green Version]
  40. Chen, Y.; Verfaillie, C.M. MicroRNAs: The fine modulators of liver development and function. Liver Int. 2014, 34, 976–990. [Google Scholar] [CrossRef][Green Version]
  41. Hand, N.J.; Master, Z.R.; Le Lay, J.; Friedman, J.R. Hepatic function is preserved in the absence of mature microRNAs. Hepatology 2008, 49, 618–626. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Kota, J.; Chivukula, R.R.; O’Donnell, K.A.; Wentzel, E.A.; Montgomery, C.L.; Hwang, H.-W.; Chang, T.-C.; Vivekanandan, P.; Torbenson, M.; Clark, K.R.; et al. Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model. Cell 2009, 137, 1005–1017. [Google Scholar] [CrossRef] [PubMed][Green Version]
  43. Hsu, S.-H.; Yu, B.; Wang, X.; Lu, Y.; Schmidt, C.R.; Lee, R.J.; Lee, L.J.; Jacob, S.T.; Ghoshal, K. Cationic lipid nanoparticles for therapeutic delivery of siRNA and miRNA to murine liver tumor. Nanomed. Nanotechnol. Biol. Med. 2013, 9, 1169–1180. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Borel, F.; Han, R.; Visser, A.; Petry, H.; Van Deventer, S.J.; Jansen, P.L.; Konstantinova, P. Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs. Hepatology 2012, 55, 821–832. [Google Scholar] [CrossRef] [PubMed]
  45. Lindow, M.; Kauppinen, S. Discovering the first microRNA-targeted drug. J. Cell Biol. 2012, 199, 407–412. [Google Scholar] [CrossRef] [PubMed]
  46. Lanford, R.E.; Hildebrandt-Eriksen, E.S.; Petri, A.; Persson, R.; Lindow, M.; Munk, M.E.; Kauppinen, S.; Ørum, H. Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection. Science 2009, 327, 198–201. [Google Scholar] [CrossRef][Green Version]
  47. Janssen, H.L.; Reesink, H.W.; Lawitz, E.; Zeuzem, S.; Rodriguez-Torres, M.; Patel, K.; Van Der Meer, A.J.; Patick, A.K.; Chen, A.; Zhou, Y.; et al. Treatment of HCV Infection by Targeting MicroRNA. N. Engl. J. Med. 2013, 368, 1685–1694. [Google Scholar] [CrossRef][Green Version]
  48. Hong, D.S.; Kang, Y.-K.; Borad, M.; Sachdev, J.; Ejadi, S.; Lim, H.Y.; Brenner, A.J.; Park, K.; Lee, J.L.; Kim, T.-Y.; et al. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br. J. Cancer 2020, 122, 1630–1637. [Google Scholar] [CrossRef]
  49. Dong, Y.W.; Wang, R.; Cai, Q.; Qi, B.; Wu, W.; Zhang, Y.H.; Wu, X.Z. Sulfatide epigenetically regulates miR-223 and promotes the migration of human hepatocellular carcinoma cells. J. Hepatol. 2014, 60, 792–801. [Google Scholar] [CrossRef]
  50. Wong, Q.W.; Lung, R.W.; Law, P.T.; Lai, P.B.; Chan, K.Y.; To, K.; Wong, N. MicroRNA-223 Is Commonly Repressed in Hepatocellular Carcinoma and Potentiates Expression of Stathmin1. Gastroenterology 2008, 135, 257–269. [Google Scholar] [CrossRef]
  51. Zhou, J.; Yu, L.; Gao, X.; Hu, J.; Wang, J.; Dai, Z.; Wang, J.-F.; Zhang, Z.; Lu, S.; Huang, X.; et al. Plasma MicroRNA Panel to Diagnose Hepatitis B Virus–Related Hepatocellular Carcinoma. J. Clin. Oncol. 2011, 29, 4781–4788. [Google Scholar] [CrossRef] [PubMed][Green Version]
  52. Xu, J.; Wu, C.; Che, X.; Wang, L.; Yu, D.; Zhang, T.; Huang, L.; Li, H.; Tan, W.; Wang, C.; et al. Circulating MicroRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol. Carcinog. 2010, 50, 136–142. [Google Scholar] [CrossRef] [PubMed]
  53. Dong, Z.; Qi, R.; Guo, X.; Zhao, X.; Li, Y.; Zeng, Z.; Bai, W.; Chang, X.; Hao, L.; Chen, Y.; et al. MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation. Biochem. Biophys. Res. Commun. 2017, 483, 630–637. [Google Scholar] [CrossRef] [PubMed][Green Version]
  54. Liu, C.; Yu, J.; Yu, S.; Lavker, R.M.; Cai, L.; Liu, W.; Yang, K.; He, X.; Chen, S. MicroRNA-21 acts as an oncomir through multiple targets in human hepatocellular carcinoma. J. Hepatol. 2010, 53, 98–107. [Google Scholar] [CrossRef]
  55. Meng, F.; Henson, R.; Wehbe–Janek, H.; Ghoshal, K.; Jacob, S.T.; Patel, T. MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology 2007, 133, 647–658. [Google Scholar] [CrossRef][Green Version]
  56. Wang, H.; Hou, L.; Li, A.; Duan, Y.; Gao, H.; Song, X. Expression of Serum Exosomal MicroRNA-21 in Human Hepatocellular Carcinoma. BioMed Res. Int. 2014, 2014, 864894. [Google Scholar] [CrossRef]
