Next Article in Journal
Close Links between Cold Shock Proteins and Cancer
Next Article in Special Issue
Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma
Previous Article in Journal
Cell–Cell Communication and Extracellular Vesicles in Cancer
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 9
10.3390/cancers15092420
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Role of MicroRNAs in Uterine Leiomyosarcoma Diagnosis and Treatment

by
Iason Psilopatis
1,2,
Kleio Vrettou
1,
Stefania Kokkali
1,3 and
Stamatios Theocharis
1,*
1
First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Bld 10, Goudi, 11527 Athens, Greece
2
Department of Gynecology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
3
Oncology Unit, 2nd Department of Medicine, National and Kapodistrian University of Athens, Medical School, Hippocratio General Hospital of Athens, V. Sofias 114, 11527 Athens, Greece
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(9), 2420; https://doi.org/10.3390/cancers15092420
Submission received: 30 March 2023 / Revised: 19 April 2023 / Accepted: 21 April 2023 / Published: 23 April 2023
(This article belongs to the Special Issue Targeted Therapy in Sarcoma)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

MicroRNAs (miRNAs) show differential expression in various cancer entities and seemingly contribute to cancer development and/or progression. Nevertheless, their role in uterine sarcoma diagnosis and treatment is poorly understood. The current work represents the most comprehensive, up-to-date review of the literature on the particular role of miRNAs as biomarkers for uterine sarcoma diagnosis and therapy.

Abstract

Uterine sarcomas are rare gynecological tumors arising from the myometrium or the connective tissue of the endometrium with a relatively poor prognosis. MicroRNAs (miRNAs) represent small, single-stranded, non-coding RNA molecules that can function as oncogenes or tumor suppressors under certain conditions. The current review aims at studying the role of miRNAs in uterine sarcoma diagnosis and treatment. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms “microRNA” and “uterine sarcoma” were employed, and we were able to identify 24 studies published between 2008 and 2022. The current manuscript represents the first comprehensive review of the literature focusing on the particular role of miRNAs as biomarkers for uterine sarcomas. miRNAs were found to exhibit differential expression in uterine sarcoma cell lines and interact with certain genes correlating with tumorigenesis and cancer progression, whereas selected miRNA isoforms seem to be either over- or under-expressed in uterine sarcoma samples compared to normal uteri or benign tumors. Furthermore, miRNA levels correlate with various clinical prognostic parameters in uterine sarcoma patients, whereas each uterine sarcoma subtype is characterized by a unique miRNA profile. In summary, miRNAs seemingly represent novel trustworthy biomarkers for the diagnosis and treatment of uterine sarcoma.

