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Review

Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

by
Ming-Ming Tsai
1,2,†,
Chia-Siu Wang
2,†,
Chung-Ying Tsai
3,
Hsiang-Wei Huang
3,
Hsiang-Cheng Chi
3,
Yang-Hsiang Lin
3,
Pei-Hsuan Lu
4 and
Kwang-Huei Lin
3,5,*
1
Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
2
Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
3
Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
4
Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan
5
Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2016, 17(6), 945; https://doi.org/10.3390/ijms17060945
Submission received: 2 April 2016 / Revised: 1 June 2016 / Accepted: 7 June 2016 / Published: 16 June 2016
(This article belongs to the Special Issue MicroRNA Regulation)
Versions Notes

Abstract

:
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients’ survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.

1. Introduction

Gastric cancer (GC), a malignant epithelial cancer disease [1], is associated with a high global incidence of mortality [2,3]. Although surgical resection, together with chemotherapy and radical therapy, shows significant improvement over surgery alone in early-stage GC patients [4,5], GC patients commonly present with late-stage cancer at initial diagnosis owing to the lack of clinical symptoms that would enable early detection [2,3,6]. The five-year survival rate for late-stage GC patients is only about 20%–30% [7]. Thus, additional studies designed to improve early detection of GC are needed to provide better quality of life and longer survival for GC patients. Early diagnosis is critical for greatly reducing the efficiency of peritoneal spread and local/distal metastasis of GC, necessitating the development of new and more sensitive tumor markers for early GC diagnosis and disease monitoring. Conventional plasma/serum-based tumor biomarkers commonly used clinically for early GC diagnosis, including carcinoembryonic antigen (CEA), the carbohydrate antigens (CA), CA19-9, CA72-4, CA125, CA24-2 and CA50, as well as pepsinogen and α-fetoprotein (AFP), have poor specificity and sensitivity [8,9].
MicroRNAs (miRNAs) are small (~22 bp) nucleic acids that function by regulating the expression of downstream target genes [10]. Their dysregulation has been reported to be involved in pathogenic processes underlying GC tumorigenesis and progression, including cell growth, invasion, metastasis, and apoptosis. Moreover, miRNAs are stable and persistent among individuals of the same species, even for several years in formalin-fixed, paraffin-embedded tissues and body fluids, such as plasma/serum, urine, saliva, and milk [11,12,13,14,15]. Therefore, aberrantly expressed miRNAs are potentially useful biomarkers for GC screening, diagnosis, prognosis and disease monitoring, as well as therapeutic targets.
A number of researchers have explored the possibility of using miRNAs as biomarkers. Here, we summarize major, up-to-date information on the subject, focusing on discoveries from systematic analysis of miRNA profiling, microarray profiling and quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) profiling approaches. Specifically, we discuss plasma/serum-based, GC-related circulating miRNAs and their clinical application, focusing particularly on their application as diagnostic and prognostic indicators. We also review tissue-based, GC-related miRNA biomarkers and their downstream targets in GC, as well as plasma/serum-based, GC-associated circulating miRNAs and their clinical applications, focusing especially on early diagnosis. Moreover, we examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. miRNA biomarkers with potential applications in GC are listed in Table 1, Table 2, Table 3 and Table 4.
In order to search of all the related literatures, we used PubMed for the GC microRNA expression profiling studies between January 2000 and December 2016. The keyword “miR and gastric cancer” was used. Selected studies should fit the following search criteria: (1) profiling studies in GC patients; (2) including the appropriate adjacent noncancerous gastric tissues or normal plasma/serum for control; (3) including the known cut-off criteria/value of differentially expressed miRNAs; and (4) including the known number of study patients or normal subjects; (5) showing statistical analysis data.

2. Cellular Functions of miRNAs in GC

Aberrantly expressed miRNAs serve oncogenic or tumor-suppressor functions in tumorigenesis. They can regulate cell proliferation, cell cycle progression, apoptosis, angiogenesis, cell migration, cell invasion and/or metastasis in GC (Table 1 and Table 2), depending on their target genes. Therefore, a given miRNA may exert dual, opposite functions in GC. Generally, oncogenic miRNAs (oncomiRs) are over-expressed in GC and act to inhibit tumor-suppressor genes. Conversely, tumor-suppressor miRNAs, which inhibit oncogene expression, are usually down-regulated in GC. miRNAs in this category regulate various biological processes to stimulate cancer development.