  57. Tomimaru, Y.; Eguchi, H.; Nagano, H.; Wada, H.; Kobayashi, S.; Marubashi, S.; Tanemura, M.; Tomokuni, A.; Takemasa, I.; Umeshita, K.; et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J. Hepatol. 2012, 56, 167–175. [Google Scholar] [CrossRef]
  58. Wang, X.; He, Y.; Mackowiak, B.; Gao, B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2020. [Google Scholar] [CrossRef]
  59. Roy, S.; Hooiveld, G.J.; Seehawer, M.; Caruso, S.; Heinzmann, F.; Schneider, A.T.; Frank, A.K.; Cardenas, D.V.; Sonntag, R.; Luedde, M.; et al. microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis. Gastroenterology 2018, 155, 1951–1966.e26. [Google Scholar] [CrossRef]
  60. Wang, J.-T.; Wang, Z.-H. Role of miR-193a-5p in the proliferation and apoptosis of hepatocellular carcinoma. Eur. Rev. Med Pharmacol. Sci. 2018, 22, 7233–7239. [Google Scholar]
  61. Loosen, S.H.; Wirtz, T.H.; Roy, S.; Vucur, M.; Castoldi, M.; Schneider, A.T.; Koppe, C.; Ulmer, T.F.; Roeth, A.A.; Bednarsch, J.; et al. Circulating levels of microRNA193a-5p predict outcome in early stage hepatocellular carcinoma. PLoS ONE 2020, 15, e0239386. [Google Scholar] [CrossRef] [PubMed]
  62. Li, P.; Xiao, Z.; Luo, J.; Zhang, Y.; Lin, L. MiR-139-5p, miR-940 and miR-193a-5p inhibit the growth of hepatocellular carcinoma by targeting SPOCK1. J. Cell Mol. Med. 2019, 23, 2475–2488. [Google Scholar] [CrossRef] [PubMed][Green Version]
  63. Pu, Y.; Zhao, F.; Cai, W.; Meng, X.; Li, Y.; Cai, S. MiR-193a-3p and miR-193a-5p suppress the metastasis of human osteosarcoma cells by down-regulating Rab27B and SRR, respectively. Clin. Exp. Metastasis 2016, 33, 359–372. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Hydbring, P.; Wang, Y.; Fassl, A.; Li, X.; Matia, V.; Otto, T.; Choi, Y.J.; Sweeney, K.E.; Suski, J.M.; Yin, H.; et al. Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell 2017, 31, 576–590.e8. [Google Scholar] [CrossRef] [PubMed]
  65. Liang, H.; Liu, M.; SuYang, Z.; Zhou, Y.; Wang, W.; Wang, X.; Fu, Z.; Wang, N.; Zhang, S.; Wang, Y.; et al. miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4. J. Biol. Chem. 2015, 290, 926–940. [Google Scholar] [CrossRef] [PubMed][Green Version]
  66. Yu, T.; Li, J.; Yan, M.; Liu, L.; Lin, H.; Zhao, F.; Li, J.; He, X.; Yao, M. MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. Oncogene 2015, 34, 413–423. [Google Scholar] [CrossRef]
  67. Liu, A.M.; Xu, Z.; Shek, F.H.; Wong, K.-F.; Lee, N.P.; Poon, R.T.; Chen, J.; Luk, J.M. miR-122 Targets Pyruvate Kinase M2 and Affects Metabolism of Hepatocellular Carcinoma. PLoS ONE 2014, 9, e86872. [Google Scholar] [CrossRef][Green Version]
  68. Gramantieri, L.; Ferracin, M.; Fornari, F.; Veronese, A.; Sabbioni, S.; Liu, C.-G.; Calin, G.A.; Giovannini, C.; Ferrazzi, E.; Grazi, G.L.; et al. Cyclin G1 Is a Target of miR-122a, a MicroRNA Frequently Down-regulated in Human Hepatocellular Carcinoma. Cancer Res. 2007, 67, 6092–6099. [Google Scholar] [CrossRef][Green Version]
  69. Franck, M.; Schütte, K.; Malfertheiner, P.; Link, A. Prognostic value of serum microRNA-122 in hepatocellular carcinoma is dependent on coexisting clinical and laboratory factors. World J. Gastroenterol. 2020, 26, 86–96. [Google Scholar] [CrossRef]
  70. Bandiera, S.; Pfeffer, S.; Baumert, T.F.; Zeisel, M.B. miR-122—A key factor and therapeutic target in liver disease. J. Hepatol. 2015, 62, 448–457. [Google Scholar] [CrossRef][Green Version]
  71. Hung, C.-H.; Hu, T.-H.; Lu, S.-N.; Kuo, F.-Y.; Chen, C.-H.; Wang, J.-H.; Huang, C.-M.; Lee, C.-M.; Lin, C.-Y.; Yen, Y.-H.; et al. Circulating microRNAs as biomarkers for diagnosis of early hepatocellular carcinoma associated with hepatitis B virus. Int. J. Cancer 2016, 138, 714–720. [Google Scholar] [CrossRef] [PubMed]
  72. Xu, H.; He, J.-H.; Xiao, Z.-D.; Zhang, Q.-Q.; Chen, Y.-Q.; Zhou, H.; Qu, L.-H. Liver-enriched transcription factors regulate MicroRNA-122 that targets CUTL1 during liver development. Hepatology 2010, 52, 1431–1442. [Google Scholar] [CrossRef] [PubMed]
  73. Ahsani, Z.; Mohammadi-Yeganeh, S.; Kia, V.; Karimkhanloo, H.; Zarghami, N.; Paryan, M. WNT1 Gene from WNT Signaling Pathway Is a Direct Target of miR-122 in Hepatocellular Carcinoma. Appl. Biochem. Biotechnol. 2016, 181, 884–897. [Google Scholar] [CrossRef] [PubMed]