1. Introduction

Uterine sarcomas are highly malignant tumors arising from the smooth muscles and/or connective tissue elements of the uterus [1]. Depending on the type of cells they start in, uterine sarcomas may be categorized into four distinct classes. Uterine leiomyosarcomas represent the most common type and derive from the myometrium. Endometrial stromal sarcomas start in the endometrial stroma of the uterus and may be subdivided into low- and high-grade tumors, according to the cancer cell characteristics and tumor growth pattern. Undifferentiated sarcomas arise either from the endometrium or the myometrium and tend to grow and spread quickly. Adenosarcomas are biphasic neoplasms composed of benign epithelial elements and a malignant mesenchymal component which is usually low-grade, although high-grade sarcomatous overgrowth may occur [1].
Uterine sarcomas are relatively rare and represent 2–5% of all uterine cancers, with leiomyosarcomas and endometrial stromal sarcomas being the most common types [2]. The prevalence of uterine leiomyosarcomas in Afro-American women is twice as high as in Caucasian women [2]. Previous pelvic radiation therapy, tamoxifen intake, congenital retinoblastoma, as well as hereditary leiomyomatosis and renal cell cancer syndrome, are all linked to an increased risk of uterine sarcomas [3]. So far, specific chromosomal translocations have also been identified in diverse uterine sarcomas, with the resulting fusion genes leading to the activation of important transcription factors [4].
The signs and symptoms of uterine sarcomas are non-specific and may be mostly attributed to non-cancerous changes of the uterus, endometrial hyperplasia, or endometrial cancer. Abnormal bleeding or spotting, especially after menopause, is the most common symptom, followed by vaginal discharge, pain, feeling of a mass, and urine or bowel problems [5].
The diagnostic evaluation of uterine sarcomas includes, in addition to a physical examination, a transvaginal ultrasound and Magnetic Resonance Imaging (MRI), eventually combined with a Positron Emission Tomography (PET) scan. Nevertheless, definite diagnosis always requires hysteroscopic endometrial biopsy and tissue sampling in order to define the tumor grade and the hormone receptor status [6]. In their up-to-date review of the literature focusing on advances in the preoperative identification of uterine sarcoma, Liu et al. underlined the fact that high serum markers Cancer Antigen 125 (CA-125), Lactate Dehydrogenase (LDH), C-reactive protein (CRP), and D-dimers, could theoretically indicate uterine sarcoma, but are strongly influenced by various other factors and, consequently, lack specificity. Despite being a cheap and convenient screening method, ultrasound may not conclusively determine the benignity or malignancy of uterine masses. On the contrary, MRI exhibits great soft tissue resolution and certain degenerative types of uterine fibroids show comparable signal intensities that account for a certain rate of misdiagnosis. Last but not least, PET-CT is costly and hard to promote, but assures the highest accuracy [7].
For patients with early-stage resectable uterine leiomyosarcoma and undifferentiated sarcoma, hysterectomy, along with bilateral salpingo-oophorectomy, represent the mainstay of treatment. In cases where sarcoma recurrence is highly expected, adjuvant radiochemotherapy might complete the treatment plan. Patients with advanced disease are mainly treated with systemic therapy, especially when complete surgical excision is impossible. The treatment concept is similar for endometrial stromal sarcomas, with the addition of hormonal therapy in cases of positive hormone receptor status [8]. In this context, Bose et al. recently published their comprehensive article on novel therapeutics in the treatment of uterine sarcomas and highlighted that, for women with advanced uterine leiomyosarcomas, the targeting of DNA damage repair pathways, alongside a depletion of immunosuppressive macrophage populations, could undoubtedly represent promising therapeutic approaches. Of note, several endometrial stromal sarcomas are even characterized by potentially actionable modifications in the Wingless/Integrate (Wnt), cyclin D-cyclin-dependent kinase (CDK), 4/6-Retinoblastoma (Rb), and murine double minute 2 (mdm2)–p53 pathways [9].
Polo-like kinase 4 (PLK4), Secreted Protein, Acidic and Rich in Cysteine (SPARC) Related Modular Calcium Binding 2 (SMOC2), Special AT-rich Sequence-Binding protein 2 (SATB2), or Forkhead box P3 (FOXP3) + T cells have all been suggested as prognostic indicators for uterine sarcomas [10]. More accurately, PLK4 has been proposed to represent a key regulator of centriole replication, which correlates with the following five hallmarks of cancer: proliferative signaling sustainment, tumor-promoting inflammation, invasion and metastasis activation, genome instability and mutation, as well as resistance to cell death [11]. Furthermore, PLK4 expression levels have been reported to be significantly higher in malignant tumor samples, with this overexpression constituting a biomarker predicting meagre prognosis for many human cancers [11]. SMOC2 is a matricellular protein which evidently not only influences cell migration, adhesion, and tissue repair, but also exhibits tumor suppressor capacities in cancer advancement, thereby embodying a promising prognostic marker [12]. Moreover, SATB2 is a transcriptional co-factor that controls chromatin architecture so as to modulate gene expression that regulates pluripotency and self-renewal [13]. According to The Cancer Genome Atlas (TCGA) expression data, SATB2, alone or combined with other proteins, could potentially be employed as a useful biomarker for cancer diagnosis [13]. Last but not least, FOXP3+ regulatory T cells play a crucial role in the maintenance of immune tolerance, alongside homeostasis of the immune system [14]. As a prognostic indicator, FOXP3+ regulatory T cells seem to negatively affect OS depending on each tumor site, the molecular subtypes, and tumor stages [14].
MicroRNAs (miRNAs) are small non-coding RNAs, with an average length of 22 nucleotides [15]. DNA sequences are first transcribed into primary miRNAs, which are then processed into precursor and mature miRNAs. miRNAs are best known to interact with the 3′ UTR of target messenger RNAs (mRNAs) to downregulate expression [16]. Under adequate circumstances, miRNAs may even activate gene expression or control the rate of translation and transcription [17,18,19]. Alternative splicing and polyadenylation of 3′ UTR, along with cell-type-specific RNA binding proteins affecting target mRNA secondary structures, influence mRNA sensitivity to miRNA-driven gene regulation in a cell type/state-specific way [15].
Upon release into extracellular fluids, miRNAs may reach target cells and act as autocrine, paracrine, and/or endocrine regulators to moderate cellular pathways [20]. By acting as intercellular signaling molecules, miRNAs may promote cell proliferation and migration [21,22], induce angiogenesis [22], activate downstream signaling events [23], as well as lead to biological responses and neurodegeneration [24]. Unlike intracellular RNAs, extracellular miRNAs show high stability and resistance to degradation in deleterious conditions [25]. Their protection in the extracellular milieu may be mainly attributed to the presence of miRNAs in vesicles, such as exosomes, microvesicles, and apoptotic bodies, or with accompanying proteins, especially Argonaute RISC Catalytic Component 2 (AGO2) [26]. Vesicle-associated extracellular miRNAs seem to employ endocytosis, phagocytosis, or direct fusion with the plasma membranes to enter cells, whereas vesicle-free secreted miRNAs take advantage of specific receptors on the cell surface [27]. The release of extracellular miRNAs is regulated by various pathways, including a ceramide-dependent pathway [28], vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23) [29], the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex [30], as well as different signaling molecules [31,32].
MiRNAs determine normal animal development and play a significant role in development, differentiation, proliferation, apoptosis, and immune responses [33]. Nevertheless, aberrant miRNA expression correlates with a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer [34]. Given their secretion into extracellular fluids, extracellular miRNAs have been widely reported as potential biomarkers. A recent comprehensive review of the literature presented a list of circulating miRNA isoforms that are most commonly associated with ten cancer diseases, ranging from esophageal or gastric cancer to melanoma and breast cancer [35]. Furthermore, Duica et al. pointed out the great potential of miRNAs in deciphering gynecological malignancies [36].
To our knowledge, no review article has, to date, been published on the role of miRNAs in the diagnosis and treatment of uterine sarcoma. The present work aims to investigate the usage of miRNAs as potential biomarkers in uterine sarcoma. The literature review was conducted using the MEDLINE and LIVIVO databases. Solely original research articles and scientific abstracts written in the English language that explicitly reported on miRNAs in uterine sarcoma were included in the data analysis. Studies that incorporated solely uterine leiomyomas or carcinosarcomas, as well as studies not clearly stating the exact histological tumor characteristics (e.g., uterine leiomyosarcoma) were excluded. The search terms ‘‘microRNA’’ and ‘‘uterine sarcoma’’ were employed, and we were able to identify a total of 37 articles published between 2008 and 2022, after the exclusion of duplicates. A total of 10 articles were discarded in the initial selection process after abstract review. The full texts of the remaining 27 publications were evaluated, and after detailed analysis, a total of 24 relevant studies published between 2008 and 2022 met the inclusion criteria and were selected for the literature review. Figure 1 presents an overview of the aforementioned selection process.

2. The Expression of miRNAs in Uterine Sarcoma

2.1. Differential Expression of miRNAs in Uterine Leiomyosarcoma Cell Lines

To date, a great number of studies have investigated the role of miRNAs in the diagnosis and treatment of uterine leiomyosarcoma.
In 2012, Chuang et al. studied the human leiomyosarcoma cell line SKLM-S1 and published two original research articles on the role of miRNAs in leiomyosarcomas [37,38]. More precisely, the gain of function of miRNA-93/106b in SKLM-S1 cells revealed that these miRNA isoforms regulated the expression of both F3 and interleukin 8 (IL8) as their direct targets, as well as the expression of connective tissue growth factor (CTGF) and plasminogen activator inhibitor 1 (PAI1) as their indirect targets through tissue factor (F3)-mediated signaling [37]. Similarly, the gain of function of miRNA-200c in SKLM-S1 cells confirmed zinc-finger E-box binding homeobox 1/2 (ZEB1/2) and vascular endothelial growth factor-A (VEGFA), and validated fibulin 5 (FBLN5) and tissue inhibitor of metalloproteinases 2 (TIMP2), as direct miRNA-200c targets through interaction with their respective 3′ UTRs [38]. Three years later, the same study group used the SK-LMS-I in vitro model and, by employing a quantitative polymerase chain reaction and Western blot analysis, suggested that miRNA-200c gain of function suppresses inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB), IL8, CDK2, and cyclin E2 (CCNE2) expression, decreases p65 transcriptional activity in the IL8 promoter, increases SK-LMS-1 caspase 3/7 activity, as well as inhibits their proliferation and migration [39]. Shi et al. examined the translational regulation of high-mobility-group AT-hook 2 (HMGA2) by lethal-7 (let-7) and outlined that the let-7-mediated HMGA2 repression in uterine leiomyosarcoma cell lines led to in vitro uterine leiomyosarcoma cell growth inhibition [40]. Additionally, Yang et al. demonstrated that miRNAs may regulate gene expression in uterine leiomyosarcoma cells in response to bromodomain 9 (BRD9) inhibition, given that the genes induced by TP-472 treatment correlated with miRNA-4776-5p, miRNA-671-3p, miRNA-3619-3p, miRNA-621, and miRNA-553, whereas genes suppressed by TP-472 treatment were associated with miRNA-542-5p, miRNA-4734, miRNA-3682-3p, as well as miRNA-4727-3p [41]. Altogether, miRNAs seem to show differential expression in uterine leiomyosarcoma cell lines and interact with genes influencing tumor development and progression (Table 1).