2.1. GC-Related miRNAs in Cell Proliferation, Cell Cycle, and Apoptosis

Accelerated cell proliferation, cell cycle progression or disturbed apoptosis are common features of malignancy that arise through silencing of cell cycle-inhibitory or apoptotic pathway-associated genes. In several malignant tumors, miRNA dysregulation stimulates cell cycle progression by up-regulating cyclin expression or down-regulating the expression of other cell cycle regulators or cyclin-CDK (cyclin-dependent kinase) inhibitors, including members of the p16 family (p15, p16, p18 and p19) and p21 family (p21, p27, p28 and p57) [212,213,214]. Moreover, transforming growth factor (TGF)-β1 has been shown to repress GC cell proliferation through transcriptional up-regulation of p21 [108]. In this context, oncomiR-106b and oncomiR-93 are both up-regulated in GC and target the downstream E2F1 (E2F transcription factor 1) and p21 (cyclin-dependent kinase inhibitor 1A), thereby inhibiting the activity of TGF-β1 [26] and contributing to GC by enhancing cell proliferation.
In addition, these oncomiR clusters are significantly up-regulated in GC. miR-106b-93-25 and miR-222-221 have been reported to inhibit the p21 family CDK inhibitors p57KIP2, p21CIP1 and p27KIP1 [27]. Kim et al. showed that over-expression of the miR-222-221 cluster also enhances the growth of GC xenografts in nude mice [27], further reporting that miR-25 targets p57. In addition, both miR-106b and miR-93 down-regulate p21, whereas miR-222 and miR-221 both control p27 and p57. miR-449, which targets cyclin E2 and geminin, among others, and normally promotes senescence and apoptosis, is down-regulated in GC. Consistent with these biological functions, down-regulation of miR-449 in GC promotes G1/S and M/G1 cell cycle progression and cell proliferation [178]. Cui et al. [166] reported that the tumor suppressors miR-449 and miR-29a both target p42.3 (suppressor APC domain containing 2) in GC, promoting increased G2/M cell cycle progression and proliferation. In addition to directly targeting CDK inhibitors, miR-24 also modulates anion exhanger-1 (AE1), and thus promotes cell proliferation [164,165]. Moreover, let-7, which targets CDC34, is frequently down-regulated in GC [105].
Some oncomiRs are significantly up-regulated in GC tissues and target downstream tumor-suppressor genes. Zhang et al. [68,69,70,71,72] showed that one such oncomiR, miR-21, directly targets the tumor-suppressor gene RECK (reversion-inducing cysteine-rich protein with kazal motifs) and contributes to GC by enhancing cell proliferation and inhibiting apoptosis. Several lines of evidence have revealed that miR-21 also has the ability to stimulate cell invasion and migration. The oncomiR miR-199a was shown to significantly inhibit SMAD4, thereby inhibiting TGF-β1 signaling control over cell proliferation and apoptosis, and promoting anchorage-independent growth in soft agar [39,58,62,63,64,65]. Another oncomiR, miR-23a, was shown to significantly promote GC cell proliferation by silencing its target, the interleukin (IL)-6 receptor (IL6R) [77,78,79].
Conversely, some tumor-suppressor miRs that target downstream oncogenes are significantly down-regulated in GC tissues. Carvalho et al. reported that the tumor suppressor miR-101, which targets EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), COX-2 (cytochrome c oxidase subunit II), MCL-1 (myeloid cell leukemia 1) and FOS (FBJ osteosarcoma oncogene), has anti-proliferative and anti-metastatic functions in GC [117,118,119,120]. In addition, the tumor suppressor miR-125a, which targets ERBB2 (erb-b2 receptor tyrosine kinase 2), and miR-129, which targets CDK6 (cyclin-dependent kinase 6), are also involved in anti-proliferative and pro-apoptotic functions [24,126,127,131]. Similarly, Song et al. showed that the tumor suppressor miR-148b, which targets CCKBR (cholecystokinin B receptor), is anti-proliferative in vitro and anti-tumorigenic in vivo [138]. These results suggest that abnormal miRNA expression may increase cell cycle progression through direct or indirect regulation of CDK inhibitors and cell cycle–associated regulators.
In addition, anti-apoptosis is a character of tumorigenesis [16]. miR-106b and miR-93 abrogate TGFβ-induced apoptosis in GC cells by targeting the expression of BIM, encoding the pro-apoptotic protein BCL2-like 11, and thereby prevent apoptosis and cause tumor progression [26]. OncomiR-130b in GC cells increases cell viability and anti-apoptosis by targeting TGFβ-induced RUNX3 (runt related transcription factor 3) [37]. Lai et al. have also reported that miR-130b suppresses TGFβ-induced BIM expression and apoptosis by targeting RUNX3 in GC cells. Moreover, several oncomiRs, namely miR-15b, miR-16, miR-181b and miR-34, directly target the gene encoding the anti-apoptotic protein Bcl-2, and thus promote apoptosis in GC. The tumor suppressors miR-15b, miR-16 and miR-181b have been shown to inhibit chemotherapeutic drug-induced apoptosis [47,48]. In addition, oncomiR-150 negatively regulates the pro-apoptotic gene EGR2 (early growth response 2) to accelerate GC growth [215]. Shen et al. [35] reported that miR-129-2 targets SOX4 to induce apoptosis by regulating the relative abundance of pro-apoptotic and anti-apoptotic members of the Bcl-2 family in GC. Bandres et al. [94] reported that miR-451 functions as a tumor suppressor by repressing migration inhibitory factor (MIF), thereby activating Bcl-2, EGFR (epidermal growth factor receptor) and the phosphoinositide 3-kinase (PI3K)/Akt pathway in GC [95,96]. Another study showed that ectopic expression of the tumor suppressor miR-375 reduced cell viability in GC cells through the proliferative PI3K/Akt pathway (by targeting JAK2 and PDK1) and the anti-apoptotic NF-κB signaling pathway (by targeting the anti-apoptotic protein 14-3-3ζ) [86,174,175]. Moreover, the tumor suppressor miR-218 regulates COX-2 (cyclooxygenase-2) via the anti-apoptotic NF-κB signaling pathway [155]. These findings suggest that the dysregulated miRs control mitochondria-mediated (intrinsic) and death receptor–mediated (extrinsic) apoptotic pathways through the Bcl-2 family target [216]. Further, dysregulated miRs are also involved in the anti-apoptotic PI3K/Akt and NF-κB signaling pathways which control apoptosis by Bad and the XIAP gene [217].
In summary, the abundance of miRs expression may accelerate cell cycle progression through direct or indirect regulation of CDK inhibitors and several cell cycle regulators. Moreover, the abundance of miRs expression also may influence anti-apoptosis or the pro-survival pathway by targeting apoptosis-associated proteins. They may play an important molecular role in GC progression.

2.2. GC-Related miRNAs in Cell Migration, Invasion, and Metastasis

Metastasis, a complex, multistep process that involves cytoskeleton remodeling, matrix metalloproteinases (MMPs), homing receptors and their ligands, intracellular signaling pathways (TGFβ and TGFβ/c-Met) and angiogenesis, is a hallmark of malignant tumors [218,219]. As noted above, Zhang et al. [68] identified RECK as a direct target of the oncomiR miR-21, and also found that oncomiR-21 is up-regulated in Helicobacter pylori-infected GC tissues. RECK might also possess anti-invasion, anti-metastasis and anti-angiogenesis functions through modulation of MMP2, MMP9 and MMP14 expression. In addition, miR-21 targeting of PDCD4 (programmed cell death 4) is associated with lymph node metastasis and venous invasion. Another report indicated that PTEN (phosphatase and tensin homologue) is a target of miR-21 that promotes anoikis through activation of the PI3K/Akt pathway [68,72]. In addition, Tsai et al. [59] have shown that oncomiR-196a/b expression promotes GC cell migration, invasion, and metastasis by increasing radixin (RDX) expression in GC tissues. OncomiR-370 was shown to decrease TGFβ-RII expression and stimulate TGFβ1-induced phosphorylation of Smad3. Thus, oncomiR-370 is capable of triggering cell migration by disturbing the TGFβ signaling pathway [85]. Moreover, oncomiR-215 was shown to target ALCAM (activated leukocyte cell adhesion molecule) and increase GC metastasis [71]. Conversely, the tumor suppressor miR-218 promotes invasion and metastasis by targeting Robo1, and thereby activating the Slit/Robo1 signaling pathway [156,157,158,159,160]. Other tumor suppressors of the let-7 family increase the expression of HMGA2 (high mobility group AT-hook 2), which is associated with tumor invasion and is an independent prognostic factor in GC [107]. Furthermore, members of the miR-200 family increase the epithelial-mesenchymal transition (EMT), and contribute to cell migration by reducing the expression of E-cadherin repressors ZEB1 and ZEB2 (zinc finger E-box binding homeobox 2) [145,146]. Down-regulation of miR-335 was found to be significantly associated with lymph node metastasis, invasion of lymphatic vessels, cell invasion and metastasis through targeting of BCL-w and SP1 (specificity protein 1) [82,83].
Interestingly, the function of miRNAs depends on the expression of their target genes. Previous studies revealed that some miRs could target both oncogenes and tumor-suppressor genes, leading to opposite roles in GC. Accordingly, miR-9 may play dual but opposing roles in GC. Thus, acting as an oncomiR, miR-9 targets CDX2 [102] and increases cell proliferation by facilitating cell cycle progression; conversely, acting as a tumor suppressor, miR-9 targets NF-κB1, cyclin D1, and ETS1 to contribute to anti-proliferation and anti-metastasis [102,112,113,114]. Nakayama et al. [20] reported that oncomiR-10b targets HOXD10 (homeobox D10) to promote GC metastasis. However, Kim et al. [116] found that miR-10b also represses the expression of MAPRE1 (microtubule associated protein RP/EB family member 1), resulting in the inhibition of colony formation and cell proliferation. Moreover, oncomiR-223 was shown to promote GC invasion and metastasis by targeting EPB41L3 (erythrocyte membrane protein band 4.1-like 3) expression [76]. However, Kang et al. [162,163] reported that miR-223 acted as a tumor suppressor, directly targeting STMN1 (stathmin 1) expression to inhibit cell growth and metastasis. Thus, some miRNAs play dual roles through targeting of different genes during GC progression. Further studies will be required to elucidate the details of these different roles.

3. Clinical Applications of MicroRNAs in GC

3.1. GC-Related miRNAs as Diagnostic Biomarkers

Early diagnosis permits effective and radical treatment of GC before it develops to an advanced and metastatic stage. Gastroscopy with biopsy, the current standard clinical practice, is not a good screen for GC on a population basis, and existing biomarkers exhibit poor sensitivity and specificity. Thus, there are currently no reliable diagnostic biomarkers for GC. Multiple or combined biomarker assays are expected to provide more accurate results [220]. Investigators continue their efforts to identify convenient, high-sensitivity, high-specificity, and noninvasive biomarkers for early GC diagnosis [185]. MiRNAs can be released from tumor tissues into bodily fluids, including serum, plasma, urine, tears, amniotic fluid and gastric juice, through the secretion of exosome particles [15,221,222]. Mitchell et al. [15,221,222] demonstrated that circulating miRNAs in plasma/serum from GC patients are consistent with those in tissues; therefore, they could be useful as noninvasive biomarkers for the initial diagnosis of GC and assessment of GC recurrence. The most widely investigated biomarkers have been discovered using newer methods, such as systematic analysis of miRNA profiling, miRNA profiling, microarray profiling, and Q-RT-PCR profiling approaches [223,224,225,226,227]. The major plasma/serum-based, GC-related circulating miRNAs that have been suggested as useful GC biomarkers are listed in Table 3 and Table 4.
Liu et al. [111] used systematic analysis of miRNA profiling, miRNA profiling to identify a signature of five circulating oncomiRs—miR-1, miR-20a, miR-27a, miR-34 and miR-423-5p—and correlated it with tumor stage. Using receiver-operating characteristic (ROC) curve analyses, these authors evaluated the diagnostic value of this miR signature, showing that it achieved a sensitivity of 80% and a specificity of 81%. They observed that the circulating five-oncomiR signature I exhibited a high diagnostic value, with an area under the ROC curve (AUC) of 0.879. By comparison, the five-oncomiR signature II exhibited an AUC of 0.831, which is higher than that of CEA, with an AUC of 0.503, and CA19-9, with an AUC of 0.6. In a large-scale analysis, four circulating oncomiRs (miR-17-5p, miR-21, miR-106a and miR-106b) significantly distinguished GC patients from healthy controls and pre-operative from post-operative GC patients [185]. Moreover, Valladares-Ayerbes et al. [42], using a Cox multivariate regression model, identified circulating oncomiR-200c as a biomarker for GC diagnosis and as an independent prognostic factor for progression-free survival and overall survival in GC patients. Liu et al. [49] found that oncomiR-378 in the GC patients was significantly higher than that in the healthy controls. OncomiR-378 exhibited a high diagnostic value, with an AUC of 0.861, a sensitivity of 87.5% and a specificity of 70.7%.
In addition, several oncomiRs circulating in the blood of GC patients can be used as diagnostic biomarkers to distinguish GC patients from healthy individuals. These include miR-1, miR-106a, miR-106b, miR-17, miR-17-5p, miR-18a, miR-192, miR-199a-3p, miR-20a, miR-200c, miR-21, miR-210, miR-218, miR-221, miR-222, miR-25, miR-27a, miR-34, miR-376c, miR-378, miR-421, miR-423-5P, miR-451, miR-486, miR-744, and miR-93 [26,27,54,68,71,80,111,184,185,186,187,188,190,191,195,196,197,199,200,203,206,207,208]. Of these, miR-17-5p, miR-18a, miR-20a, miR-200c, miR-21, miR-218, miR-221, miR-222, miR-25, miR-27a, miR-376c, and miR-744 were found to be significantly elevated in GC patients, and their expression was significantly reduced after surgery [26,27,54,68,71,80,81,155,187,192,193,195,196,198,199,200,201,202,203,204,205].
Conversely, several tumor-suppressor miRNAs circulating in the blood of GC patients can also be used as diagnostic biomarkers to distinguish GC patients from healthy individuals, including miR-122, miR-195-5p, miR-203, miR-218, and miR-375 [155,189,198,209,210,211]. Of these, miR-122, miR-203, and miR-218 were found to be significantly reduced in GC patients, and their expression was significantly increased following surgery [155,189,198,211].
Taken together, these findings suggest that circulating miRNAs are useful, noninvasive biomarkers for early diagnosis or monitoring of cancer survivors after treatment of GC. The significance of these biomarkers compares favorably to the use of the traditional biomarkers CEA or CA19.9 alone.

3.2. GC-Related miRNAs as Prognostic Biomarkers

To predict GC patient survival time, cancer progression (disease stage), prognostic outcome, lymph node metastasis or response to treatment is challenging. Recurrence is also a key problem leading to the failure of treatments, including radical or chemical treatment and surgical resection. Although the clinical outcome of GC has improved, prognostic indicators capable of predicting recurrence in GC patients after treatment are still lacking. Recently, due to the stability and specificity of expression in tissues and circulation, accumulating evidence has shown that miRNAs can be regarded as novel biomarkers with a potential clinical significance tool for GC patients’ outcomes.
In general, the occurrence of a distant metastasis frequently leads to advanced-stage cancer and shorter survival. In this context, it has been shown that oncomiR-10b, miR-21, and miR-212 in GC patients are associated with a high metastasis risk and poor clinical outcomes, including tumor-node-metastasis, tumor size, stage, lymph node metastasis, and five-year survival rate [69,126,228].
Li et al. [229] showed that a seven-miRNA signature (miR-10b, miR-21, miR-223, let-7a, miR-338, miR-30a-5p and miR-126) could predict relapse-free and overall survival of GC patients. In addition, oncomiR-20b, miR-150 [23], miR-214 [24,74], miR-375 [39,74,86,87,88], tumor suppressor Let-7g [24,109,110], miR-125-5p [126], miR-146a [24,134], miR-218 [154], miR-433 [24,86,109,110,174], and miR-451 [24,94,230] are associated with a poor survival prediction in GC. In GC, high expression of miR-195 [58], miR-199a [39,58,62,63,64,65], miR-1952 [58], miR-335 [82,83], miR-375 [39,74,86,87,88], miR-451 [58,94,95,96] and miR-4512 [39], and low expression of miR-142-5p [39] are more likely to indicate relapse or recurrence of GC patients. Moreover, GC patients with over-expression of miR-107 [28,29,30], miR-143 [40], miR-145 [41,42], miR-181b/c [17,47,48,55,56], miR-196a/b [59], miR-20b [23,66], miR-23a/b [77,78,79], miR-34 [17,47,48,55,56] and miR-630 [100] and decreased expression of miR-1 [111], miR-1207-5p [121], miR-125a-3p/-5p [24,125,126,127], miR-185 [140], miR-193b [60], miR-20a [111], miR-206 [150,151], miR-215 [142], miR-217 [153], miR-27a [111], miR-29c [169], miR-34a [172,173], miR-423-5p [111], and miR-520d-3p [99] indicate advanced tumor stage or TNM stage. High levels of miR-107 [28,29,30], miR-181b/c [17,47,48,55,56], miR-192 [57], miR-196a/b [59], miR-20b [23,66], miR-21 [68,69,70,71,72], miR-214 [24,74], miR-23a/b [77,78,79], miR-25 [26,27,80], miR-27a [23,81], miR-630 [100], and miR-650 [101] and decreased levels of Let-7g [24,109,110], miR-1207-5p [121], miR-125a-3p/-5p [24,125,126,127] and miR-126 [128,129,130], miR-146a [24,134], miR-148a [46,135,136,137], miR-153 [139], miR-218 [154,155,156,157,158,159,160], miR-22 [151,161], miR-27a [111], miR-29c [169], miR-335 [171], miR-34a [172,173], miR-429 [177], miR-433 [24,86,109,110,174] and miR-520d-3p [99] are associated with invasion or LNM, as well as metastasis.
Conversely, the tumor suppressors miR-125a and miR146a are significantly correlated with lymph node metastasis, indicating that they could be prognostic factors of overall survival [126,134]. Other study showed that low expression of let-7 is related to tumor invasiveness and prognosis by targeting HMGA2 [231].
Therefore, many potential predictors have been regarded as beneficial for mediating the prognosis of GC patients and are the basis for targeted therapy. In future, these prognostic miRNAs could be useful for making choices concerning treatment.

3.3. GC-Related miRNAs as Treatment Biomarkers

One miRNA may regulate multi-target gene expression and multiple pathways, affecting the process of tumor development [232,233,234]. Thus, miRNAs are more effective than coding genes as biological regulation molecules.
The methods of current miRNA-mediated treatment are focused on miRNA knockout or silencing the endogenous oncomiRs, including anti-miRNA oligonucleotides (AMOs) [13], miRNA sponges [235], miR-Mask [236], antagomiRs and miRNA inhibitors [12,237]. For example, Chun et al. [200] transfected AS-miR-221/222 with liposomes into GC cell line SGC7901 to inhibit GC cell growth and invasion. Moreover, high expression of miR-196a/-196b promotes GC cell migration and invasion. Elevated miR-196a/-196b expression results in decreasing target RDX protein in GC cells and vice versa. Similar results were obtained in a mouse model of human GC. Tsai et al. [59], through AMOs, used anti-miR-196a/-196b oligonucleotides or the over-expression of RDX, which may serve a therapeutic purpose to inhibit GC metastasis.
Conversely, forced expression the tumor suppressor miRNAs is used to gain the resolution of tumor treatment. miRNA over-expression is often performed by using an in vivo or in vitro RNA delivery system as in cancer therapeutics, including adeno-associated viruses [238] or nonpathogenic bacteria [239] as a carrier to introduce a specific miRNA or miRNA mimics to up-regulate miRNA [240]. miR-1207-5p and miR-1266 are significantly down-regulated in GC tissues. Over-expression of these two miRs inhibited GC growth through targeting hTERT system in vitro and in vivo. Chen et al. [241] showed a novel therapeutic method for the delivery of these two miRs for GC treatment.
However, some problems must be considered. For example, one miRNA modulates multi-target genes and multiple pathways. Also, the off-target effects are unexpected. Thus, better specificity and an effective miRNA delivery system for a therapeutic strategy must be developed [242,243].

4. Conclusions

miRNA biomarkers have been found at elevated levels in the blood or tissues of patients with tumors. Changes in different biomarkers during tumor progression can help clinicians monitor cancer status. Although higher levels of a biomarker can potentially predict a tumor, other factors may also account for such elevated levels. Dysregulation of tumor markers can occur in response to the presence of a tumor or a change in status, enabling them to be used for a range of applications, including screening, diagnosis, staging, prognosis, and monitoring of recurrence after treatment. The values of these miRNAs as biomarkers will require further confirmation in human GC patients. In the future, an miRNA or an miRNA signature could be a better diagnostic or therapeutic tool than a single gene. However, the challenge is to develop a standard protocol for collecting large specimens, re-analyzing them in a large independent cohort, and validating their significance in clinical applications.
Moreover, several studies have suggested that tumor-derived circulating miRs might be secreted into circulation. Circulating miRs in the plasma/serum of GC patients can be used as diagnostic biomarkers to compare GC patients with healthy controls [185,244]. Most of these biomarkers are more sensitive and specific than the traditional biomarkers CEA or CA19.9 alone [111,185,190]. These findings provide novel indicators for monitoring GC dynamics and early diagnosis for GC to improve survival.
Currently, biomarkers are only used as a reference and not to diagnose the disease per se. A professional physician will still need to provide a comprehensive judgment, including choice of tumor marker, evaluation of clinical symptoms, assessment of related imaging performance, and other non-specific factors. Ultimately, the personalized management, diagnosis, and prognosis of the disease can be achieved using a panel of miRNAs.

Acknowledgments

This work was supported by grants from Chang-Gung University, Taoyuan, Taiwan (NMRPD150311, NMRPD170441-42, CMRPG640042-43, CMRPG670291-93, CMRPG6B0011, CMRPF190073, CMRPF1C0151, CMRPF1C0152, CMRPF1C0153) and the National Science Council of the Republic of China (NSC 95-2314-B-182-027, 97-2314-B-182-009-MY2, 99-2314-B-182-022, 102-2314-B-182A-074).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AE1: Anion exhanger-1; AFP: Alphafetoprotein; ALCAM: Activated leukocyte cell adhesion molecule; AMOs: Anti-miRNA oligonucleotides; AUCs: Areas under the ROC curves; CA19-9: Carbohydrate antigen 19-9; CCKBR: Cholecystokinin B receptor; CEA: Carcinoembryonic antigen; COX-2: Cyclooxygenase-2; Cyclin-CDK: Cyclin-dependent kinase; CDK6: Cyclin-dependent kinase 6; E2F1: E2F transcription factor 1; EGFR: Epidermal growth factor receptor; EGR2: Early growth response 2; EMT: Epithelial–mesenchymal transition; EPB41L3: Erythrocyte membrane protein band 4.1-like 3; ERBB2: Erb-b2 receptor tyrosine kinase 2; EZH2: Enhancer of zeste 2 polycomb repressive complex 2 subunit; FFPE: Formalin-fixed paraffin-embedded; FOS: FBJ osteosarcoma oncogene; GC: Gastric cancer; HMGA2: High mobility group AT-hook 2; HOXD10: Homeobox D10; IL6R: interleukin (IL)-6 receptor; MAPRE1: Microtubule associated protein RP/EB family member 1; MCL-1: Myeloid cell leukemia 1; MIF: Migration inhibitory factor; miRNAs: MicroRNAs; MMP: Matrix metalloproteinase; NF-κB: Nuclear factor-κB; OncomiRs: Oncogenic miRNAs; OS: Overall survival; p21: cyclin-dependent kinase inhibitor 1A; PDCD4: Programmed cell death 4; PFS: progression free survival; PI3K: phosphoinositide 3-kinase; Post-op: Post-operative; Pre-op: Pre-operative; PTEN: Phosphatase and tensin homologue; Q-RT-PCR: quantitative reverse transcription-polymerase chain reaction; RDX: Radixin; RECK: reversion-inducing cysteine-rich protein with kazal motifs; ROC: Receiver operating characteristic; RUNX3: Runt related transcription factor 3; SP1: Specificity protein 1; STMN1: Stathmin 1; TGF-β1: Transforming growth factor-β1; TNM: Tumor-node-metastasis; Tumor suppressor-miRs: Tumor suppressive miRNAs; ZEB2: Zinc finger E-box binding homeobox 2.