  74. Shyu, Y.-C.; Lee, T.-L.; Lu, M.-J.; Chen, J.-R.; Chien, R.-N.; Chen, H.-Y.; Lin, J.-F.; Tsou, A.-P.; Chen, Y.-H.; Hsieh, C.-W.; et al. miR-122-mediated translational repression of PEG10 and its suppression in human hepatocellular carcinoma. J. Transl. Med. 2016, 14, 1–11. [Google Scholar] [CrossRef] [PubMed][Green Version]
  75. Wu, Q.; Liu, H.-O.; Liu, Y.-D.; Liu, W.-S.; Pan, D.; Zhang, W.-J.; Yang, L.; Fu, Q.; Xu, J.-J.; Gu, J.-X. Decreased Expression of Hepatocyte Nuclear Factor 4α (Hnf4α)/MicroRNA-122 (miR-122) Axis in Hepatitis B Virus-associated Hepatocellular Carcinoma Enhances Potential Oncogenic GALNT10 Protein Activity. J. Biol. Chem. 2015, 290, 1170–1185. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Parpart, S.; Roessler, S.; Dong, F.; Rao, V.; Takai, A.; Ji, J.; Qin, L.X.; Ye, Q.H.; Jia, H.L.; Tang, Z.Y.; et al. Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome. Hepatology 2014, 60, 872–883. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Xiong, Y.; Fang, J.-H.; Yun, J.-P.; Yang, J.; Zhang, Y.; Jia, W.-H.; Zhuang, S.-M. Effects of MicroRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 2009, 51, 836–845. [Google Scholar] [CrossRef]
  78. Lin, X.-J.; Chong, Y.; Guo, Z.-W.; Xie, C.; Yang, X.-J.; Zhang, Q.; Li, S.-P.; Xiong, Y.; Yuan, Y.; Min, J.; et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: A multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015, 16, 804–815. [Google Scholar] [CrossRef]
  79. Wong, C.-M.; Wei, L.; Law, C.-T.; Ho, D.W.-H.; Tsang, F.H.-C.; Au, S.L.-K.; Sze, K.M.-F.; Lee, J.M.-F.; Wong, C.C.-L.; Ng, I.O.-L. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology 2015, 63, 474–487. [Google Scholar] [CrossRef][Green Version]
  80. Zhang, H.; Wang, Y.; Han, Y. MicroRNA-34a inhibits liver cancer cell growth by reprogramming glucose metabolism. Mol. Med. Rep. 2018, 17, 4483–4489. [Google Scholar] [CrossRef][Green Version]
  81. Sun, T.-Y.; Xie, H.-J.; Li, Z.; Kong, L.-F.; Gou, X.-N.; Li, D.-J.; Shi, Y.-J.; Ding, Y.-Z. miR-34a regulates HDAC1 expression to affect the proliferation and apoptosis of hepatocellular carcinoma. Am. J. Transl. Res. 2017, 9, 103–114. [Google Scholar] [PubMed]
  82. Chen, Q.; Li, L.; Tu, Y.; Zheng, L.L.; Liu, W.; Zuo, X.Y.; He, Y.M.; Zhang, S.Y.; Zhu, W.; Cao, J.P.; et al. MiR-34a regulates apoptosis in liver cells by targeting the KLF4 gene. Cell. Mol. Biol. Lett. 2014, 19, 52–64. [Google Scholar] [CrossRef] [PubMed][Green Version]
  83. Tryndyak, V.P.; Ross, S.A.; Beland, F.A.; Pogribny, I.P. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol. Carcinog. 2009, 48, 479–487. [Google Scholar] [CrossRef] [PubMed]
  84. Song, J.; Wang, Q.; Luo, Y.; Yuan, P.; Tang, C.; Hui, Y.; Wang, Z. miR-34c-3p inhibits cell proliferation, migration and invasion of hepatocellular carcinoma by targeting MARCKS. Int. J. Clin. Exp. Pathol. 2015, 8, 12728–12737. [Google Scholar] [PubMed]
  85. Yu, W.-S.; Wang, Z.-G.; Guo, R.-P.; Lin, Z.-Q.; Ye, Z.-W.; Lu, C.-L. Hepatocellular carcinoma progression is protected by miRNA-34c-5p by regulating FAM83A. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 6046–6054. [Google Scholar]
  86. Bharali, D.; Jebur, H.B.; Baishya, D.; Kumar, S.; Sarma, M.P.; Masroor, M.; Akhter, J.; Husain, S.A.; Kar, P. Expression Analysis of Serum microRNA-34a and microRNA-183 in Hepatocellular Carcinoma. Asian Pac. J. Cancer Prev. 2018, 19, 2561–2568. [Google Scholar]
  87. Wang, X.-P.; Zhou, J.; Han, M.; Chen, C.-B.; Zheng, Y.-T.; He, X.-S.; Yuan, X.-P. MicroRNA-34a regulates liver regeneration and the development of liver cancer in rats by targeting Notch signaling pathway. Oncotarget 2017, 8, 13264–13276. [Google Scholar] [CrossRef][Green Version]
  88. Dong, P.; Xiong, Y.; Watari, H.; Hanley, S.J.B.; Konno, Y.; Ihira, K.; Yamada, T.; Kudo, M.; Yue, J.; Sakuragi, N. MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells. J. Exp. Clin. Cancer Res. 2016, 35, 1–9. [Google Scholar] [CrossRef]