2.2. Different miRNA Profiles between Uterine Leiomyosarcomas versus Normal Uteri and Benign Uterine Tumors

Benna et al. employed the Sarcoma miRNA Expression Database for the comparison of leiomyosarcoma and smooth muscle samples, in terms of differential miRNA expression. The expression of 301 out of the 1120 miRNAs tested was found to significantly differ between leiomyosarcoma and smooth muscle samples, with 172 of these identified miRNAs targeting a total of 438 genes involved in specific molecular pathways. Most importantly, pathway analysis revealed the involvement of RNA Polymerase III, transfer RNA (tRNA) functions, as well as dopamine-mediated synaptic neurotransmission in leiomyosarcoma development [42]. Furthermore, Danielson et al. hybridized ten frozen samples of uterine leiomyosarcoma to Agilent arrays and found 32 upregulated and 40 downregulated miRNAs, whereas unsupervised hierarchical clustering revealed that the miRNA profile may accurately cluster normal myometrium, benign tumors, and uterine leiomyosarcoma, based on the distance along uterine smooth muscle differentiation. Of note, time progression and phylogenetic analyses based on miRNA expression profiles clustered uterine leiomyosarcomas with human mesenchymal stem cells [43]. Kowalewska et al. assessed 88 miRNAs by quantitative real-time polymerase chain reaction (qRT-PCR) in normal uteri and cancerous samples from patients with leiomyosarcoma, endometrial sarcoma, and mixed epithelial–mesenchymal tumors and highlighted that miRNA-23b, miRNA-1, let-7f, and let-7c, are downregulated in endometrial sarcomas, whereas there are no statistically significant changes in miRNA expression levels between leiomyosarcomas and normal uteri [44]. Moreover, Nuovo et al. studied miRNA expression in 15 leiomyosarcomas and detected high miRNA-221 expression levels by in situ hybridization in 13 out of 15 cases. On the contrary, miRNA-221 was not expressed in leiomyoma nor in benign metastasizing leiomyoma patients [45]. Renner et al. collected 13 leiomyosarcomas for miRNA profiling and found 28 upregulated miRNAs (including the muscle-specific myomiRNAs miRNA-133a, miRNA-133b, and miRNA-1) and 13 downregulated miRNAs. Interestingly, 10 out of 13 leiomyosarcoma samples clustered to the subgroup with decreased 14q32.2 miRNA expression [46]. Even though miRNA-1 was found to be strongly suppressed in uterine leiomyosarcoma tissue samples, Stope et al. failed to detect the growth inhibitory capacities of miRNA-1 in the SK-UT-1 cell line, with miRNA-1 not affecting the expression of the cell survival and mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 [47]. Yokoi et al. detected the downregulation of miRNA-4430, miRNA-6511b-5p, miRNA-451a, miRNA-4485-5p, miRNA-4635, miRNA-1246, and miRNA-191-5p in uterine leiomyosarcoma serum samples and pointed out the supremacy of miRNA-1246 and miRNA-191-5p for uterine leiomyosarcoma diagnosis, with an area under the receiver operating characteristic curve (AUC) of 0.97 (95% confidence interval (CI), 0.91–1.00) [48]. Additionally, Ventura et al. analyzed uterine tissue samples and described a trend toward miRNA-126 hypo-expression between uterine leiomyoma and benign metastasizing leiomyoma, whereas higher miRNA-221 and lower miRNA-126 expression was observed in leiomyosarcomas [49]. Taken together, selected miRNA isoforms seem to be either upregulated or downregulated in uterine leiomyosarcoma samples compared to normal uteri or benign tumors, constituting a significantly different miRNA profile for malignant tumor entities (Table 2).

2.3. Other Smooth Muscle Neoplasms versus Leiomyosarcoma

In addition to leiomyosarcoma, smooth muscle neoplasms of the uterus include leiomyoma (with variants such as cellular leiomyoma, mitotically active leiomyoma, and atypical or bizarre leiomyoma) and smooth muscle tumor of uncertain malignant potential (STUMP). Zhang et al. analyzed a cohort of 167 uterine smooth muscle tumors, including 38 leiomyosarcomas, 18 STUMPs, 42 bizarre leiomyomas, 22 cellular leiomyomas, 7 mitotically active leiomyomas, and 40 conventional leiomyomas. They found that bizarre leiomyomas and leiomyosarcomas share similar miRNA signatures [50].

2.4. Endometrial Stromal Sarcoma versus Leiomyosarcoma

Endometrial stromal sarcomas start in the endometrial uterine stroma and, together with leiomyosarcomas, represent the most common histological types of uterine sarcoma [51].
Ravid et al. compared the miRNA profiles of uterine endometrial stromal sarcoma and leiomyosarcoma, alongside the miRNA signatures of primary and metastatic uterine leiomyosarcoma, and pointed out that 76 miRNAs were overexpressed in endometrial stromal sarcoma, 18 in leiomyosarcoma, 45 in primary leiomyosarcoma, and 4 in metastases. Using short-interfering RNA (siRNA), frizzled-6 was silenced in the SK-LMS-1 uterine leiomyosarcoma cell line, thus significantly inhibiting cellular invasion, wound healing, and matrix metalloproteinase-2 (MMP-2) activity [51].

2.5. Undifferentiated Pleomorphic Sarcoma versus Leiomyosarcoma

Undifferentiated pleomorphic sarcoma is an adult soft tissue sarcoma and an exclusion diagnosis without any specific known differentiation lineages and with (myo-)fibroblastic or smooth-muscle-like spindle cell components [52].
Guled et al. conducted miRNA profiling on 37 leiomyosarcoma and 31 undifferentiated pleomorphic sarcoma samples and reported differential expression for miRNA-199b-5p, miRNA-320a, miRNA-199a-3p, miRNA-126, as well as miRNA-22. To be more accurate, miRNA-199b-5p was highly expressed in undifferentiated pleomorphic sarcomas, whereas leiomyosarcomas were associated with high miRNA-320a levels. Notably, miRNA-22 seemed to have the leiomyosarcoma-associated receptor tyrosine kinase (RTR)-like orphan receptor 2 (ROR2) as its target gene [52].
Taken together, each uterine sarcoma class seems to be characterized by a unique miRNA profile.