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Table 1. Up-regulated miRNAs in tissues for GC.
Table 1. Up-regulated miRNAs in tissues for GC.
Tissue OncomiRsSamplesCell FunctionsTarget (Official Gene Name)Clinical ApplicationReferences
let-7bSystematic integrative bioinformatics frameworkNDNDDiagnosis[16]
let-7gGCCLsChemosensitivityNDND[17]
miR-10bGCCLsMetastasisHOXD10ND[18,19,20]
miR-105GCTsNDNDDiagnosis[21]
miR-106aGCCLsCell cycleRB1
TIMP2
FAS		ND[22]
miR-106b-93-25 clusterGCTs
GCCLs		Apoptosis
Cell cycle		BIM
E2F1
CDKN1A
CDKN1B
CDKN1C		Diagnosis[23,24,25,26,27]
miR-107GCTs
GCCLs		Invasion
Metastasis		CDK6
DICER1		LNM
Tumor stage
Prognosis		[28,29,30]
miR-1271GCCLsNDIGFIR
MTOR
BCL2		ND[31]
miR-129GCTs
GCCLs		Cell proliferation
Cell cycle		SOX2
SOX4
CDK6
PDCD2		Prognosis
Diagnosis		[32,33,34,35]
miR-130aGCCLsMetastasis
Invasion
Cell proliferation		NDND[36]
miR-130bGCCLsApoptosis
Epigenetic regulation
Cell proliferation		RUNX3
BIM		ND[37]
miR-135aGCTsNDNDPrognosis[38]
miR-142-5pGCTsNDNDPoor Survival
Prognosis		[39]
miR-143GCTsNDNDTumor stage
Scirrhous type
Prognosis		[40]
miR-145GCTs
GCCLs		AngiogenesisCDH2
ETS1		Tumor stage
Scirrhous type
Prognosis
[41,42]
miR-146aGCCLsApoptosis
Cell proliferation		IRAK1
TRAF6
SMAD4		ND[43,44,45]
miR-148aGCCLsInvasion
Metastasis
Cell proliferation
Cell cycle		CDKN1BND[46]
miR-150GCTs
GCCLs		Apoptosis
Cell proliferation		EGR2Poor Survival
Prognosis		[23]
miR-15bGCCLsApoptosisBCL-2ND[47,48,49]
miR-155GCCLsApoptosisIKK-ε
SMAD4
FADD
PLIα		ND[50,51,52,53]
miR-16GCCLsChemosensitivity
Apoptosis		BCL-2ND[17,47,48,49]
miR-17GCCLsCell cycleCDKN1A
UBE2C
FBXO31		ND[54]
miR-181GCCLsNDNDND
miR-181b/cGCTs
GCCLs		Apoptosis
Chemosensitivity		NOTCH4
K-RAS
BCL-2		Differentiation
Invasive depth
Tumor stage
Prognosis		[17,47,48,55,56]
miR-192GCTsNDNDLNM
Prognosis		[57]
miR-195GCTsNDNDRecurrence[58]
miR-196aGCTs
GCCLs		Metastasis
Invasion
Migration		RADIXINInvasion depth
Serosal invasion
Lymphatic invasion
LNM
Distant metastasis
TNM stage
Peritoneal seeding
Gross type
Lauren subtype
Prognosis		[59]
miR-196aGCTs
GCCLs		NDNDDifferentiation[60]
miR-196a-5pGCTsNDNDLNM
TNM stage
Prognosis		[61]
miR-196bGCTs
GCCLs		Metastasis
Invasion
Migration		RADIXINInvasion depth
Serosal invasion
Lymphatic invasion
LNM
Distant metastasis
TNM stage
Peritoneal seeding
Gross type
Prognosis		[59]
miR-199aGCTs
GCCLs		Cell proliferation
Metastasis		SMARCA2
SMAD4
MAP3K11
ZHX1		Recurrence
Diagnosis
Relapse		[39,58,62,63,64,65]
miR-1952GCTsNDNDRelapse[58]
miR-20aGCTs
GCCLs		Cell cycleCDKN1ADiagnosis[23,24,25]
miR-20bGCTsNDNDPoor Survival
LNM
Distance metastasis
TNM stage
Prognosis		[23,66]
miR-200cGCTs
GCCLs		Metastasis
Chemoresistance		E-CDH
ZEB2
RHO E		ND[67]
miR-21GCTs
GCCLs		Apoptosis
Cell proliferation
Invasion
Cell cycle
Metastasis
Differentiation		RECK
PTEN
SERPINI1
PDCD4
NF-KB
CDKN1A
E2F5
CDKN1C		LNM
Prognosis		[68,69,70,71,72]
miR-210Hp-positive human gastric biopsies/Hp-negative controlsNDSTMN1
DIMT1		ND[73]
miR-211Systematic integrative bioinformatics frameworkNDNDDiagnosis[16]
miR-213GCTsNDNDDiagnosis[21]
miR-214GCTsNDNDPoor Survival
Invasion depth
Lymph node metastasis
Prognosis		[24,74]
miR-215GCTs
GCCLs		MetastasisALCAMPrognosis[71]
miR-221/222GCTs
GCCLs		Radioresistance
Cell cycle		CDKN1A
CDKN1B
CDKN1C		Prognosis[27,68]
miR-2214GCTsNDNDAdvanced GC
Prognosis		[75]
miR-223GCCLsInvasion
Metastasis		EPB41L3
FBXW7
HCDC4
STMN1		ND[76]
miR-23a/bGCTs
GCCLs		Invasion
Cell proliferation		IL6R
IRF1		LNM
TNM stage
Prognosis		[77,78,79]
miR-25GCTs
GCCLs		Invasion
Cell proliferation
Migration		CDKN1C
BCL2L11
FBXW7
LASTS2
RECK		LNM
Prognosis		[26,27,80]
miR-27aGCTs
GCCLs		Metastasis
Cell proliferation		APC
PHB		Lymph node metastasis
Prognosis		[23,81]
miR-335GCTsMetastasisNDRecurrence
Prognosis		[82,83]
miR-34GCTs
GCCLs		Chemosensitivity
Apoptosis		BCL-2Tumor stage
Prognosis		[17,47,48,55,56]
miR-342GCCLsChemosensitivityNDND[17]
miR-362GCCLsApoptosisNF-KBND[84]
miR-363GCCLsChemoresistanceNDND[17]
miR-370GCCLsMetastasisTGF-β-RIIND[85]
miR-375GCTs
GCCLs		Apoptosis
Inhibits Helicobacter
pylori-induced
gastric carcinogenesis		PDK1
YWHAZ
JAK2
STAT3		Poor Survival
Relapse/Recurrence
Prognosis		[39,74,86,87,88]
miR-382GCTs
GCCLs		AngiogenesisPTENND[89]
miR-421GCTs
GCCLs		NDBAX
BCL-2		Diagnosis[90,91]
miR-43cGCTs
GCCLs		Cell proliferation
Cell cycle		VEZTEpigenetic regulation
Prognosis		[92]
miR-442aGCCLsChemoresistanceNDND[93]
miR-451GCTs
GCCLs		Apoptosis
Radiosensitivity		MIFRecurrence[58,94,95,96]
miR-4512GCTsNDNDRelapse[39]
miR-4732-5pGCCLsChemoresistanceNDND[93]
miR-4758-3pGCCLsChemoresistanceNDND[93]
miR-503GCCLsNDIGFIR
BCL2		ND[97]
miR-512-5pGCCLsApoptosisMCL-1ND[98]
miR-514bGCTsNDNDDiagnosis[21]
miR-517GCCLsChemoresistanceNDND[17]
miR-518fGCCLsChemoresistanceNDND[17]
miR-519eGCCLsChemoresistanceNDND[17]
miR-520aGCCLsChemoresistanceNDND[17]
miR-520d/hGCCLsChemoresistanceHDAC1ND[17]
miR-520d-3pGCTs
GCCLs		Cell proliferation
Migration
Invasion		EPHA2ND[99]
miR-548NGCTsNDNDDiagnosis[21]
miR-630GCTs
GCCLs		InvasionNDLNM
Distant metastasis
TNM stage
Prognosis		[100]
miR-650GCTsNDNDLymph node Metastasis
Prognosis		[101]
miR-708GCTsNDNDDiagnosis[16]
miR-9GCCLsCell proliferation
Cell cycle		CDX2ND[102]
miR-92GCCLsCell proliferation
Invasion		FXRND[103]
miR-92aGCTsNDE2F1
HIPK1		Tumor growth
Prognosis		[93,104]
miR-93GCCLsApoptosisBIM
DAB2		ND[23,24,25]
Chemoresistance drugs were cisplatin, 5-fluorouracil and hydroxy camptothecin. GCTs: Gastric cancer tissues, GCCLs: Gastric cancer cell lines, ND: not determined.
Table 2. Down-regulated miRNAs in tissues for GC.
Table 2. Down-regulated miRNAs in tissues for GC.
Tissue Tumor Suppressor miRsSamplesCell FunctionsTarget (Official Gene Name)Clinical ApplicationReferences
Let-7aGCCLsCell proliferation
Cell cycle
Invasion		RAB40C
HMGA2
CDC34
CCR7		ND[105,106,107]
Let-7fGCCLsMetastasisMYH9ND[108]
Let-7gGCTsNDNDDiagnosis
Invasion depth
Lymph node metastasis
Poor Survival
Chemoresistance
Prognosis		[24,109,110]
miR-1GCTsNDNDTumor stage
Prognosis		[111]
miR-9GCTs
GCCLs		Cell proliferation
Metastasis		ETS1
NFKB1
CCND1
CUL4A
CDX2		ND[102,112,113,114]
miR-10bGCTs
GCCLs		Cell proliferationMAPRE1
CCND1		ND[19,115,116]
miR-101GCTs
GCCLs		MetastasisEZH2
COX2
MCL1
FOS		ND[117,118,119,120]
miR-1207-5pGCTs
GCCLs		NDNDLNM
Lymphovascular invasion
Stromal reaction type
TNM stage
Prognosis		[121]
miR-124GCCLsCell proliferation
Invasion		ROCK1ND[122]
miR-124aGCCLsCell cycleCDK6ND[123]
miR-1246, miR-302a and miR-4448GCCLsNDDYRK1AND[124]
miR-125a-3pGCTs
GCCLs		NDNDInvasion
LNM
Liver metastasis
Tumor stage
Tumor size
Peritoneal dissemination
Prognosis		[125]
miR-125a-5pGCTs
GCCLs		Cell proliferation
Metastasis
Invasion
Migration		ERBB2
E2F3		Invasion depth
Liver metastasis
Tumor stage
Tumor size
Poor Survival
Prognosis		[24,126,127]
miR-125-5pGCTsNDNDPoor Survival
Prognosis		[126]
miR-126GCTs
GCCLs		Cell cycle
Cell proliferation
Metastasis
Invasion
Migration		CRK
PI3KR2
PLK2		Lymph node metastasis
Prognosis		[128,129,130]
miR-126GCTsNDNDAdvanced GC[128]
miR-126GCCLsChemoresistanceNDND[109]
miR-129GCCLsProliferation
Cell cycle		CDK6ND[131]
miR-129-1-3pGCCLsMigrationNDND[34]
miR-129-2GCTs
GCCLs		Cell proliferationSOX4Epigenetic regulation
Differentiation		[35]
miR-141GCCLsInvasion
Cell proliferation
Metastasis		NDND[132]
miR-142-5pGCTsNDNDRelapse[39]
miR-143GCCLsCell proliferationAKTND[133]
miR-145GCCLsCell proliferationIRS1ND[133]
miR-146aGCTs
GCCLs		Invasion
Migration		EGFR
IRAK1		Lymph node metastasis
Venous invasion
Poor Survival
Prognosis		[24,134]
miR-148aGCTs
GCCLs		NDNDAdvanced GC[135]
miR-148aGCTs
GCCLs		MetastasisDNMT1
CDKN1B
ROCK1		Distant metastasis
Organ invasion
Peritoneal invasion
Prognosis		[46,135,136,137]
miR-148bGCTs
GCCLs		Cell proliferationCCKBRND[138]
miR-148GCTs
GCCLs		NDNDLymph node metastasis
Prognosis		[135]
miR-15bGCTs
GCCLs		ChemoresistanceNDND[47]
miR-153GCTs
GCCLs		Migration
Invasion		NDLNM
Prognosis		[139]
miR-155GCTs
GCCLs		Cell proliferation
Invasion
Migration		C-MYCND[130]
miR-16GCTs
GCCLs		ChemoresistanceNDND[47]
miR-181cGCTs
GCCLs		Cell proliferationNOTCH4
KRAS		Transcriptional activation[56]
miR-185GCTs
GCCLs		NDNDPrognosis
TNM stage		[140]
miR-19bGCTs
GCCLs		NDNDDiagnosis[104,141]
miR-192GCTs
GCCLs		NDNDTumor sizes
Borrmann type
Prognosis		[142]
miR-193bGCTs
GCCLs		Invasion
Metastasis		NDDifferentiation
Lauren type
Tumor stage
Prognosis		[60]
miR-196aGCTs
GCCLs		ChemoresistanceNDND[109]
miR-20aGCTs
GCCLs		NDNDTumor stage
Prognosis		[111]
miR-200bGCTs
GCCLs		Invasion
metastasis		NDND[143]
miR-200 familyGCTs
GCCLs		EMT
Chemoresistance
Cell proliferation
Invasion
Migration
Apoptosis		ZEB1
ZEB2
CDH1
BCL2
XIAP		ND[109,144,145,146]
miR-203GCTs
GCCLs		Cell proliferation
Invasion		ABL1ND[147,148]
miR-204GCTs
GCCLs		Cell proliferation
Invasion		EZR
SOX4		ND[149]
miR-206GCTs
GCCLs		NDCCND2Venous invasion
LNM
Hematogenous recurrence
PStage
Prognosis		[150,151]
miR-212GCTs
GCCLs		Cell proliferationMECP2ND[152]
miR-215GCTs
GCCLs		NDNDBorrmann type
Tumor sizes
pT stage
Prognosis		[142]
miR-217GCTs
GCCLs		Differentiation Distant Metastasis
Invasion		NDTumor size
TNM stage
Prognosis		[153]
miR-218GCTs
GCCLs		Metastasis
Invasion		ROBO1
COX2
NFkB
ECOP
VOPP1		Lymph node metastasis
Transcriptional activation
Prognosis
Advanced gastric cancer
Prognosis		[154,155,156,157,158,159,160]
miR-22GCTs
GCCLs		NDSP1LNM
Distant metastasis
Tumor stage
Prognosis		[151,161]
miR-223GCTs
GCCLs		MetastasisSTMN1ND[162,163]
miR-24GCCLsCell cycleAE1ND[164,165]
miR-27aGCTs
GCCLs		NDNDTumor stage
Lymph node metastasis
TNM stag
Prognosis		[111]
miR-29aGCTs
GCCLs		Cell proliferation
Cell cycle
Metastasis		P42.3
CDC42		ND[166,167,168]
miR-29cGCTs
GCCLs		NDNDVenous invasion
TNM stage
Prognosis		[169]
miR-30bGCTs
GCCLs		ApoptosisPAI-1ND[170]
miR-31GCTs
GCCLs		ChemoresistanceNDND[109]
miR-335GCTs
GCCLs		Metastasis
Cell invasion		BCL-W
SP1		Lymph node metastasis
Prognosis
Invasion of lymphatic vessels		[171]
miR-338GCTs
GCCLs		ChemoresistanceNDND[109]
miR-34aGCTs
GCCLs		NDBCL2
PDGFR
YY1		Lymph node involvement
TNM stage
Differentiation
Recurrence
Prognosis		[172,173]
miR-34GCTs
GCCLs		Cell proliferationBCL2
NOTCH1
HMGA2
C-MYC
SIRT1		TNM stage
Transcription
Epigenetic regulation
Prognosis		[111,172]
miR-370GCTs
GCCLs		NDNDDiagnosis[31]
miR-375GCTs
GCCLs		Apoptosis
Cell proliferation		PDK1
YWHAZ
JAK2
ERBB2
STAT3
TP53		ND[86,174,175]
miR-410GCTs
GCCLs		migration
invasion		MDM2ND[176]
miR-423-5pGCTs
GCCLs		NDNDTNM stage
Prognosis		[111]
miR-429GCTs
GCCLs		Cell proliferation
Apoptosis		C-MYC
BCL2
XIAP		Lymph node metastasis
Prognosis		[177]
miR-433GCTs
GCCLs		NDGRB2Diagnosis
Invasion depth
Lymph node metastasis
Poor Survival
Prognosis		[24,86,109,110,174]
miR-449GCTs
GCCLs		Cell proliferation
Apoptosis
Cell cycle		GEMININ
P42.3
CCNE2
GMNN
MET
CCNE3
SIRT1
CDK6		ND[131,166,178]
miR-451GCTs
GCCLs		Cell proliferationMIFPoor Survival
Prognosis		[24,94]
miR-486GCTs
GCCLs		Cell proliferationOLFM4ND[179,180]
miR-512-5pGCTs
GCCLs		Cell proliferationMCI-1ND[98]
miR-520d-3pGCTs
GCCLs		NDNDInvasion depth
LNM
Tumor stage
Prognosis		[99]
miR-610GCTs
GCCLs		Invasion
Metastasis		NDND[181]
miR-7GCTs
GCCLs		Invasion Metastasis
Chemoresistance		NDND[109,182]
miR-9GCTs
GCCLs		Cell proliferation
Cell cycle		RAB34
CDX2
NFKB1		Diagnosis[24,172,183]
miR-98GCTs
GCCLs		ChemoresistanceNDND[109]
Chemoresistance drugs were cisplatin, 5-fluorouracil and hydroxy camptothecin. GCTs: Gastric cancer tissues, GCCLs: Gastric cancer cell lines, ND: not determined.
Table 3. Up-regulated circulating miRNAs for GC.
Table 3. Up-regulated circulating miRNAs for GC.
Circulating OncomiRsSamplesMethodsSensitivitySpecificityAUCTarget (Official Gene Name)Clinical ApplicationReferences
miR-1164 GC
127 HC		Microarray + qRT-PCR79.386.50.879NDDiagnosis[111]
miR-106a90 GC
27 HC		Microarray + qRT-PCR48.290.20.684NDDiagnosis[184]
miR-106a69 GC
30 HC		Microarray + qRT-PCR85.5800.879NDDiagnosis[185]
miR-106b69 GC
30 HC		Microarray + qRT-PCRNDND0.72NDDiagnosis[185]
miR-106b40 Pre GC
20 Post GC		qRT-PCRNDNDNDNDTNM stage
Diagnosis
Prognosis		[186]
miR-1790 GC
27 HC		Microarray + qRT-PCR48.290.20.743NDDiagnosis[184]
miR-17-5p79 Pre GC
30 Post GC
6 Relapse GC		qRT-PCRNDNDNDNDDiagnosis
Poor Survival
Differentiation
TNM stages
Prognosis		[54]
miR-18a82 GC
65 HC		qRT-PCRNDNDNDNDPoor Survival
LNM
Pathological grade
Prognosis		[54,187]
miR-18a104 GC
65 HC		qRT-PCRNDNDNDNDDiagnosis[188]
miR-19212 GC
12 HC		qRT-PCRNDND0.732NDDiagnosis
Distant metastasis
No Distant metastasis		[189]
miR-199a-3p30 EGC
70 HC		Microarray + qRT-PCR0.760.740.818NDDiagnosis[190,191]
miR-20a79 Pre GC
30 Post GC
6 Relapse GC		qRT-PCRNDNDNDNDPoor Survival
Differentiation
TNM stages
Prognosis		[54]
miR-20a164 GC
127 HC		Microarray + qRT-PCR79.386.50.879NDDiagnosis[111]
miR-200c67 GC
15 HC		qRT-PCR65.41000.715BCL2
XIAP		Diagnosis
LNM
Poor Survival
Prognosis		[192,193]
miR-21174 GC
39 HC		Microarray + qRT-PCR56.794.90.81NDDiagnosis[194]
miR-2169 GC
42 Pre GC
42 Post GC		qRT-PCRNDNDNDRECK
PTEN
SERPINI1		Venous invasion
Poor Survival
Prognosis Differentiation
LNM
Poor Survival
Prognosis		[68,71,195,196]
miR-21103 GC
103 HC		qRT-PCRNDNDNDNDDiagnosis
Prognosis		[197]
miR-21868 GC
56 HC		qRT-PCRNDNDNDECOPMetastasis
Tumor stage
Poor Survival
Prognosis		[155,198]
miR-22182 GC
46 Dysplasia
128 SG or CAG		qRT-PCRNDNDNDCDKN1B
CDKN1C
PTEN		Differentiation
Poor Survival
Prognosis		[27,199,200]
miR-22182 GC
82 HC		qRT-PCR82.458.8NDNDDiagnosis[199]
miR-222114 GC
36 CAG
56 HC		qRT-PCR66.188.30.85CDKN1B
CDKN1C
PTEN
RECK		Diagnosis
LNM
TNM stages
Serosal Invasion
Poor Survival
Prognosis		[27,200,201,202]
miR-2570 GC
70 HC		qRT-PCRNDNDNDCDKN1C
BCL2L11
FBXW7		LNM
TNM stage
Poor Survival
Prognosis		[26,27,80,203]
miR-2540 Pre GC
20 Post GC		qRT-PCRNDNDNDNDTNM stage
Diagnosis
Prognosis		[186]
miR-27a82 GCqRT-PCRNDNDNDPHB
APC		Metastasis
Poor Survival
Recurrent
Prognosis		[81,204,205]
miR-27a164 GC
127 HC		Microarray + qRT-PCR79.386.50.879NDDiagnosis[111]
miR-34164 GC
127 HC		Microarray + qRT-PCR79.386.50.879NDDiagnosis[111]
miR-376c82 GC
82 HC
46 dysplasia
128 SG
or CAG		qRT-PCR82.458.8NDNDDiagnosis Differentiation
Poor Survival
Prognosis		[199]
miR-37861 GC
61 HC		qRT-PCR87.570.70.861NDDiagnosis[206]
miR-42190 GC
90 HC		qRT-PCRNDNDNDNDDiagnosis[207]
miR-423-5P164 GC
127 HC		Microarray + qRT-PCR79.386.50.879NDDiagnosis[111]
miR-45156 GC
30 HC		Microarray + qRT-PCR961000.96NDDiagnosis[208]
miR-48656 GC
30 HC		Microarray + qRT-PCR86970.92NDDiagnosis[208]
miR-74482 GC
82 HC
46 dysplasia
128 SG
or CAG		qRT-PCR82.458.8NDNDDiagnosis Differentiation
Poor Survival
Prognosis		[199]
miR-9340 Pre GC
20 Post GC		qRT-PCRNDNDNDNDTNM stage
Diagnosis
Prognosis		[186]
AG: chronic atrophic gastritis; GC: Gastric cancer; HC: Healthy control; LNM: Lymph node metastasis; Pre: pre-operative; Post: post-operative; SG: superficial gastritis; qRT-PCR: Quantitative reverse transcriptase polymerase chain reaction; AUC: Area under curve; ND: not determined.
Table 4. Down-regulated circulating miRNAs for GC.
Table 4. Down-regulated circulating miRNAs for GC.
Circulating Tumor Suppressor miRsSamplesMethodsSensitivitySpecificityAUCTarget (Official Gene Name)Clinical ApplicationReferences
miR-12212 GC
12 HC		qRT-PCRNDND0.808NDDistance metastases
Poor Survival
Prognosis
No Distant metastasis
Diagnosis		[189]
miR-195-5p20 GC
190 HC		qRT-PCRNDNDNDNDPrognosis[209,210]
miR-203154 GC
22 HC		qRT-PCRNDNDNDNDGender
Lymphatic invasion
Venous invasion
Peritoneal metastasis
Distance metastasis
LNM
Liver metastasis
TNM stage
Poor Survival
Prognosis		[211]
miR-21868 GC
56 HC		qRT-PCRNDNDNDECOPMetastasis
Tumor stage
Poor Survival
Prognosis		[155,198]
miR-375NAMicroarray + qRT-PCR0.850.800.835NDPrognosis[210]
GC: Gastric cancer; HC: Healthy control; Pre: pre-operative; Post: post-operative; qRT-PCR: Quantitative reverse transcriptase polymerase chain reaction; AUC: Area under curve; ND: not determined.