  89. Chen, W.; Liu, Y.; Liang, X.; Huang, Y.; Li, Q. Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery. Acta Biomater. 2017, 57, 238–250. [Google Scholar] [CrossRef]
  90. Zhang, L.; Liao, Y.; Tang, L. MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer. J. Exp. Clin. Cancer Res. 2019, 38, 1–13. [Google Scholar] [CrossRef][Green Version]
  91. Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2009, 17, 193–199. [Google Scholar] [CrossRef] [PubMed]
  92. Meng, F.; Glaser, S.S.; Francis, H.; Yang, F.; Han, Y.; Stokes, A.; Staloch, D.; McCarra, J.; Liu, J.; Venter, J.; et al. Epigenetic Regulation of miR-34a Expression in Alcoholic Liver Injury. Am. J. Pathol. 2012, 181, 804–817. [Google Scholar] [CrossRef] [PubMed][Green Version]
  93. Murakami, Y.; Yasuda, T.; Saigo, K.; Urashima, T.; Toyoda, H.; Okanoue, T.; Shimotohno, K. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2005, 25, 2537–2545. [Google Scholar] [CrossRef] [PubMed]
  94. Yin, J.; Hou, P.; Wu, Z.; Wang, T.; Nie, Y. Circulating miR-375 and miR-199a-3p as potential biomarkers for the diagnosis of hepatocellular carcinoma. Tumor Biol. 2015, 36, 4501–4507. [Google Scholar] [CrossRef] [PubMed]
  95. Mudduluru, G.; Ceppi, P.; Kumarswamy, R.; Scagliotti, G.V.; Papotti, M.; Allgayer, H. Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene 2011, 30, 2888–2899. [Google Scholar] [CrossRef]
  96. Fornari, F.; Milazzo, M.; Chieco, P.; Negrini, M.; Calin, G.A.; Grazi, G.L.; Pollutri, D.; Croce, C.M.; Bolondi, L.; Gramantieri, L.; et al. MiR-199a-3p Regulates mTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells. Cancer Res. 2010, 70, 5184–5193. [Google Scholar] [CrossRef][Green Version]
  97. Kim, S.; Lee, U.J.; Kim, M.-N.; Lee, E.-J.; Kim, J.Y.; Lee, M.Y.; Choung, S.; Kim, Y.J.; Choi, Y.-C. MicroRNA miR-199a* Regulates the MET Proto-oncogene and the Downstream Extracellular Signal-regulated Kinase 2 (ERK2). J. Biol. Chem. 2008, 283, 18158–18166. [Google Scholar] [CrossRef][Green Version]
  98. Jia, X.Q.; Cheng, H.Q.; Qian, X.; Bian, C.X.; Shi, Z.M.; Zhang, J.-P.; Jiang, B.-H.; Feng, Z.Q. Lentivirus-Mediated Overexpression of MicroRNA-199a Inhibits Cell Proliferation of Human Hepatocellular Carcinoma. Cell Biophys. 2011, 62, 237–244. [Google Scholar] [CrossRef]
  99. Henry, J.C.; Park, J.K.; Jiang, J.; Kim, J.H.; Nagorney, D.M.; Roberts, L.R.; Banerjee, S.; Schmittgen, T.D. miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines. Biochem. Biophys. Res. Commun. 2010, 403, 120–125. [Google Scholar] [CrossRef][Green Version]
  100. Zhan, Y.; Zheng, N.; Teng, F.; Bao, L.; Liu, F.; Zhang, M.; Guo, M.; Guo, W.; Ding, G.; Wang, Q. MiR-199a/b-5p inhibits hepatocellular carcinoma progression by post-transcriptionally suppressing ROCK1. Oncotarget 2017, 8, 67169–67180. [Google Scholar] [CrossRef]
  101. Johnnidis, J.B.; Harris, M.H.; Wheeler, R.T.; Stehling-Sun, S.; Lam, M.H.; Kirak, O.; Brummelkamp, T.R.; Fleming, M.D.; Camargo, F.D. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nat. Cell Biol. 2008, 451, 1125–1129. [Google Scholar] [CrossRef] [PubMed]
  102. Haneklaus, M.; Gerlic, M.; O’Neill, L.A.J.; Masters, S.L. miR-223: Infection, inflammation and cancer. J. Intern. Med. 2013, 274, 215–226. [Google Scholar] [CrossRef] [PubMed]
  103. Ye, D.; Zhang, T.; Lou, G.; Liu, Y. Role of miR-223 in the pathophysiology of liver diseases. Exp. Mol. Med. 2018, 50, 1–12. [Google Scholar] [CrossRef][Green Version]
  104. Bao, S.; Zheng, J.; Li, N.; Huang, C.; Chen, M.; Cheng, Q.; Yu, K.; Chen, S.; Zhu, M.; Shi, G. Serum MicroRNA Levels as a Noninvasive Diagnostic Biomarker for the Early Diagnosis of Hepatitis B Virus-Related Liver Fibrosis. Gut Liver 2017, 11, 860–869. [Google Scholar] [CrossRef] [PubMed][Green Version]
  105. Giray, B.G.; Emekdas, G.; Tezcan, S.; Ulger, M.; Serin, M.S.; Sezgin, O.; Altintas, E.; Tiftik, E.N. Profiles of serum microRNAs; miR-125b-5p and miR223-3p serve as novel biomarkers for HBV-positive hepatocellular carcinoma. Mol. Biol. Rep. 2014, 41, 4513–4519. [Google Scholar] [CrossRef] [PubMed]