2.6. miRNAs Correlate with Prognosis of Uterine Leiomyosarcomas and Could Predict Response to Treatment

De Almeida et al. cultured the uterine leiomyosarcoma SK-UT-1 HTB-114 cell line and, after performing qRT-PCR, identified five upregulated and eight downregulated miRNAs. Specifically, miRNA-1-3p, miRNA-202-3p, and miRNA-7-5p, which presented a similar expression pattern in the SK-UT-1 HTB-114 cell line in comparison with 16 formalin-fixed paraffin-embedded uterine leiomyosarcoma samples, showed significant expression in uterine leiomyosarcoma [53]. Two years later, the same study group assessed the miRNA expression profile in 34 leiomyosarcoma paraffin-embedded samples and reported downregulation of all the let-7 miRNA group members. Decreased let-7e expression was associated with a worse overall survival (OS) and a high distant metastasis rate, whereas patients with low let-7b and let-7d levels showed worse disease-free survival (DFS). As for the patients’ age, older patients had the lowest let-7d, let-7e, and let-7f expression levels [54]. Gonzalez dos Anjos et al. selected 37 uterine leiomyosarcoma formalin-fixed paraffin-embedded samples and underlined the association of lower cancer-specific survival (CSS) with the upregulation of miRNA-196a-5p and miRNA-34c-5p, as well as the downregulation of miRNA-125a-5p and miRNA-10a-5p. In 18 endometrial stromal sarcoma formalin-fixed paraffin-embedded samples, the overexpression of miRNA-373-3p, miRNA-372-3p, and let-7b-5p, along with the decrease of let-7f-5p, miRNA-23-3p, and let-7b-5p, correlated with a lower CSS, respectively. High miRNA-138-5p levels were associated with better survival. Furthermore, miRNA-335-5p, miRNA-301a-3p, and miRNA-210-3p correlated with uterine sarcoma metastasis and relapse, whereas miRNA-138-5p, miRNA-146b-5p, and miRNA-218-5p expression predicated higher DFS in treated patients [55]. Additionally, Schiavon et al. performed RT-PCR analyses in 37 formalin-fixed paraffin-embedded uterine leiomyosarcoma tissue samples and reported the downregulation of 19 miRNAs and the upregulation of 25 miRNAs. More precisely, miRNA-148a-3p significantly correlated with tumor relapse, miRNA-27b-3p with metastasis, and miRNA-124-3p and miRNA-183-5p with patient death, whereas low miRNA135b-5p levels were associated with DFS. In comparison with normal myometrium or benign leiomyomas, miRNA144-3p, miRNA34a-5p, and miRNA206 constituted a signature for the distinction of uterine leiomyomas from leiomyosarcomas [56]. The Cancer Genome Atlas Research Network discovered that 12 miRNAs correlated with recurrence-free survival (RFS) in leiomyosarcoma, with miRNA-181b-5p representing the miRNA with the highest association with RFS and high miRNA-181b being more common in uterine than in soft tissue leiomyosarcoma [57]. Tong et al. enrolled 101 patients with uterine sarcoma and measured the levels of different serum miRNAs by qRT-PCR. miRNA-152 and miRNA-24 were downregulated, whereas miRNA-205, miRNA-222, and miRNA-150 were upregulated. Furthermore, all the miRNAs correlated with the sarcoma stage and uterine sarcoma patients with high-level miRNA-152 and miRNA-24 exhibited significantly better survival rates [58]. Wiemer et al. explored the role of microRNAs in terms of eribulin sensitivity or resistance in sarcomas and presented statistically significant differences in the expression of miRNA-1271, miRNA-146a, let-7g, miRNA-574-3p, miRNA-362-3p, miRNA-181a-2, miRNA-29b-2, and miRNA-590-3p between eribulin responders and non-responders for leiomyosarcomas [59]. Eribulin is a marine-derived drug, a structurally modified analog of halichondrin B, which is isolated from the sponge Halichondria okadai and has clinical activity mainly against liposarcomas and to a lesser extent leiomyosarcoma [60,61]. In other cancers, the expression of specific miRNAs has been associated with drug resistance [62]. Accurate biomarkers that predict the response to a certain therapy are valuable tools for personalized treatment in clinical practice. Altogether, miRNA overexpression or depletion seem to correlate with various clinical prognostic parameters in uterine leiomyosarcoma patients (Table 3).