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MDPI and ACS Style

Tsai, M.-M.; Wang, C.-S.; Tsai, C.-Y.; Huang, H.-W.; Chi, H.-C.; Lin, Y.-H.; Lu, P.-H.; Lin, K.-H. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int. J. Mol. Sci. 2016, 17, 945. https://doi.org/10.3390/ijms17060945

AMA Style

Tsai M-M, Wang C-S, Tsai C-Y, Huang H-W, Chi H-C, Lin Y-H, Lu P-H, Lin K-H. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. International Journal of Molecular Sciences. 2016; 17(6):945. https://doi.org/10.3390/ijms17060945

Chicago/Turabian Style

Tsai, Ming-Ming, Chia-Siu Wang, Chung-Ying Tsai, Hsiang-Wei Huang, Hsiang-Cheng Chi, Yang-Hsiang Lin, Pei-Hsuan Lu, and Kwang-Huei Lin. 2016. "Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer" International Journal of Molecular Sciences 17, no. 6: 945. https://doi.org/10.3390/ijms17060945

APA Style

Tsai, M.-M., Wang, C.-S., Tsai, C.-Y., Huang, H.-W., Chi, H.-C., Lin, Y.-H., Lu, P.-H., & Lin, K.-H. (2016). Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. International Journal of Molecular Sciences, 17(6), 945. https://doi.org/10.3390/ijms17060945

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