  106. Gyöngyösi, B.; Végh, É.; Járay, B.; Székely, E.; Fassan, M.; Bodoky, G.; Schaff, Z.; Kiss, A. Pretreatment MicroRNA Level and Outcome in Sorafenib-treated Hepatocellular Carcinoma. J. Histochem. Cytochem. 2014, 62, 547–555. [Google Scholar] [CrossRef][Green Version]
  107. Han, Z.-B.; Zhong, L.; Teng, M.-J.; Fan, J.-W.; Tang, H.-M.; Wu, J.-Y.; Chen, H.; Wang, Z.-W.; Qiu, G.-Q.; Peng, Z. Identification of recurrence-related microRNAs in hepatocellular carcinoma following liver transplantation. Mol. Oncol. 2012, 6, 445–457. [Google Scholar] [CrossRef][Green Version]
  108. Ludwig, N.; Leidinger, P.; Becker, K.; Backes, C.; Fehlmann, T.; Pallasch, C.; Rheinheimer, S.; Meder, B.; Stähler, C.; Meese, E.; et al. Distribution of miRNA expression across human tissues. Nucleic Acids Res. 2016, 44, 3865–3877. [Google Scholar] [CrossRef]
  109. Beltrami, C.; Besnier, M.; Shantikumar, S.; Shearn, A.I.; Rajakaruna, C.; Laftah, A.; Sessa, F.; Spinetti, G.; Petretto, E.; Angelini, G.D.; et al. Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis. Mol. Ther. 2017, 25, 679–693. [Google Scholar] [CrossRef][Green Version]
  110. Zhu, H.; Luo, H.; Li, Y.; Zhou, Y.; Jiang, Y.; Chai, J.; Xiao, X.; You, Y.; Zuo, X. MicroRNA-21 in Scleroderma Fibrosis and its Function in TGF-β-Regulated Fibrosis-Related Genes Expression. J. Clin. Immunol. 2013, 33, 1100–1109. [Google Scholar] [CrossRef]
  111. Kumarswamy, R.; Volkmann, I.; Thum, T. Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011, 8, 706–713. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Shih, Y.-T.; Wang, M.-C.; Zhou, J.; Peng, H.-H.; Lee, D.-Y.; Chiu, J.-J. Endothelial progenitors promote hepatocarcinoma intrahepatic metastasis through monocyte chemotactic protein-1 induction of microRNA-21. Gut 2014, 64, 1132–1147. [Google Scholar] [CrossRef] [PubMed]
  113. Li, S.; Yao, J.; Xie, M.; Liu, Y.; Zheng, M. Exosomal miRNAs in hepatocellular carcinoma development and clinical responses. J. Hematol. Oncol. 2018, 11, 1–9. [Google Scholar] [CrossRef] [PubMed]
  114. Zhang, T.; Yang, Z.; Kusumanchi, P.; Han, S.; Liangpunsakul, S. Critical Role of microRNA-21 in the Pathogenesis of Liver Diseases. Front. Med. 2020, 7, 7. [Google Scholar] [CrossRef] [PubMed][Green Version]
  115. Guo, X.; Lv, X.; Lv, X.; Ma, Y.; Chen, L.; Chen, Y. Circulating miR-21 serves as a serum biomarker for hepatocellular carcinoma and correlated with distant metastasis. Oncotarget 2017, 8, 44050–44058. [Google Scholar] [CrossRef] [PubMed][Green Version]
  116. Grossi, I.; Salvi, A.; Abeni, E.; Marchina, E.; De Petro, G. Biological Function of MicroRNA193a-3p in Health and Disease. Int. J. Genom. 2017, 2017, 1–13. [Google Scholar] [CrossRef] [PubMed][Green Version]
  117. Iliopoulos, D.; Rotem, A.; Struhl, K. Inhibition of miR-193a Expression by Max and RXRα Activates K-Ras and PLAU to Mediate Distinct Aspects of Cellular Transformation. Cancer Res. 2011, 71, 5144–5153. [Google Scholar] [CrossRef][Green Version]
  118. Williams, M.; Kirschner, M.B.; Cheng, Y.Y.; Hanh, J.; Weiss, J.; Mugridge, N.; Wright, C.M.; Linton, A.; Kao, S.C.; Edelman, J.J.B.; et al. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma. Oncotarget 2015, 6, 23480–23495. [Google Scholar] [CrossRef][Green Version]
  119. Jin, Y.; Wong, Y.S.; Goh, B.K.P.; Chan, C.Y.; Cheow, P.C.; Chow, P.K.H.; Lim, T.K.H.; Goh, G.B.B.; Krishnamoorthy, T.L.; Kumar, R.; et al. Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma. Sci. Rep. 2019, 9, 1–12. [Google Scholar] [CrossRef][Green Version]
  120. Salvi, A.; Conde, I.; Abeni, E.; Arici, B.; Grossi, I.; Specchia, C.; Portolani, N.; Barlati, S.; De Petro, G. Effects of miR-193a and sorafenib on hepatocellular carcinoma cells. Mol. Cancer 2013, 12, 162. [Google Scholar] [CrossRef][Green Version]
  121. Jopling, C. Liver-specific microRNA-122: Biogenesis and function. RNA Biol. 2012, 9, 137–142. [Google Scholar] [CrossRef] [PubMed][Green Version]
  122. Girard, M.; Jacquemin, E.; Munnich, A.; Lyonnet, S.; Henrion-Caude, A. miR-122, a paradigm for the role of microRNAs in the liver. J. Hepatol. 2008, 48, 648–656. [Google Scholar] [CrossRef] [PubMed][Green Version]