3. Discussion

Uterine sarcomas are rare gynecologic tumors with a high degree of malignancy and a relatively poor prognosis. Although low grade endometrial stromal sarcomas are associated with a five-year relative survival rate of 78%. Even in a distant Surveillance, Epidemiology, and End Results (SEER) stage, the five-year relative survival rates for high grade endometrial stromal sarcomas resemble those for undifferentiated sarcomas. Leiomyosarcomas are the subgroup with the worst prognosis, given that the five-year relative survival rate amounts to only 39% for all the SEER stages combined [63]. Importantly, each uterine sarcoma histologic subtype also shows a unique clinical course, may only be accurately diagnosed postoperatively, and can be challenging to differentiate from similar benign lesions [64]. As such, uterine sarcomas still represent a diagnostic and therapeutic challenge that seemingly requires our better understanding of immunophenotypes and molecular characterization. In the present review of the literature, we highlight the role of miRNAs as novel biomarkers in terms of the diagnosis and treatment of uterine sarcoma. To our knowledge, the current work represents the most up-to-date comprehensive literature review on this topic and includes a total of 24 relevant original research articles.
By carefully analyzing the aforementioned articles, firstly, we conclude that miRNAs exhibit differential expression in uterine leiomyosarcoma cell lines and interact with certain genes that are (partly) responsible for tumorigenesis and cancer progression. This observation is very interesting, especially in the context of personalized/targeted medicine, as the involved miRNAs might act as useful targets of novel treatment agents ranging from miRNA mimics to overexpress the transcript, to miRNA repressors to silence transcript function. Of note, alleged miRNA drugs have so far displayed significant efficacy in various health conditions, such as cancer, hepatitis C, heart abnormalities, and kidney failure [62].
Secondly, selected miRNA isoforms show either elevated or decreased expression in uterine leiomyosarcoma samples compared to normal uteri or benign tumors. Consecutively, miRNAs might preoperatively give the clinicians the opportunity to determine the malignancy of a suspicious uterine mass and hopefully help avoid unnecessary and complicated surgical procedures.
Thirdly, miRNA overexpression or depletion is associated with various clinical prognostic parameters in uterine leiomyosarcoma patients. More precisely, miRNA expression levels significantly correlate with OS, DFS, metastasis rate, or tumor relapse, all of which are of utmost importance for accurate patient education. This prognostic information could be used to make adjuvant therapy (chemotherapy, radiation therapy) decisions. The role of these therapies is not well established in localized uterine leiomyosarcomas. Future clinical trials exploring the potential benefit of adjuvant treatment based on biomarkers, such as miRNAs, could at least partially reverse the poor prognosis of distinct uterine sarcoma histotypes. Interestingly, a study in patients with osteosarcoma is currently investigating potential prognostic and predictive tumor tissue and blood biomarkers, including miRNAs (NCT01190943). Another study is currently assessing plasma miRNAs as potential biomarkers to guide the decision for lymphadenectomy in patients with endometrial cancer (NCT03776630). Studies on miRNAs expression in other cancers, such as breast and lung cancer, have demonstrated an association with the efficacy of curative surgical treatment [35].
Even among the different uterine sarcoma subgroups, each uterine sarcoma class is characterized by a unique miRNA profile. This finding is undoubtedly promising because, as mentioned above, low grade endometrial stromal sarcomas, for instance, have a better prognosis or require a much less complicated treatment plan than leiomyosarcomas [63]. The different miRNAs that regulate gene expression in uterine leiomyosarcoma cell lines, show differential expression in uterine leiomyosarcomas vs. normal uteri and benign uterine tumors, or correlate with clinical prognostic parameters in uterine leiomyosarcoma patients are comprehensively summarized in Table 1, Table 2 and Table 3. miRNA-23b, miRNA-1, let-7f, and let-7c are downregulated in endometrial sarcomas, whereas the overexpression of miRNA-373-3p, miRNA-372-3p, and let-7b-5p, along with a decrease in let-7f-5p, miRNA-23-3p, and let-7b-5p, correlate with a lower CSS. miRNA-199b-5p seems to be overexpressed in undifferentiated pleomorphic sarcomas.
Nevertheless, despite the numerous advantages, several shortcomings of miRNAs as new biomarkers in the diagnosis and treatment of uterine sarcoma need to be discussed. The experimental determination of the miRNA–mRNA interactions is both costly and time-consuming, whereas miRNA–mRNA base pairing in mammals is not always necessarily complementary, thereby rendering the accurate prediction of miRNA targets rather demanding [65]. Besides, our limited experience with miRNAs justifies the absence of well-established detection limits, concentration levels in body fluids, or the parameters modulating miRNA expression [66]. Another important drawback is the fact that the use of venous miRNAs for cancer detection might be challenged in certain cases [67]. Last but not least, several identified miRNAs are characterized by relatively poor diagnostic specificity and reproducibility and, therefore, require novel standardized detection techniques [68].

4. Conclusions

In summary, miRNAs might successfully represent novel trustworthy biomarkers in the field of uterine sarcoma diagnosis and treatment. However, further clinical studies in larger patient collectives need to be conducted in order to verify the clinical utility of miRNAs in the diagnosis and treatment of uterine sarcoma, as well as to clarify contradictory results that arise from small, heterogenous patient cohorts [46,47].

Author Contributions

Literature analysis and conceptualization, I.P.; original draft preparation and writing, I.P.; review and supervision, K.V., S.K., and S.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. American Cancer Society. What Is Uterine Sarcoma? American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  2. American Cancer Society. Key Statistics for Uterine Sarcoma; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  3. American Cancer Society. Risk Factors for Uterine Sarcoma; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  4. Trope, C.G.; Abeler, V.M.; Kristensen, G.B. Diagnosis and treatment of sarcoma of the uterus. A review. Acta Oncol. 2012, 51, 694–705. [Google Scholar] [CrossRef] [PubMed]
  5. American Cancer Society. Signs and Symptoms of Uterine Sarcomas; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  6. American Cancer Society. Tests for Uterine Sarcoma; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  7. Liu, J.; Wang, Z. Advances in the Preoperative Identification of Uterine Sarcoma. Cancers 2022, 14, 3517. [Google Scholar] [CrossRef] [PubMed]
  8. American Cancer Society. Treatment for Uterine Sarcoma, by Type and Stage; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  9. Bose, S.; Schwartz, G.K.; Ingham, M. Novel Therapeutics in the Treatment of Uterine Sarcoma. Am. Soc. Clin. Oncol. Educ. Book 2022, 42, 900–909. [Google Scholar] [CrossRef] [PubMed]
  10. Holmes, B. Identifying New Biomarkers and Targets in Uterine Sarcomas. Target. Ther. Oncol. 2022, 11. Available online: https://www.targetedonc.com/view/identifying-new-biomarkers-and-targets-in-uterine-sarcomas (accessed on 19 April 2023).
  11. Zhang, X.; Wei, C.; Liang, H.; Han, L. Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy. Front. Oncol. 2021, 11, 587554. [Google Scholar] [CrossRef]
  12. Gutierrez, A.; Demond, H.; Brebi, P.; Ili, C.G. Novel Methylation Biomarkers for Colorectal Cancer Prognosis. Biomolecules 2021, 11, 1722. [Google Scholar] [CrossRef]
  13. Roy, S.K.; Shrivastava, A.; Srivastav, S.; Shankar, S.; Srivastava, R.K. SATB2 is a novel biomarker and therapeutic target for cancer. J. Cell. Mol. Med. 2020, 24, 11064–11069. [Google Scholar] [CrossRef] [PubMed]
  14. Shang, B.; Liu, Y.; Jiang, S.J.; Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci. Rep. 2015, 5, 15179. [Google Scholar] [CrossRef] [PubMed]
  15. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed]
  16. Ha, M.; Kim, V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 2014, 15, 509–524. [Google Scholar] [CrossRef] [PubMed]
  17. Broughton, J.P.; Lovci, M.T.; Huang, J.L.; Yeo, G.W.; Pasquinelli, A.E. Pairing beyond the Seed Supports MicroRNA Targeting Specificity. Mol. Cell 2016, 64, 320–333. [Google Scholar] [CrossRef]
  18. Makarova, J.A.; Shkurnikov, M.U.; Wicklein, D.; Lange, T.; Samatov, T.R.; Turchinovich, A.A.; Tonevitsky, A.G. Intracellular and extracellular microRNA: An update on localization and biological role. Prog. Histochem. Cytochem. 2016, 51, 33–49. [Google Scholar] [CrossRef] [PubMed]
  19. Vasudevan, S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip. Rev. RNA 2012, 3, 311–330. [Google Scholar] [CrossRef] [PubMed]
  20. Iftikhar, H.; Carney, G.E. Evidence and potential in vivo functions for biofluid miRNAs: From expression profiling to functional testing: Potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange. Bioessays 2016, 38, 367–378. [Google Scholar] [CrossRef] [PubMed]
  21. Zhou, W.; Fong, M.Y.; Min, Y.; Somlo, G.; Liu, L.; Palomares, M.R.; Yu, Y.; Chow, A.; O’Connor, S.T.; Chin, A.R.; et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 2014, 25, 501–515. [Google Scholar] [CrossRef]
  22. Hu, Y.; Rao, S.S.; Wang, Z.X.; Cao, J.; Tan, Y.J.; Luo, J.; Li, H.M.; Zhang, W.S.; Chen, C.Y.; Xie, H. Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics 2018, 8, 169–184. [Google Scholar] [CrossRef] [PubMed]
  23. Fabbri, M. MicroRNAs and miRceptors: A new mechanism of action for intercellular communication. Philos. Trans. R. Soc. B Biol. Sci. 2018, 373, 1737. [Google Scholar] [CrossRef]
  24. Lehmann, S.M.; Kruger, C.; Park, B.; Derkow, K.; Rosenberger, K.; Baumgart, J.; Trimbuch, T.; Eom, G.; Hinz, M.; Kaul, D.; et al. An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 2012, 15, 827–835. [Google Scholar] [CrossRef] [PubMed]
  25. Mitchell, P.S.; Parkin, R.K.; Kroh, E.M.; Fritz, B.R.; Wyman, S.K.; Pogosova-Agadjanyan, E.L.; Peterson, A.; Noteboom, J.; O’Briant, K.C.; Allen, A.; et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518. [Google Scholar] [CrossRef] [PubMed]
  26. Gallo, A.; Tandon, M.; Alevizos, I.; Illei, G.G. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 2012, 7, e30679. [Google Scholar] [CrossRef]
  27. Chen, X.; Liang, H.; Zhang, J.; Zen, K.; Zhang, C.Y. Secreted microRNAs: A new form of intercellular communication. Trends Cell Biol. 2012, 22, 125–132. [Google Scholar] [CrossRef]
  28. Kosaka, N.; Iguchi, H.; Yoshioka, Y.; Takeshita, F.; Matsuki, Y.; Ochiya, T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 2010, 285, 17442–17452. [Google Scholar] [CrossRef]
  29. Zhu, J.J.; Liu, Y.F.; Zhang, Y.P.; Zhao, C.R.; Yao, W.J.; Li, Y.S.; Wang, K.C.; Huang, T.S.; Pang, W.; Wang, X.F.; et al. VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia. Proc. Natl. Acad. Sci. USA 2017, 114, 8271–8276. [Google Scholar] [CrossRef]
  30. Gumurdu, A.; Yildiz, R.; Eren, E.; Karakulah, G.; Unver, T.; Genc, S.; Park, Y. MicroRNA exocytosis by large dense-core vesicle fusion. Sci. Rep. 2017, 7, 45661. [Google Scholar] [CrossRef] [PubMed]
  31. Hannafon, B.N.; Carpenter, K.J.; Berry, W.L.; Janknecht, R.; Dooley, W.C.; Ding, W.Q. Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol. Cancer 2015, 14, 133. [Google Scholar] [CrossRef] [PubMed]
  32. Yang, M.; Chen, J.; Su, F.; Yu, B.; Su, F.; Lin, L.; Liu, Y.; Huang, J.D.; Song, E. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol. Cancer 2011, 10, 117. [Google Scholar] [CrossRef] [PubMed]
  33. Tufekci, K.U.; Meuwissen, R.L.; Genc, S. The role of microRNAs in biological processes. Methods Mol. Biol. 2014, 1107, 15–31. [Google Scholar] [CrossRef]
  34. Paul, P.; Chakraborty, A.; Sarkar, D.; Langthasa, M.; Rahman, M.; Bari, M.; Singha, R.S.; Malakar, A.K.; Chakraborty, S. Interplay between miRNAs and human diseases. J. Cell. Physiol. 2018, 233, 2007–2018. [Google Scholar] [CrossRef] [PubMed]
  35. Filipow, S.; Laczmanski, L. Blood Circulating miRNAs as Cancer Biomarkers for Diagnosis and Surgical Treatment Response. Front. Genet. 2019, 10, 169. [Google Scholar] [CrossRef] [PubMed]
  36. Duica, F.; Condrat, C.E.; Danila, C.A.; Boboc, A.E.; Radu, M.R.; Xiao, J.; Li, X.; Cretoiu, S.M.; Suciu, N.; Cretoiu, D.; et al. MiRNAs: A Powerful Tool in Deciphering Gynecological Malignancies. Front. Oncol. 2020, 10, 591181. [Google Scholar] [CrossRef] [PubMed]
  37. Chuang, T.D.; Luo, X.; Panda, H.; Chegini, N. miR-93/106b and their host gene, MCM7, are differentially expressed in leiomyomas and functionally target F3 and IL-8. Mol. Endocrinol. 2012, 26, 1028–1042. [Google Scholar] [CrossRef] [PubMed]
  38. Chuang, T.D.; Panda, H.; Luo, X.; Chegini, N. miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5. Endocr. Relat. Cancer 2012, 19, 541–556. [Google Scholar] [CrossRef] [PubMed]
  39. Chuang, T.D.; Ho, M.; Khorram, O. The regulatory function of miR-200c on inflammatory and cell-cycle associated genes in SK-LMS-1, a leiomyosarcoma cell line. Reprod. Sci. 2015, 22, 563–571. [Google Scholar] [CrossRef] [PubMed]
  40. Shi, G.; Perle, M.A.; Mittal, K.; Chen, H.; Zou, X.; Narita, M.; Hernando, E.; Lee, P.; Wei, J.J. Let-7 repression leads to HMGA2 overexpression in uterine leiomyosarcoma. J. Cell. Mol. Med. 2009, 13, 3898–3905. [Google Scholar] [CrossRef] [PubMed]
  41. Yang, Q.; Bariani, M.V.; Falahati, A.; Khosh, A.; Lastra, R.R.; Siblini, H.; Boyer, T.G.; Al-Hendy, A. The Functional Role and Regulatory Mechanism of Bromodomain-Containing Protein 9 in Human Uterine Leiomyosarcoma. Cells 2022, 11, 2160. [Google Scholar] [CrossRef] [PubMed]
  42. Benna, C.; Rajendran, S.; Rastrelli, M.; Mocellin, S. miRNA deregulation targets specific pathways in leiomyosarcoma development: An in silico analysis. J. Transl. Med. 2019, 17, 153. [Google Scholar] [CrossRef]
  43. Danielson, L.S.; Menendez, S.; Attolini, C.S.; Guijarro, M.V.; Bisogna, M.; Wei, J.; Socci, N.D.; Levine, D.A.; Michor, F.; Hernando, E. A differentiation-based microRNA signature identifies leiomyosarcoma as a mesenchymal stem cell-related malignancy. Am. J. Pathol. 2010, 177, 908–917. [Google Scholar] [CrossRef]
  44. Kowalewska, M.; Bakula-Zalewska, E.; Chechlinska, M.; Goryca, K.; Nasierowska-Guttmejer, A.; Danska-Bidzinska, A.; Bidzinski, M. microRNAs in uterine sarcomas and mixed epithelial-mesenchymal uterine tumors: A preliminary report. Tumour. Biol. 2013, 34, 2153–2160. [Google Scholar] [CrossRef]
  45. Nuovo, G.J.; Schmittgen, T.D. Benign metastasizing leiomyoma of the lung: Clinicopathologic, immunohistochemical, and micro-RNA analyses. Diagn. Mol. Pathol. 2008, 17, 145–150. [Google Scholar] [CrossRef]
  46. Renner, M.; Czwan, E.; Hartmann, W.; Penzel, R.; Brors, B.; Eils, R.; Wardelmann, E.; Buttner, R.; Lichter, P.; Schirmacher, P.; et al. MicroRNA profiling of primary high-grade soft tissue sarcomas. Genes Chromosomes Cancer 2012, 51, 982–996. [Google Scholar] [CrossRef]
  47. Stope, M.B.; Cernat, V.; Kaul, A.; Diesing, K.; Koensgen, D.; Burchardt, M.; Mustea, A. Functionality of the Tumor Suppressor microRNA-1 in Malignant Tissue and Cell Line Cells of Uterine Leiomyosarcoma. Anticancer Res. 2018, 38, 1547–1550. [Google Scholar] [CrossRef] [PubMed]
  48. Yokoi, A.; Matsuzaki, J.; Yamamoto, Y.; Tate, K.; Yoneoka, Y.; Shimizu, H.; Uehara, T.; Ishikawa, M.; Takizawa, S.; Aoki, Y.; et al. Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma. Cancer Sci. 2019, 110, 3718–3726. [Google Scholar] [CrossRef] [PubMed]
  49. Ventura, L.; Gnetti, L.; Rossi, M.; Tiseo, M.; Giordano, G.; Corradi, M.; Silva, M.; Milanese, G.; Minari, R.; Leonetti, A.; et al. The role of miRNA-221 and miRNA-126 in patients with benign metastasizing leiomyoma of the lung: An overview with new interesting scenarios. Mol. Biol. Rep. 2021, 48, 3485–3494. [Google Scholar] [CrossRef] [PubMed]
  50. Zhang, Q.; Ubago, J.; Li, L.; Guo, H.; Liu, Y.; Qiang, W.; Kim, J.J.; Kong, B.; Wei, J.J. Molecular analyses of 6 different types of uterine smooth muscle tumors: Emphasis in atypical leiomyoma. Cancer 2014, 120, 3165–3177. [Google Scholar] [CrossRef] [PubMed]
  51. Ravid, Y.; Formanski, M.; Smith, Y.; Reich, R.; Davidson, B. Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures. Gynecol. Oncol. 2016, 140, 512–517. [Google Scholar] [CrossRef]
  52. Guled, M.; Pazzaglia, L.; Borze, I.; Mosakhani, N.; Novello, C.; Benassi, M.S.; Knuutila, S. Differentiating soft tissue leiomyosarcoma and undifferentiated pleomorphic sarcoma: A miRNA analysis. Genes Chromosomes Cancer 2014, 53, 693–702. [Google Scholar] [CrossRef]
  53. de Almeida, B.C.; Garcia, N.; Maffazioli, G.; dos Anjos, L.G.; Baracat, E.C.; Carvalho, K.C. Oncomirs Expression Profiling in Uterine Leiomyosarcoma Cells. Int. J. Mol. Sci. 2017, 19, 52. [Google Scholar] [CrossRef]
  54. de Almeida, B.C.; Dos Anjos, L.G.; Uno, M.; Cunha, I.W.D.; Soares, F.A.; Baiocchi, G.; Baracat, E.C.; Carvalho, K.C. Let-7 miRNA’s Expression Profile and Its Potential Prognostic Role in Uterine Leiomyosarcoma. Cells 2019, 8, 1452. [Google Scholar] [CrossRef]
  55. Gonzalez Dos Anjos, L.; de Almeida, B.C.; Gomes de Almeida, T.; Mourao Lavorato Rocha, A.; De Nardo Maffazioli, G.; Soares, F.A.; Werneck da Cunha, I.; Baracat, E.C.; Carvalho, K.C. Could miRNA Signatures be Useful for Predicting Uterine Sarcoma and Carcinosarcoma Prognosis and Treatment? Cancers 2018, 10, 315. [Google Scholar] [CrossRef]
  56. Schiavon, B.N.; Carvalho, K.C.; Coutinho-Camillo, C.M.; Baiocchi, G.; Valieris, R.; Drummond, R.; da Silva, I.T.; De Brot, L.; Soares, F.A.; Werneck da Cunha, I. miRNAs 144-3p, 34a-5p, and 206 are a useful signature for distinguishing uterine leiomyosarcoma from other smooth muscle tumors. Surg. Exp. Pathol. 2019, 2, 5. [Google Scholar] [CrossRef]
  57. Cancer Genome Atlas Research Network. Electronic address, e.d.s.c.; Cancer Genome Atlas Research, N. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell 2017, 171, 950–965.e928. [Google Scholar] [CrossRef] [PubMed]
  58. Tong, X.; Wang, X.; Wang, C.; Li, L. Elevated levels of serum MiR-152 and miR-24 in uterine sarcoma: Potential for inducing autophagy via SIRT1 and deacetylated LC3. Br. J. Biomed. Sci. 2018, 75, 7–12. [Google Scholar] [CrossRef] [PubMed]
  59. Wiemer, E.A.C.; Wozniak, A.; Burger, H.; Smid, M.; Floris, G.; Nzokirantevye, A.; Sciot, R.; Sleijfer, S.; Schoffski, P. Identification of microRNA biomarkers for response of advanced soft tissue sarcomas to eribulin: Translational results of the EORTC 62052 trial. Eur. J. Cancer 2017, 75, 33–40. [Google Scholar] [CrossRef] [PubMed]
  60. Schoffski, P.; Chawla, S.; Maki, R.G.; Italiano, A.; Gelderblom, H.; Choy, E.; Grignani, G.; Camargo, V.; Bauer, S.; Rha, S.Y.; et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, multicentre, phase 3 trial. Lancet 2016, 387, 1629–1637. [Google Scholar] [CrossRef] [PubMed]
  61. Blay, J.Y.; Schoffski, P.; Bauer, S.; Krarup-Hansen, A.; Benson, C.; D’Adamo, D.R.; Jia, Y.; Maki, R.G. Eribulin versus dacarbazine in patients with leiomyosarcoma: Subgroup analysis from a phase 3, open-label, randomised study. Br. J. Cancer 2019, 120, 1026–1032. [Google Scholar] [CrossRef] [PubMed]
  62. Hanna, J.; Hossain, G.S.; Kocerha, J. The Potential for microRNA Therapeutics and Clinical Research. Front. Genet. 2019, 10, 478. [Google Scholar] [CrossRef] [PubMed]
  63. American Cancer Society. Survival Rates for Uterine Sarcoma; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  64. Desar, I.M.E.; Ottevanger, P.B.; Benson, C.; van der Graaf, W.T.A. Systemic treatment in adult uterine sarcomas. Crit. Rev. Oncol. Hematol. 2018, 122, 10–20. [Google Scholar] [CrossRef] [PubMed]
  65. Loganantharaj, R.; Randall, T.A. The Limitations of Existing Approaches in Improving MicroRNA Target Prediction Accuracy. Methods Mol. Biol. 2017, 1617, 133–158. [Google Scholar] [CrossRef]
  66. Gillespie, P.; Ladame, S.; O’Hare, D. Molecular methods in electrochemical microRNA detection. Analyst 2018, 144, 114–129. [Google Scholar] [CrossRef]
  67. Condrat, C.E.; Thompson, D.C.; Barbu, M.G.; Bugnar, O.L.; Boboc, A.; Cretoiu, D.; Suciu, N.; Cretoiu, S.M.; Voinea, S.C. miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis. Cells 2020, 9, 276. [Google Scholar] [CrossRef]
  68. Wang, J.; Chen, J.; Sen, S. MicroRNA as Biomarkers and Diagnostics. J. Cell. Physiol. 2016, 231, 25–30. [Google Scholar] [CrossRef] [PubMed]
Cancers 15 02420 g001 550
Figure 1. PRISMA flow diagram visually summarizing the screening process.
Figure 1. PRISMA flow diagram visually summarizing the screening process.
Cancers 15 02420 g001
Table
Table 1. miRNA-mediated gene expression regulation in uterine leiomyosarcoma cell lines.
Table 1. miRNA-mediated gene expression regulation in uterine leiomyosarcoma cell lines.
miRNAExpression LevelAssociated GeneReference
miRNA-93/106bGain of functionF3[37]
IL8
CTGF
PAI1
miRNA-200cGain of functionZEB1/2[38,39]
VEGFA
FBLN5
TIMP2
IKBKB
IL8
CDK2
CCNE2
let-7UpregulationHMGA2[40]
miRNA-4776-5pUpregulation or downregulationGenes linked to BRD9 inhibition[41]
miRNA-671-3p
miRNA-3619-3p
miRNA-621
miRNA-553
miRNA-542-5p
miRNA-4734
miRNA-3682-3p
miRNA-4727-3p
Table
Table 2. Differentially expressed miRNAs in uterine leiomyosarcomas vs. normal uteri and benign uterine tumors.
Table 2. Differentially expressed miRNAs in uterine leiomyosarcomas vs. normal uteri and benign uterine tumors.
miRNADifferential ExpressionReference
miRNA-23bDownregulation in endometrial sarcomas
No statistically significant changes between leiomyosarcomas
and normal uteri		[44]
miRNA-1
let-7f
let-7c
miRNA-221Upregulation in leiomyosarcoma
Absence in leiomyoma and benign metastasizing leiomyoma		[45]
miRNA-133aUpregulation in leiomyosarcoma[46]
miRNA-133b
miRNA-1
miRNA-1Strong suppression in leiomyosarcoma[47]
miRNA-4430Downregulation in leiomyosarcoma[48]
miRNA-6511b-5p
miRNA-451a
miRNA-4485-5p
miRNA-4635
miRNA-1246
miRNA-191-5p
miRNA-126Downregulation in leiomyosarcoma
Hypo-expression between uterine leiomyoma and benign
metastasizing leiomyoma		[49]
miRNA-221Upregulation in leiomyosarcoma[49]
Table
Table 3. miRNA isoforms associated with clinical prognostic parameters in uterine leiomyosarcoma patients.
Table 3. miRNA isoforms associated with clinical prognostic parameters in uterine leiomyosarcoma patients.
miRNAClinical ParameterReference
let-7bOS
DFS
Distant metastasis rate		[54]
let-7d
let-7e
let-7f
miRNA-196a-5pCCS
DFS
Metastasis
Tumor relapse		[55]
miRNA-34c-5p
miRNA-125a-5p
miRNA-10a-5p
miRNA-373-3p
miRNA-372-3p
let-7b-5p
let-7f-5p
miRNA-23-3p
let-7b-5p
miRNA-138-5p
miRNA-335-5p
miRNA-301a-3p
miRNA-210-3p
miRNA-146b-5p
miRNA-218-5p
miRNA-148a-3pTumor relapse
Metastasis
Patient death
DFS		[56]
miRNA-27b-3p
miRNA-124-3p
miRNA-183-5p
miRNA135b-5p
miRNA-181b-5pRFS[57]
miRNA-152Tumor stage
Patient survival		[58]
miRNA-24
miRNA-205
miRNA-222
miRNA-150
miRNA-1271Response to eribulin[59]
miRNA-146a
let-7g
miRNA-574-3p
miRNA-362-3p
miRNA-181a-2
miRNA-29b-2
miRNA-590-3p
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Psilopatis, I.; Vrettou, K.; Kokkali, S.; Theocharis, S. The Role of MicroRNAs in Uterine Leiomyosarcoma Diagnosis and Treatment. Cancers 2023, 15, 2420. https://doi.org/10.3390/cancers15092420

AMA Style

Psilopatis I, Vrettou K, Kokkali S, Theocharis S. The Role of MicroRNAs in Uterine Leiomyosarcoma Diagnosis and Treatment. Cancers. 2023; 15(9):2420. https://doi.org/10.3390/cancers15092420

Chicago/Turabian Style

Psilopatis, Iason, Kleio Vrettou, Stefania Kokkali, and Stamatios Theocharis. 2023. "The Role of MicroRNAs in Uterine Leiomyosarcoma Diagnosis and Treatment" Cancers 15, no. 9: 2420. https://doi.org/10.3390/cancers15092420

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