  123. Hsu, S.-H.; Delgado, E.R.; Otero, P.A.; Teng, K.-Y.; Kutay, H.; Meehan, K.M.; Moroney, J.B.; Monga, J.K.; Hand, N.J.; Friedman, J.R.; et al. MicroRNA-122 regulates polyploidization in the murine liver. Hepatology 2016, 64, 599–615. [Google Scholar] [CrossRef] [PubMed][Green Version]
  124. Lambrecht, J.; Verhulst, S.; Reynaert, H.; van Grunsven, L.A. The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis. Cells 2019, 8, 1003. [Google Scholar] [CrossRef] [PubMed][Green Version]
  125. Liu, C.-H.; Ampuero, J.; Gil-Gómez, A.; Montero-Vallejo, R.; Rojas, Á.; Muñoz-Hernández, R.; Gallego-Durán, R.; Romero-Gómez, M. miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J. Hepatol. 2018, 69, 1335–1348. [Google Scholar] [CrossRef] [PubMed]
  126. Lambrecht, J.; Poortmans, P.J.; Verhulst, S.; Reynaert, H.; Mannaertsa, I.; Van Grunsven, L.A. Circulating ECV-Associated miRNAs as Potential Clinical Biomarkers in Early Stage HBV and HCV Induced Liver Fibrosis. Front. Pharmacol. 2017, 8. [Google Scholar] [CrossRef][Green Version]
  127. Qi, P.; Cheng, S.-Q.; Wang, H.; Li, N.; Chen, Y.-F.; Gao, C.-F. Serum MicroRNAs as Biomarkers for Hepatocellular Carcinoma in Chinese Patients with Chronic Hepatitis B Virus Infection. PLoS ONE 2011, 6, e28486. [Google Scholar] [CrossRef][Green Version]
  128. Teufel, M.; Seidel, H.; Köchert, K.; Meinhardt, G.; Finn, R.S.; Llovet, J.M.; Bruix, J. Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma. Gastroenterology 2019, 156, 1731–1741. [Google Scholar] [CrossRef][Green Version]
  129. Church, R.J.; Kullak-Ublick, G.A.; Aubrecht, J.; Bonkovsky, H.L.; Chalasani, N.; Fontana, R.J.; Goepfert, J.C.; Hackman, F.; King, N.M.P.; Kirby, S.; et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology 2019, 69, 760–773. [Google Scholar] [CrossRef]
  130. Cheng, D.; Deng, J.; Zhang, B.; He, X.; Meng, Z.; Li, G.; Ye, H.; Zheng, S.; Wei, L.; Deng, X.; et al. LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation. EBioMedicine 2018, 36, 159–170. [Google Scholar] [CrossRef][Green Version]
  131. Fu, X.; Calin, G.A. miR-122 and hepatocellular carcinoma: From molecular biology to therapeutics. EBioMedicine 2018, 37, 17–18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  132. Roderburg, C.; Urban, G.-W.; Bettermann, K.; Vucur, M.; Zimmermann, H.W.; Schmidt, S.; Janssen, J.; Koppe, C.; Knolle, P.; Castoldi, M.; et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2010, 53, 209–218. [Google Scholar] [CrossRef] [PubMed]
  133. Kwon, J.J.; Factora, T.D.; Dey, S.; Kota, J. A Systematic Review of miR-29 in Cancer. Mol. Ther. Oncolytics 2019, 12, 173–194. [Google Scholar] [CrossRef][Green Version]
  134. Alizadeh, M.; Safarzadeh, A.; Beyranvand, F.; Ahmadpour, F.; Hajiasgharzadeh, K.; Baghbanzadeh, A.; Baradaran, B. The potential role of miR-29 in health and cancer diagnosis, prognosis, and therapy. J. Cell. Physiol. 2019, 234, 19280–19297. [Google Scholar] [CrossRef] [PubMed]
  135. Matsumoto, Y.; Itami, S.; Kuroda, M.; Yoshizato, K.; Kawada, N.; Murakami, Y. MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery from Liver Fibrosis in Mice. Mol. Ther. 2016, 24, 1848–1859. [Google Scholar] [CrossRef][Green Version]
  136. Fang, J.-H.; Zhou, H.-C.; Zeng, C.; Yang, J.; Liu, Y.; Huang, X.; Zhang, J.-P.; Guan, X.-Y.; Zhuang, S.-M. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology 2011, 54, 1729–1740. [Google Scholar] [CrossRef]
  137. Tao, J.; Ji, J.; Li, X.; Ding, N.; Wu, H.; Liu, Y.; Wang, X.W.; Calvisi, D.F.; Song, G.; Chen, X. Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer. Oncotarget 2015, 6, 6977–6988. [Google Scholar] [CrossRef][Green Version]
  138. Zhang, Z.; Shen, S. Combined low miRNA-29s is an independent risk factor in predicting prognosis of patients with hepatocellular carcinoma after hepatectomy: A Chinese population-based study. Medicine 2017, 96, e8795. [Google Scholar] [CrossRef]
  139. Misso, G.; Di Martino, M.T.; De Rosa, G.; Farooqi, A.A.; Lombardi, A.; Campani, V.; Zarone, M.R.; Gullà, A.; Tagliaferri, P.; Tassone, P.; et al. Mir-34: A new weapon against cancer? Mol. Ther. Nucleic Acids 2014, 3, e194. [Google Scholar] [CrossRef]
  140. Li, X.J.; Ren, Z.J.; Tang, J.H. MicroRNA-34a: A potential therapeutic target in human cancer. Cell Death Dis. 2014, 5, e1327. [Google Scholar] [CrossRef]
  141. Liu, C.; Peng, X.; Li, Y.; Liu, S.; Hou, R.; Zhang, Y.; Zuo, S.; Liu, Z.; Luo, R.; Li, L.; et al. Positive feedback loop of FAM83A/PI3K/AKT/c-Jun induces migration, invasion and metastasis in hepatocellular carcinoma. Biomed. Pharmacother. 2020, 123, 109780. [Google Scholar] [CrossRef] [PubMed]
  142. Amaral, A.E.D.; Rode, M.P.; Cisilotto, J.; Da Silva, T.E.; Fischer, J.; Matiollo, C.; Rateke, E.C.D.M.; Narciso-Schiavon, J.L.; Schiavon, L.L.; Creczynski-Pasa, T.B. MicroRNA profiles in serum samples from patients with stable cirrhosis and miRNA-21 as a predictor of transplant-free survival. Pharmacol. Res. 2018, 134, 179–192. [Google Scholar] [CrossRef] [PubMed]
  143. Beg, M.S.; Brenner, A.J.; Sachdev, J.; Borad, M.; Kang, Y.-K.; Stoudemire, J.; Smith, S.; Bader, A.G.; Kim, S.; Hong, D.S. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig. New Drugs 2017, 35, 180–188. [Google Scholar] [CrossRef] [PubMed]
  144. Daige, C.L.; Wiggins, J.F.; Priddy, L.; Nelligan-Davis, T.; Zhao, J.; Brown, D. Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer. Mol. Cancer Ther. 2014, 13, 2352–2360. [Google Scholar] [CrossRef][Green Version]
  145. Murakami, Y.; Toyoda, H.; Tanaka, M.; Kuroda, M.; Harada, Y.; Matsuda, F.; Tajima, A.; Kosaka, N.; Ochiya, T.; Shimotohno, K. The Progression of Liver Fibrosis Is Related with Overexpression of the miR-199 and 200 Families. PLoS ONE 2011, 6, e16081. [Google Scholar] [CrossRef]
  146. Qu, K.; Zhang, K.; Li, H.; Afdhal, N.H.; Albitar, M. Circulating MicroRNAs as Biomarkers for Hepatocellular Carcinoma. J. Clin. Gastroenterology 2011, 45, 355–360. [Google Scholar] [CrossRef]
  147. Amr, K.S.; Ezzat, W.M.; Elhosary, Y.A.; Hegazy, A.E.; Fahim, H.H.; Kamel, R.R. The potential role of miRNAs 21 and 199-a in early diagnosis of hepatocellular carcinoma. Gene 2016, 575, 66–70. [Google Scholar] [CrossRef]
  148. Callegari, E.; Elamin, B.K.; D’Abundo, L.; Falzoni, S.; Donvito, G.; Moshiri, F.; Milazzo, M.; Altavilla, G.; Giacomelli, L.; Fornari, F.; et al. Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus. PLoS ONE 2013, 8, e73964. [Google Scholar] [CrossRef][Green Version]
Figure 1. Cycle of microRNAs. Abbreviations: microRNA (miRNA), RNA-induced silencing complex (RISC), double-stranded miRNA (ds-mi RNA), messenger RNA (mRNA). Created with
Figure 1. Cycle of microRNAs. Abbreviations: microRNA (miRNA), RNA-induced silencing complex (RISC), double-stranded miRNA (ds-mi RNA), messenger RNA (mRNA). Created with
Ijms 22 01492 g001
Figure 2. Overview of mechanisms of important miRNAs (expressed in liver tissue) in hepatocarcinogenesis. Created with
Figure 2. Overview of mechanisms of important miRNAs (expressed in liver tissue) in hepatocarcinogenesis. Created with
Ijms 22 01492 g002
Table 1. Overview of important miRNAs in hepatocarcinogenesis. Abbreviations: Stathmin 1 (STMN1), Ras-related protein 1 (Rab1), phosphatase and tensing homolog (PTEN), Programmed Cell Death 4 (PDCD4), reversion-inducing cysteine-rich protein with Kazal motifs (RECKS), metalloproteinkinase inhibitor 3 (TIMP3), Nucleolar And Spindle-Associated Protein 1 (NUSAP1), secreted protein/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), Mcl-1 (myeloid cell leukemia 1), Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), Wnt family member 1 (WNT1), paternally expressed gene 10 (PEG10), pyruvate kinase isoform M2 (PKM2), hepatocyte nuclear factor 4α (HNF4α), UDP-N-acetyl-α-D-galactosamine polypeptide N-acetylglucosaminyltransferase-10 (GALNT10), KLF6 (Kruppel-like factor 6), Bcl-2 (B-cell lymphoma 2), SET domain bifurcated 1 (SETDB1), Notch homolog 1, translocation-associated (NOTCH1), Histone deacetylase 1 (HDAC1), myristoylated alanine-rich protein kinase c substrate (MARCKS), Cyclin-dependent Kinase 6 (CDK6), sirtuin 1 (SIRT1), mechanistic Target of Rapamycin (mTOR), hypoxia-inducible-factor 1 (HIF-1)α, Rho-associated protein kinase 1 (ROCK1).
Table 1. Overview of important miRNAs in hepatocarcinogenesis. Abbreviations: Stathmin 1 (STMN1), Ras-related protein 1 (Rab1), phosphatase and tensing homolog (PTEN), Programmed Cell Death 4 (PDCD4), reversion-inducing cysteine-rich protein with Kazal motifs (RECKS), metalloproteinkinase inhibitor 3 (TIMP3), Nucleolar And Spindle-Associated Protein 1 (NUSAP1), secreted protein/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), Mcl-1 (myeloid cell leukemia 1), Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), Wnt family member 1 (WNT1), paternally expressed gene 10 (PEG10), pyruvate kinase isoform M2 (PKM2), hepatocyte nuclear factor 4α (HNF4α), UDP-N-acetyl-α-D-galactosamine polypeptide N-acetylglucosaminyltransferase-10 (GALNT10), KLF6 (Kruppel-like factor 6), Bcl-2 (B-cell lymphoma 2), SET domain bifurcated 1 (SETDB1), Notch homolog 1, translocation-associated (NOTCH1), Histone deacetylase 1 (HDAC1), myristoylated alanine-rich protein kinase c substrate (MARCKS), Cyclin-dependent Kinase 6 (CDK6), sirtuin 1 (SIRT1), mechanistic Target of Rapamycin (mTOR), hypoxia-inducible-factor 1 (HIF-1)α, Rho-associated protein kinase 1 (ROCK1).
miRNAExpression in Liver TissueLevel in CirculationFunctions in HCCSelected Targets
miR223↓ [49,50]↓ ↑ [51,52]Inhibition of cell growth, induction of apoptosis [53]STMN [50], Rab1 [53], integrin αV [49]
miR-21↑ [54,55]↑ [52,56,57]increased cell invasion, migration, proliferationPTEN [54,55], PDCD4, RECKS [54], TIMP3 [58]
miR-193↓ ↑ [59,60]↑ [61]Increased cell proliferation, inhibition of apoptosis [33]NUSAP1 [33], SPOCK1 [59,62], MCL1, ERBB4, S6K2 [63,64,65,66]
miR-122↓ [67,68]↑ [28,52,69,70,71] hepatocarcinogenesis, forming metastasis [28,67,68]CUTL1 [72], WNT1, PEG10, PKM2 [67,68,73,74], HNF4α, GALNT10 [75], KLF6 [31,32]
miR-29↓ [76,77]↑ [78]promotes apoptosis [77], associated with HCC disease progression, cancer aggressiveness [79]MCL-1, BCL2 [77], SETDB1 [79], DNMT3A [76]
miR-34↓ [80,81,82,83,84,85]↓ [86]inhibition of cell growth, increase in cell apoptosis rate [87]NOTCH1 [87], HDAC1 [81], MARCKS [84], FAM83A [85], c-MYC, CDK6, c-MET [80,88,89,90,91], caspase-2, SIRT1 [92], BCL2
miR-199↓ [93]↓ [94]inhibits cell proliferation, migration and invasion [95]mTOR, c-Met, HIF-1α, CD44 [96,97,98,99], ROCK1 [100], Axl [95]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mohr, R.; Özdirik, B.; Lambrecht, J.; Demir, M.; Eschrich, J.; Geisler, L.; Hellberg, T.; Loosen, S.H.; Luedde, T.; Tacke, F.; et al. From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis. Int. J. Mol. Sci. 2021, 22, 1492.

AMA Style

Mohr R, Özdirik B, Lambrecht J, Demir M, Eschrich J, Geisler L, Hellberg T, Loosen SH, Luedde T, Tacke F, et al. From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis. International Journal of Molecular Sciences. 2021; 22(3):1492.

Chicago/Turabian Style

Mohr, Raphael, Burcin Özdirik, Joeri Lambrecht, Münevver Demir, Johannes Eschrich, Lukas Geisler, Teresa Hellberg, Sven H. Loosen, Tom Luedde, Frank Tacke, and et al. 2021. "From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis" International Journal of Molecular Sciences 22, no. 3: 1492.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop