- Open Access
Key nodes of a microRNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer
Chinese Journal of Cancer volume 34, pages28–40(2015)
Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition (EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas (TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This “paradox” can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating mRNA and microRNA (miRNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major miRNAs and 214 mRNAs. Among the 8 miRNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 miRNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer.
Cancer is a complex and dynamic disease that defies the normal differentiation process in which pluripotent embryonic stem cells are differentiated into almost all cell types; this process is driven mostly by epigenetic nuclear programming events such as DNA methylation and selective expression of a series of non-coding RNAs. However, the extensive nuclear reprogramming that accompanies genetic events such as mutation and gene copy number alterations confers remarkable plasticity on cancer cells, particularly regarding the phenotypic switches often found in cancer. Epithelial cells can adopt mesenchymal features, mesenchymal cells can adopt epithelial features, and mesenchymal cells can become endothelial cells[3,4]. The most well-studied cell fate switch is epithelial-to-mesenchymal transition (EMT), a process whereby epithelial cells lose both polarity and cell-to-cell contacts, thus acquiring increased motility and invasiveness. This pathophysiological transition is necessary for the conversion from a benign tumor to an aggressive, highly invasive carcinoma; it is the mechanism that allows tumor cells to escape from the primary tumor, evade into neighboring normal parenchyma, and enter lymphatic and blood circulation to initiate lymphohematogenous metastasis. The early escape of certain epithelial cells in tumors was noticed and documented by pathologists more than 100 years ago in drawings. EMT properties are acquired as a result of complex changes in cancer cells and their microenvironment that lead to the dissolution of intracellular junctions and detachment from the basolateral membrane; changes in the interactions between cancer cells and the extracellular matrix also contribute to EMT.
The phenotypic switch from epithelial to mesenchymal is characterized by profound morphologic changes, such as the loss of apico-basal polarity and reorganization in the distribution of organelles and cytoskeleton components that are related to a mesenchymal switch in the expression of cell lineage-specific genes and levels of proteins. The levels of epithelial proteins (e.g., E-cadherin, claudin, occluding, cytokeratins) progressively decrease while the levels of mesenchymal proteins [e.g., N-cadherin, vimentin, alpha-smooth muscle actin (a-SMA), fibronectin] increase.
In addition to these well-known marker genes, more complex gene signature sets that take into account the intrinsic heterogeneity of tumor cells have been proposed to define mesenchymal and epithelial subtypes[6–12]. Practically, these gene sets are used to estimate whether a cell population is more likely to express mesenchymal or epithelial features. Examining genes that cluster a group of tumors together is a frequently used strategy in cancer classification[6,9–11]. If these genes are enriched in a mesenchymal gene set, these tumors are often classified as mesenchymal subtypes. Using data from The Cancer Genome Atlas (TCGA), mesenchymal subtypes have been identified in multiple cancer types, including serous ovarian cancer.
Because of the importance of EMT and mesenchymal-to-epithelial transition (MET), a concerted effort has been made to determine the regulators of these processes[14–17]. In this article, we focus on the post-transcriptional regulatory mechanism based on microRNAs (miRNAs), which are 22-nucleotide, non-coding RNAs that suppress gene expression through mRNA destabilization or translational inhibition. miRNAs are deregulated in a wide variety of human cancers and have been shown to contribute to the control of cell growth, differentiation, and apoptosis, which are all important for the development and progression of cancer[18–26]. miRNAs regulate multiple signaling pathways involved in EMT. Because of the intimate relationship between miRNAs and EMT signature genes, we believe that an integrated analysis of these two groups of genes (protein coding and non-coding) is critical to define the core regulatory network that may underlie specific phenotypes associated with cancer subtypes. In a recent report, we performed such an analysis and identified a core regulatory network that better describes an integrated mesenchymal subtype of serous ovarian cancer patients in the TCGA cohort. This network includes 8 key node miRNAs and 214 protein-coding genes (Figure 1 ).
In the integrated miRNA-mRNA network, 3 of the 8 miRNAs (miR-101, miR-200c, and miR-141) are well-known regulators of EMT, and the work performed by our group and others has also shown that miR-506 is a potent regulator of EMT[28–30]. The role of other 4 miRNAs (miR-25, miR-29c, miR-182, and miR-128) in EMT is less clear, although some of these have been shown to affect cell migration, invasion, and metastasis. This article briefly summarizes these 8 miRNAs and their roles in cancer. We first review the newly defined EMT suppressor miR-506, followed by the other known EMT regulators (miR-101, miR-200c, and miR-141), and then the remaining 4 miRNAs.
miR-506 is located in Xq27.3, a chromosomal region associated with fragile X syndrome. Female patients with fragile X syndrome suffer from primary ovarian insufficiency. miR-506 belongs to a chrXq27.3 miRNA cluster that is associated with early relapse in advanced stage ovarian cancer. In our previous study, we demonstrated that miR-506 is a potent inhibitor of the mesenchymal phenotype and transforming growth factor β (TGF-β)-induced EMT by directly targeting snail family zinc finger 2 (SNAI2), a transcriptional repressor of the epithelial protein E-cadherin. Subsequently, we further illustrated a broader role of miR-506 in the suppression of EMT via its direct regulation of 2 well-known mesenchymal proteins, vimentin and N-cadherin, in all epithelial ovarian carcinoma subtypes. Therefore, miR-506 represents a novel class of miRNA that regulates both E-cadherin and vimentin/N-cadherin to suppress EMT.
The expression of E-cadherin and vimentin/N-cadherin represents 2 spectrums of EMT and MET. Accumulating evidence suggests that these pathways crosstalk closely and regulate one another. In our study, we found that the knockdown of vimentin up-regulated E-cadherin expression. Rodriguez et al. reported that vimentin inhibited E-cadherin and induced EMT via glycogen synthase kinase 3β (GSK-3β), an upstream regulator of SNAI1. Our recent study showed that miR-506 inhibited the expression of forkhead box protein M1 (FoxM1) by directly down-regulating cyclin-dependent kinase 4 (CDK4)/CDK6. FoxM1 is a transcriptional activator of SNAI1, another major E-cadherin repressor[35,36]. miR-506 also targets nuclear factor kappa B (NFκB) p65, which was implicated in the regulation of EMT. Kuphal et al. identified the NFκB-binding site in the N-cadherin promoter and reported that the loss of E-cadherin activated NFκB and induced N-cadherin expression during the EMT of melanoma cells. Vimentin expression was also transactivated by NFκB. Therefore, miR-506 has emerged as a key network gatekeeper for epithelial and mesenchymal lineage switches by simultaneously regulating multiple nodes in the sophisticated regulatory network (Figure 2 ).
Because miR-506 functions as a potent suppressor of EMT, it may be useful as a small-molecule therapeutic agent for cancer. We tested this possibility in a preclinical study in which nanoparticle delivery of miR-506 effectively suppressed tumor growth and spread in 2 orthotopic ovarian cancer models[28,29]. In addition to its effect on EMT, this tumor suppression function of miR-506 may also be partly caused by its recently recognized role in the inhibition of cell proliferation and the promotion of senescence by directly targeting its binding sites on the 3′-untranslated regions (3-UTRs) of CDK4 and CDK6. CDK4/6 is a druggable target for cancer therapies. The CDK4/6 inhibitor PD-0332991 is currently undergoing clinical testing in several cancer types[41–43]. The transcription factor network CDK4/6-FoxM1 is activated in more than 80% of high-grade serous ovarian cancer cases. Collectively, these data suggest that miR-506 is a potential therapeutic agent for ovarian cancer, and further studies are needed to validate the clinical value of miR-506 in the treatment of ovarian cancer.
The role of miR-506 in EMT inhibition, cell senescence, and differentiation has also been demonstrated in several other cancer types, including breast cancer, lung cancer, cervical cancer, and neuroblastoma[30,37,44,45], indicating that miR-506 functions as a tumor suppressor in a wide spectrum of cancers. However, the regulation of miR-506 expression remains understudied. We previously reported that miR-506 is partially regulated by methylation. This is consistent with the result of a recent large-scale screening of epigenetically regulated miRNAs in ovarian cancer, which showed the Xq27.3 miRNA cluster (including miR-506) was regulated by epigenetic mechanisms. Further studies using larger sample sizes are needed to reveal the relationship between miR-506 methylation and miR-506 expression.
There are 2 separate copies of the miR-101 gene, located on 1p31.3 and 9p24. Both regions have been identified as fragile regions of the genome that are associated with abnormal deletion or amplification in cancer. Down-regulation of miR-101 has been observed in bladder cancer, intraductal papillary mucinous neoplasms of the pancreas, and ovarian carcinoma[50–52], suggesting that miR-101 plays a role in tumor progression. Recent reports showed that miR-101 is methylated in several cancer types, explaining its decreased expression.
Abnormal expression of miR-101 may lead to a more malignant phenotype and promote cancer progression. A recent study found that low miR-101 expression in several subtypes of ovarian cancer tissues is significantly associated with poor cell differentiation, advanced International Federation of Gynecology and Obstetrics (FIGO) stages, and resistance to cisplatin. By contrast, miR-101 overexpression reduced the proliferation and migration of ovarian cancer cells and re-sensitized drug-resistant cancer cells to cisplatin-induced cytotoxicity. Thus, miR-101 may act as a suppressor of tumor progression. miR-101 may suppress tumor proliferation and migration and induce apoptosis by targeting enhancer of zeste homolog 2 (EZH2)[54,55] and Janus kinase 2 (JAK2). miR-101 may also induce senescence in breast cancer cells by targeting ubiquitin-conjugating enzyme E2N (UBE2N)- and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) and inhibit the G1-to-S phase transition of cervical cancer cells by targeting FBJ murine osteosarcoma viral oncogene homolog (Fos).
Like most miRNAs, miR-101 acts as a tumor suppressor in cancers by targeting the 3-UTR of multiple genes, including EZH2, UBE2N and SMARCA4, mitogen-activated protein kinase 1 (MAPK1) and Fos, Kruppel-like factor 6 (KLF6), DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A), and cyclooxygenase-2 (COX-2).
Several recent publications have demonstrated that miR-101 can suppress EMT in cancers, including colon cancer. Our investigations of the miRNA network that regulates the EMT of ovarian carcinoma have identified miR-101 as a key regulator Recent studies have shown that miR-101 regulates EMT through its effects on EZH2[64,65] and the Wnt signaling pathway Our group has provided evidence that miR-101 suppresses EMT in ovarian cancer by directly targeting the E-cadherin suppressor genes zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2 via specific binding sites on their 3-UTRs. Therefore, the literature consistently supports that miR-101 is a tumor suppressing miRNA and that one of the key cellular processes miR-101 regulates is EMT (Figure 3 ).
miR-200a and miR-141
miR-200 is a family of tumor suppressor miRNAs that consists of 5 members (miR-200a, miR-200b, miR-200c, miR-141, and miR-429), which are significantly involved in the inhibition of EMT. The miR-200 family is often down-regulated in human cancer cells and tumors as a result of aberrant epigenetic gene silencing[66,67]. Recent studies reported that the miR-200 family plays a critical role in suppressing EMT as well as cancer invasion and metastasis by targeting transcriptional repressors of ZEB1 and ZEB2. Furthermore, ZEB1 and ZEB2 repress the expression of miR-200a and miR-141 by binding to a conserved pair of ZEB-type E-box elements proximal to the transcription start site in the promoter region. Therefore, ZEB1 and ZEB2 and miR-200 family members repress the expression of one another in a reciprocal feedback loop, which may lead to an amplification of EMT. Targeting this loop may be a novel therapeutic strategy for cancer.
Extensive research has been performed to characterize the regulation of the miR-200 family. Both P300 and PCAF act as cofactors for ZEB1, forming a P300/PCAF/ZEB1 complex on the miR200c/141 promoter. This results in lysine acetylation of ZEB1 and abrogates ZEB1’s suppression of miR-200c/141 transcription. p53 has been reported to transactivate miR-200 family members by directly binding to the promoters of miR-200c and repress the expression of ZEB1 and ZEB2, leading to an inhibition of EMT[72,73]. Moreover, NPV-LDE-225 (Erismodegib) suppressed EMT by increasing the expression of miR-200a, miR-200b, and miR-200c. By contrast, the overexpression of signal transducer and activator of transcription 3 (Stat3), platelet-derived growth factor D (PDGF-D), Notch1, and doublecortin-like kinase 1 (DCLK1) in cancer cells led to a significant down-regulation of miR-200 family members, resulting in the up-regulation of ZEB1, ZEB2, and SNAI2 expression and acquisition of the EMT phenotype. Several miRNAs, such as miR-103 and miR-107, can induce EMT by down-regulating miR-200 via Dicer. Moreover, miR-130b silencing can restore dicer 1 to a threshold level that allows miR-200 family members to repress EMT in endometrial cancer. Together, these findings suggest that targeting these molecules may suppress EMT by increasing expression of the miR-200 family.
miR-25 is a member of the miR-106b-25 cluster, which is a part of the miR-92a family. Recent studies found that miR-25 is located on the 13th intron of the minichromosome maintenance protein 7 (MCM7) gene of human chromosome 7q22.1. The expression of miR-25 can be regulated at multiple levels. Liu et al. reported that a single nucleotide polymorphism (SNP), rs999885, in the promoter region of the miR-106b-25 cluster influences the expression of miR-25. Kunej et al. showed that the expression of miR-25 was regulated epigenetically in gastric cancer. Up-regulation of C-MYC induced the expression of a variety of miRNAs, including the miR-17-92 cluster, miR-106a-363 cluster, and miR-106b-25 cluster[85–87]. The transcription factor homeoprotein Sine oculis homeobox homolog 1 (Six1), a regulator of EMT, was shown to up-regulate the expression of the miR-106b-25 cluster. miR-25 has been reported to regulate EMT. It is known that TGF-β has suppressive effects on normal epithelial cells and during the early stages of carcinogenesis. As cancer progresses, tumor cells become resistant to TGF-β-mediated growth inhibition, and TGF-β promotes tumor invasion and metastasis, partly via its promotion of EMT. It was reported that miR-25 targets the cell cycle inhibitor p21 and the pro-apoptotic factor Bim (also known as BCL2-like 11) in the TGF-β signaling pathway, thus inhibiting the TGF-β-mediated growth suppression of tumor cells[89,90]. Furthermore, it was shown that the miR-106b-25 cluster could also target the inhibitory Smad7 directly, resulting in increased levels of the TGF-β type I receptor and downstream activation of TGF-β signaling[88,91]. miR-25 was also reported to directly target the CDH1 gene, which is closely associated with the lymphatic metastasis and invasion of esophageal squamous cell carcinoma (ESCC)[92,93]. Fang et al. demonstrated that miR-25 could target desmocollin 2 (DSC2), a member of the desmocollin subfamily of the cadherin superfamily, which is involved in cell-cell adhesion and plays a critical role in maintaining normal tissue architecture in the epithelium. Down-regulated DSC2 promoted the aggressiveness of ESCC cells by redistributing the adherens junctions and inducing the transposition of β-catenin from the cytoplasm to the nucleus, thus further activating the β-catenin/T-cell factor (TCF) transactivation axis.
In our network analysis of integrated mesenchymal serous ovarian cancer, miR-25 had the largest number of connected protein-coding genes. However, the current data on whether miR-25 acts as an oncogene or a tumor suppressor gene are inconsistent. miR-25 is more highly expressed in a variety of tumor tissues, including gastric cancer, prostate cancer, esophageal cancer, and colorectal cancer (CRC) tissues, than in normal tissue controls[91,94–96]. However, Li et al. reported that miR-25 functions as a potential tumor suppressor by targeting SMAD family member 7 (Smad7) in colon cancer. They showed that the introduction of miR-25 inhibited the proliferation and migration of colon cancer cells. Furthermore, miR-25 suppressed the growth of colon cancer xenografts in vivo. miR-25 was also suggested to act as a tumor suppressor in anaplastic thyroid carcinoma by targeting the polycomb protein EZH2.
Using an integrated analysis of TCGA cases, we found that miR-25 expression was decreased in our integrated mesenchymal subtype of high-grade serous ovarian cancer, suggesting that miR-25 is inversely associated with EMT. By contrast, miR-25 has been considered an oncogene in ovarian cancer. miR-25 was highly expressed in both clinical ovarian cancer samples and cell lines[99,100], and the miR-25 expression level was significantly positively associated with tumor stage, regional lymph node status, and poor survival in epithelial ovarian cancer. Zhang et al. demonstrated that miR-25 directly regulated apoptosis by targeting Bim in ovarian cancer. In ovarian cancer cells, the down-regulation of miR-25 induced apoptosis, whereas the overexpression of miR-25 enhanced cell proliferation. Feng et al. reported that miR-25 promoted ovarian cancer proliferation and motility by targeting LATS2. However, the above results were from a single bioinformatics analysis, in vitro studies without in vivo validation[99,101], or a small-scale clinical analysis (86 cases). Therefore, further studies should be performed, such as measuring the expression of miR-25 in serous and other subtypes of ovarian cancer cases in a large-scale, multiple-center study and demonstrating the function of miR-25 in EMT, MET, and metastasis both in vitro and in vivo.
The miR-29 family consists of miR-29a, miR-29b, and miR-29c; miR-29b includes 2 members, miR-29b-1 and miR-29b-2. Dysregulation of the miR-29 family is reported in many aspects of tumorigenesis and cancer progression, including cell proliferation, cell cycle, cell differentiation, apoptosis, and metastasis. However, the mechanism responsible for the deregulation of miR-29 family members in tumors remains unclear. Zhang et al. reported that miR-29 members were suppressed by c-Myc in B-cell lymphoma. Although not explicitly stated, the miR-29 family is involved in the regulation of EMT. miR-29 expression is induced by the TGF-β-Smad signaling pathway[104,105], which is a key signaling pathway for EMT. DNA damage-induced TP53 was shown to promote the expression of miR-29. Furthermore, TP53-induced miR-200 expression provides critical evidence for the role of TP53 in EMT regulation. Further studies are needed to determine whether TP53-induced miR-29 also contributes to TP53-regulated EMT.
The reported functions of miR-29 family members consistently support their roles as tumor suppressing miRNAs in many systems, including melanoma, peripheral nerve sheath tumors, glioma, and nasopharyngeal, colorectal, gastric, hepatocellular, breast and lung cancers. Zhang et al. reported that miR-29c dramatically suppressed CRC cell migration, invasion, and metastasis in vivo. These authors further demonstrated that miR-29c mediates EMT in CRC by directly targeting guanine nucleotide-binding protein alpha 13 (GNA13) and protein tyrosine phosphatase type IV A (PTP4A). These 2 proteins are known to be involved in the ERK/GSK3β/β-catenin and Akt/GSK3β/β-catenin signaling pathways, respectively. Han et al. showed that ectopic treatment with miR-29c mimics in gastric cancer cell lines resulted in reduced proliferation, adhesion, invasion, and migration and that high miR-29c expression suppressed xenograft tumor growth in nude mice by directly targeting integrin beta 1 (ITGB1). In hepatocellular carcinoma (HCC), miR-29c directly targeted and suppressed sirtuin 1 (SIRT1) expression and blocked HCC cell growth and proliferation, thus suggesting a tumor suppressive role. Consistently, miR-29c recapitulated SIRT1-knockdown effects in HCC cells. In addition, miR-29c expression was down-regulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC. Currently, besides our report of the association between decreased miR-29c expression and the mesenchymal subtype of high-grade serous ovarian cancer, there are no other reports on miR-29c dysregulation in ovarian cancer. Further studies are needed to determine whether miR-29c is a strong tumor suppressor in ovarian cancer and the cause of its dysregulation.
The miR-183 family is highly conserved and consists of miR-96, miR-182, and miR-183. Several studies have demonstrated that the miR-183 family is abnormally expressed in various tumors and is directly involved in human cancer processes, such as cellular differentiation, proliferation, apoptosis, and metabolism[111–113]. Zhang et al. performed a meta-analysis of the expression of the miR-183 family in human cancers and found that miR-182 expression was consistently up-regulated in 15 cancer types, including ovarian cancer, but inconsistently expressed in gastric cancer tissues and adjacent noncancerous tissues. Kong et al.  revealed that the miR-183 family was significantly up-regulated in gastric cancer tissues. However, Li et al. observed that miR-182 was down-regulated in gastric adenocarcinoma tissues and may function as a tumor suppressor via down-regulation of cAMP responsive element-binding protein 1 (CREB1).
miR-182 has been consistently reported to be significantly up-regulated in ovarian cancer tissue[117–120]. Liu et al. reported that miR-182 expression was significantly higher in serous tubal intraepithelial carcinoma, which is recognized as a precursor lesion of high-grade serous ovarian cancer, than in matched normal fallopian tube. Furthermore, miR-182 was significantly overexpressed in most high-grade serous ovarian cancer cases. Overexpressing miR-182 in immortalized ovarian surface cells, fallopian tube secretory cells and malignant ovarian cell lines resulted in increased tumor transformation in vitro, enhanced tumor invasiveness in vitro, and metastasis in vivo. miR-182 plays an ontogenic role in ovarian cancer partly via its effects on repairing DNA double-strand breaks, its negative regulation of breast cancer 1 (BRCA1) and metastasis suppressor 1 (MTSS1), and its positive regulation of the oncogene high-mobility group AT-hook 2 (HMGA2). Wang et al. measured 1,722 miRNAs from 15 normal ovarian tissue samples and 48 ovarian cancer samples using a quantificational real-time polymerase chain reaction (qRT-PCR) assay and identified a 10-miRNA signature that distinguished ovarian cancer tissues from normal tissues. Wang et al. demonstrated that miR-182 promotes cell growth, invasion, and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian cancer. Interestingly, inactivation of BRCA1, although less potent than that of BRCA2, has been shown to confer beneficial effects on ovarian cancer survival. Among the 8 miRNAs in our network, the expression of miR-506 and miR-182 is associated with increased survival in the TCGA cohort.
In prostate cancer, miR-182 was reported to suppress EMT via its repression of SNAI2. However, miR-182 was shown to increase the invasiveness of breast cancer by targeting reversion-inducing-cysteine-rich protein with kazal motifs (RECK), a matrix metalloproteinase inhibitor. miR-182 also promoted gallbladder cancer metastasis partly by targeting cell adhesion molecule 1 (CADM1). Furthermore, miR-182 was shown to stimulate angiogenesis and promote non-small cell lung cancer (NSCLC) progression partly by directly targeting fibroblast growth factor receptor substrate 2 (FRS2). In addition, miR-182 drove metastasis of primary sarcomas by targeting MTSS1 and Ras suppressor protein-1 (Rsu1). Therefore, miR-182 may play different roles in the development and progression of various cancers depending on their target downstream genes.
miR-128 is a brain-enriched miRNA. The expression of miR-128 exhibits tissue-specific and developmental stage-specific patterns. It is mainly expressed in neurons rather than astrocytes, and it is abundantly represented in the hippocampal region of brains of fetus, adults, and the patients with Alzheimer’s disease. miR-128 consists of 2 distinct genes, miR-128-1 and miR-128-2, which are embedded in the introns of the R3H domain containing 1 (R3HDM1) that is located on human chromosome 2q21.3 and in the introns of the cyclic AMP-regulated phosphoprotein, 21 kDa (ARPP21) that is located on 3p22.3, respectively. miR-128-1 and miR-128-2 are processed to generate the same mature miRNA with an identical sequence, miR-128. It is also known that the majority of intronic miRNAs transcriptionally depend on the expression of their host gene. However, researchers have found that approximately 26% of the mammalian intronic miRNAs may be transcribed using their own promoters. Monteys et al. demonstrated that miR-128-2 has a Pol III promoter in its 5’-flanking region, which may permit an independent expression from its host gene, ARPP21. Muinos-Gimeno et al. also found that there were 3 SNPs located in the genomic region that corresponds to hsa-miR-128-1-R3HDM1 and that there was a strong geographical genetic variation among different populations from HapMap. Mi et aA examined the DNA methylation status of CpG islands located in the miR-128b promoters of 10 acute lymphoblastic leukemia (ALL), 14 acute myeloid leukemia (AML), and 3 normal samples, and they found that the average methylation rate of the ALL group was 2.7%, lower than that of the AML group (17.1%). Their results suggested that the up-regulation of miR-128b in ALL patients may be due to a lower degree of CpG island methylation in its promoter regions. miR-128 can also be regulated by transcription factors. SNAIL can down-regulate the expression of miR-128 by directly binding to its promoter regions of both E-box 1 and 2. The mutant TP53 can bind to the putative promoter of the miR128-2 host gene ARPP21 and increase the expression of both miR-128 and ARPP21 mRNA[134,135].
Aberrant expression of miR-128 has been observed in many malignant tumors. Under-expression of miR-128 was observed in glioma compared with tumor-adjacent brain tissue, particularly in the more aggressive subtypes, glioblastoma multiforme (GBM) and medulloblastoma, based on miRNA array, Northern blot, and qRT-PCR analyses[1,19,27]. However, the levels of miR-128 expression in other solid tumor tissues were highly variable. Using a large-scale miRnome analysis, Volinia et al. measured 540 different malignant tumor samples and found that the expression of miR-128b was significantly up-regulated in tumor tissues of the colon, lung, and pancreas. By contrast, Katada et al. measured the expression levels of miR-128 in 42 undifferentiated gastric cancer tissues and paired controls. Their findings showed that miR-128a was up-regulated, whereas miR-128b was down-regulated, in undifferentiated gastric cancer tissues. Khan et al. measured 21 independent prostate specimens and found a significant reduction in the levels of miR-128 in a progressive fashion from benign prostatic hyperplasia to prostate cancer and then to metastatic prostate cancer. The level of miR-128 was also lower in more invasive ovarian cancer cells than in less invasive cancer cells.
Examining the role of miR-128 in EMT and tumor cell invasion and motility, Qian et al. demonstrated that overexpression of miR-128 suppressed the morphologic transformation associated with EMT, retarded wound closing, and reduced cell migration and invasion in MDA-MB-231 cells. Evangelisti et al. found that ectopic overexpression of miR-128 down-regulated glioblastoma cell invasion by directly targeting Reelin and doublecortin (DCX). Woo et al. reported that overexpression of miR-128 in ovarian cancer cells resulted in reduced cell motility and adhesion by directly targeting colony-stimulating factor-1 (CSF-1). Because reducing cell motility and adhesion adversely affects cell migration, the function of miR-128 in ovarian cancer metastasis via its effects on CSF-1 needs to be studied in vivo. In addition, the regulation of miR-128 on multiple targets related to EMT should be further studied.
Conclusions and Future Directions
Most studies have shown that as post-transcriptional regulators, miRNAs play important roles in EMT and are important markers and tools in cancer diagnosis, prognosis, and therapeutics. Using an integrated analysis, we identified a core regulatory network, including 8 key node miRNAs and 214 protein-coding genes, related to an integrated mesenchymal subtype of serous ovarian cancer, suggesting that these 8 miRNAs can regulate EMT and MET in ovarian cancer. However, in various tumors, including ovarian cancer, the functions of some of the 8 miRNAs in EMT and MET are contradictory, possibly because miRNAs play different roles by targeting different targets in specific conditions. Therefore, further studies are needed on these miRNAs and their targets.
In addition, the function of a single miRNA in EMT and MET may be limited, thus the combination of several miRNAs may generate an entirely different cellular phenotype and therapeutic outcome. Shahab et al. monitored the consequent changes in the global patterns of gene expression using microarray and qRT-PCR after transfecting 2 miRNAs, miR-7 and miR-128, and found that the changes in gene expression induced by the individual miRNAs was functionally coordinated but distinct. miR-7 transfection into ovarian cancer cells induces changes in cell adhesion and other developmental networks previously associated with EMT and other processes linked with metastasis. By contrast, miR-128 transfection induces changes in cell cycle control and other processes commonly linked with cellular replication. Therefore, the function of an individual miRNA in EMT and MET may be influenced by other miRNAs. The effects of combining several miRNAs should be investigated in the future. Preclinical mouse model studies have already provided evidence that miRNAs, such as miR-506, can exhibit strong tumor suppressive effects[28,29]. With the development and perfection of miRNA delivery techniques such as nanoparticles and mesenchymal stem cells, miRNAs are quickly becoming a promising therapeutic tool for cancer treatment.
Huang T, Alvarez A, Hu B, et al. Noncoding RNAs In cancer and cancer stem cells. Chin J Cancer, 2013,32:582–593.
Taranger CK, Noer A, Sorensen AL, et al. Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells. Mol Biol Cell, 2005,16:5719–5735.
Lu M, Jolly MK, Levine H, et al. MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination. Proc Natl Acad Sci U S A, 2013,110:18144–18149.
Ubil E, Duan J, Pillai IC, et al. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature, 2014,514:585–590.
Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med, 2009,1:303–314.
Chung CH, Parker JS, Ely K, et al. Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res, 2006,66:8210–8218.
Joyce T, Cantarella D, Isella C, et al. A molecular signature for Epithelial to Mesenchymal transition in a human colon cancer cell system is revealed by large-scale microarray analysis. Clin Exp Metastasis, 2009,26:569–587.
Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res, 2009,69:4116–4124.
Kim J, Hong SJ, Park JY, et al. Epithelial-mesenchymal transition gene signature to predict clinical outcome of hepatocellular carcinoma. Cancer Sci, 2010,101:1521–1528.
Cheng WY, Kandel JJ, Yamashiro DJ, et al. A multi-cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma. PLoS One, 2012,7:e34705.
Cheng Q, Chang JT, Gwin WR, et al. A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype. Breast Cancer Res, 2014,16:407.
Gujral TS, Chan M, Peshkin L, et al. A noncanonical frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell, 2014,159:844–856.
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature, 2011,474:609–615.
Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res, 2005,65:5991–5995.
Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res, 2005,65:5996–6000.
Lee JM, Dedhar S, Kalluri R, et al. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol, 2006,172:973–981.
Steinestel K, Eder S, Schrader AJ, et al. Clinical significance of epithelial-mesenchymal transition. Clin Transl Med, 2014,3:17.
Chai S, Ma S. Clinical implications of microRNAs in liver cancer stem cells. Chin J Cancer, 2013,32:419–426.
Bruce JP, Liu FF. MicroRNAs in nasopharyngeal carcinoma. Chin J Cancer, 2014,33:539–544.
Hassan O, Ahmad A, Sethi S, et al. Recent updates on the role of microRNAs in prostate cancer. J Hematol Oncol, 2012,5:9.
Del Vescovo V, Grasso M, Barbareschi M, et al. MicroRNAs as lung cancer biomarkers. World J Clin Oncol, 2014,5:604–620.
Kinose Y, Sawada K, Nakamura K, et al. The role of microRNAs in ovarian cancer. Biomed Res Int, 2014,2014:249393.
Sun E, Shi Y. MicroRNAs: Small molecules with big roles in neurodevelopment and diseases. Exp Neurol, 2014, pii: S0014-4886(14)00257-X. doi: 10.1016/j.expneurol.2014.08.005. [Epub ahead of print].
Matuszcak C, Haier J, Hummel R, et al. MicroRNAs: Promising chemoresistance biomarkers in gastric cancer with diagnostic and therapeutic potential. World J Gastroenterol, 2014,20:13658–13666.
Fortunato O, Boeri M, Verri C, et al. Therapeutic use of microRNAs in lung cancer. Biomed Res Int, 2014,2014:756975.
Budhu A, Ji J, Wang XW. The clinical potential of microRNAs. J Hematol Oncol, 2010,3:37.
Ding XM. MicroRNAs: regulators of cancer metastasis and epithelial-mesenchymal transition (EMT). Chin J Cancer, 2014,33:140–147.
Yang D, Sun Y, Hu L, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell, 2013,23:186–199.
Sun Y, Hu L, Zheng H, et al. MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer. J Pathol, 2015,235:25–36.
Arora H, Qureshi R, Park WY. miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines. PLoS One, 2013,8:e64273.
Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol, 2012,7:219–245.
Bagnoli M, De Cecco L, Granata A, et al. Identification of a chrXq27. 3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients. Oncotarget, 2011,2:1265–1278.
Rodriguez MI, Peralta-Leal A, O’Valle F, et al. PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genet, 2013,9:e1003531.
Liu G, Sun Y, Ji P, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol, 2014,233:308–318.
Hao L, Ha JR, Kuzel P, et al. Cadherin switch from E- to N-cadherin in melanoma progression is regulated by the PI3K/PTEN pathway through Twist and Snail. Br J Dermatol, 2012,166:1184–1197.
Balli D, Ustiyan V, Zhang Y, et al. Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. EMBO J, 2013,32:231–244.
Yin M, Ren X, Zhang X, et al. Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting NF-kappaB p65 to evoke reactive oxygen species generation and p53 activation. Oncogene, 2014, doi: 10.1038/onc.2013.597. [Epub ahead of print].
Kuphal S, Bosserhoff AK. Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma. Oncogene, 2006,25:248–259.
Min C, Eddy SF, Sherr DH, et al. NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem, 2008,104:733–744.
Graf F, Mosch B, Koehler L, et al. Cyclin-dependent kinase 4/6 (cdk4/6) inhibitors: perspectives in cancer therapy and imaging. Mini Rev Med Chem, 2010,10:527–539.
Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood, 2012,119:4597–4607.
Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol, 2013,31:2024–2028.
Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res, 2012,18:568–576.
Wen SY, Lin Y, Yu YQ, et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene, 2014, doi: 10.1038/onc.2013.597. [Epub ahead of print].
Zhao Z, Ma X, Hsiao TH, et al. A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation. Oncotarget, 2014,5:2499–2512.
Zhang L, Volinia S, Bonome T, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci U S A, 2008,105:7004–7009.
Cui J, Eldredge JB, Xu Y, et al. MicroRNA expression and regulation in human ovarian carcinoma cells by luteinizing hormone. PLoS One, 2011,6:e21730.
Hu Z, Lin Y, Chen H, et al. MicroRNA-101 suppresses motility of bladder cancer cells by targeting c-Met. Biochem Biophys Res Commun, 2013,435:82–87.
Caponi S, Funel N, Frampton AE, et al. The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms. Ann Oncol, 2013, 24:734–741.
Semaan A, Qazi AM, Seward S, et al. MicroRNA-101 inhibits growth of epithelial ovarian cancer by relieving chromatin-mediated transcriptional repression of p21(waf(1)/cip(1)). Pharm Res, 2011,28:3079–3090.
Liu L, Guo J, Yu L, et al. miR-101 regulates expression of EZH2 and contributes to progression of and cisplatin resistance in epithelial ovarian cancer. Tumour Biol, 2014, Sep 27. [Epub ahead of print].
Guo F, Cogdell D, Hu L, et al. miR-101 suppresses the epithelial-to-mesenchymal transition by targeting ZEB1 and ZEB2 in ovarian carcinoma. Oncol Rep, 2014,31:2021–2028.
Wei X, Xiang T, Ren G, et al. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A. Cell Signal, 2013, 25:439–446.
Lin C, Huang F, Li QZ, et al. miR-101 suppresses tumor proliferation and migration, and induces apoptosis by targeting EZH2 in esophageal cancer cells. Int J Clin Exp Pathol, 2014,7:6543–6550.
Lei Q, Shen F, Wu J, et al. miR-101, downregulated in reti noblastoma, functions as a tumor suppressor in human retinoblastoma cells by targeting EZH2. Oncol Rep, 2014,32:261–269.
Wang L, Li L, Guo R, et al. miR-101 promotes breast cancer cell apoptosis by targeting Janus kinase 2. Cell Physiol Biochem, 2014,34:413–422.
Manvati S, Mangalhara KC, Kalaiarasan P, et al. miR-101 Induces Senescence and Prevents Apoptosis in the Background of DNA Damage in MCF7 Cells. PLoS One, 2014,9:e111177.
Liang X, Liu Y, Zeng L, et al. miR-101 inhibits the G1-to-S phase transition of cervical cancer cells by targeting Fos. Int J Gynecol Cancer, 2014,24:1165–1172.
Liu JJ, Lin XJ, Yang XJ, et al. A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells. Nucleic Acids Res, 2014,42:12041–12051.
Yao YL, Ma J, Wang P, et al. miR-101 acts as a tumor suppressor by targeting kruppel-like factor 6 in glioblastoma stem cells. CNS Neurosci Ther, 2014, doi: 10.1111/cns.12321. [Epub ahead of print].
Yan F, Shen N, Pang J, et al. Restoration of miR-101 suppresses lung tumorigenesis through inhibition of DNMT3a-dependent DNA methylation. Cell Death Dis, 2014,5:e1413.
Bu Q, Fang Y, Cao Y, et al. Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by modulating the cyclooxygenase-2 pathway. Mol Med Rep, 2014,10:2203–2209.
Strillacci A, Valerii MC, Sansone P, et al. Loss of miR-101 expression promotes Wnt/beta-catenin signalling pathway activation and malignancy in colon cancer cells. J Pathol, 2013,229:379–389.
Carvalho J, van Grieken NC, Pereira PM, et al. Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 up-regulation in intestinal gastric cancer. J Pathol, 2012,228:31–44.
Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science, 2008,322:1695–1699.
Castilla MA, Diaz-Martin J, Sarrio D, et al. MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS One, 2012,7:e47709.
Hur K, Toiyama Y, Takahashi M, et al. MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut, 2013,62:1315–1326.
Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol, 2008,10:593–601.
Wellner U, Schubert J, Burk UC, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol, 2009,11:1487–1495.
Bracken CP, Gregory PA, Kolesnikoff N, et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res, 2008,68:7846–7854.
Mizuguchi Y, Specht S, Lunz JG 3rd, et al. Cooperation of p300 and PCAF in the control of microRNA 200c/141 transcription and epithelial characteristics. PLoS One, 2012,7:e32449.
Chang CJ, Chao CH, Xia W, et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol, 2011,13:317–323.
Schubert J, Brabletz T. p53 Spreads out further: suppression of EMT and stemness by activating miR-200c expression. Cell Res, 2011,21:705–707.
Fu J, Rodova M, Nanta R, et al. NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro Oncol, 2013,15:691–706.
Guo L, Chen C, Shi M, et al. Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene, 2013,32:5272–5282.
Kong D, Li Y, Wang Z, et al. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells, 2009,27:1712–1721.
Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett, 2011,307:26–36.
Sureban SM, May R, Qu D, et al. DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer. PLoS One, 2013,8:e73940.
Martello G, Rosato A, Ferrari F, et al. A microRNA targeting dicer for metastasis control. Cell, 2010,141:1195–1207.
Li BL, Lu C, Lu W, et al. miR-130b is an EMT-related microRNA that targets DICER1 for aggression in endometrial cancer. Med Oncol, 2013,30:484.
Li M, Guan X, Sun Y, et al. miR-92a family and their target genes in tumorigenesis and metastasis. Exp Cell Res, 2014,323:1–6.
Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell, 2008,133:217–222.
Liu Y, Zhang Y, Wen J, et al. A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma. PLoS One, 2012,7:e32230.
Kunej T, Godnic I, Ferdin J, et al. Epigenetic regulation of microRNAs in cancer: an integrated review of literature. Mutat Res, 2011,717:77–84.
Schulte JH, Horn S, Otto T, et al. MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int J Cancer, 2008,122:699–704.
Aguda BD, Kim Y, Piper-Hunter MG, et al. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci U S A, 2008,105:19678–19683.
Zhao ZN, Bai JX, Zhou Q, et al. TSA suppresses miR-106b-93-25 cluster expression through downregulation of MYC and inhibits proliferation and induces apoptosis in human EMC. PLoS One, 2012,7:e45133.
Smith AL, Iwanaga R, Drasin DJ, et al. The miR-106b-25 cluster targets Smad7, activates TGF-beta signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene, 2012,31:5162–5171.
Petrocca F, Visone R, Onelli MR, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell, 2008,13:272–286.
Kan T, Sato F, Ito T, et al. The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology, 2009,136:1689–1700.
Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res, 2008, 68:8191–8194.
Xu X, Chen Z, Zhao X, et al. MicroRNA-25 promotes cell migration and invasion in esophageal squamous cell carcinoma. Biochem Biophys Res Commun, 2012,421:640–645.
Chen ZL, Zhao XH, Wang JW, et al. MicroRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem, 2011,286:10725–10734.
Fang WK, Liao LD, Li LY, et al. Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma. J Pathol, 2013,231:257–270.
Poliseno L, Salmena L, Riccardi L, et al. Identification of the miR-106b∼25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal, 2010,3:ra29.
Nishida N, Nagahara M, Sato T, et al. Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters. Clin Cancer Res, 2012,18:3054–3070.
Li Q, Zou C, Han Z, et al. MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett, 2013,335:168–174.
Esposito F, Tornincasa M, Pallante P, et al. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab, 2012,97:E710–E718.
Zhang H, Zuo Z, Lu X, et al. miR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep, 2012,27:594–598.
Wang X, Meng X, Li H, et al. MicroRNA-25 expression level is an independent prognostic factor in epithelial ovarian cancer. Clin Transl Oncol, 2014,16:954–958.
Feng S, Pan W, Jin Y, et al. miR-25 promotes ovarian cancer proliferation and motility by targeting LATS2. Tumour Biol, 2014, Sep 2. [Epub ahead of print].
Wang Y, Zhang X, Li H, et al. The role of miRNA-29 family in cancer. Eur J Cell Biol, 2013,92:123–128.
Zhang X, Zhao X, Fiskus W, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell, 2012,22:506–523.
Maurer B, Stanczyk J, Jungel A, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum, 2010,62:1733–1743.
Roderburg C, Urban GW, Bettermann K, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology, 2011,53:209–218.
Ugalde AP, Ramsay AJ, de la Rosa J, et al. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J, 2011,30:2219–2232.
Zhang JX, Mai SJ, Huang XX, et al. MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of beta-catenin signaling. Ann Oncol, 2014,25:2196–2204.
Han TS, Hur K, Xu G, et al. MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1. Gut, 2014, pii: gutjnl-2013-306640. doi: 10.1136/gutjnl-2013-306640. [Epub ahead of print].
Bae HJ, Noh JH, Kim JK, et al. MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene, 2014,33:2557–2567.
Pierce ML, Weston MD, Fritzsch B, et al. MicroRNA-183 family conservation and ciliated neurosensory organ expression. Evol Dev, 2008,10:106–113.
Abraham D, Jackson N, Gundara JS, et al. MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets. Clin Cancer Res, 2011,17:4772–4781.
Lin S, Sun JG, Wu JB, et al. Aberrant microRNAs expression in CD133(+)/CD326(+) human lung adenocarcinoma initiating cells from A549. Mol Cells, 2012,33:277–283.
Xu X, Dong Z, Li Y, et al. The upregulation of signal transducer and activator of transcription 5-dependent microRNA-182 and microRNA-96 promotes ovarian cancer cell proliferation by targeting forkhead box O3 upon leptin stimulation. Int J Biochem Cell Biol, 2013,45:536–545.
Zhang QH, Sun HM, Zheng RZ, et al. Meta-analysis of microRNA-1 83 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. Gene, 2013,527:26–32.
Kong WQ, Bai R, Liu T, et al. MicroRNA-182 targets cAMP-responsive element-binding protein 1 and suppresses cell growth in human gastric adenocarcinoma. FEBS J, 2012,279:1252–1260.
Li X, Luo F, Li Q, et al. Identification of new aberrantly expressed miRNAs in intestinal-type gastric cancer and its clinical significance. Oncol Rep, 2011,26:1431–1439.
Vaksman O, Stavnes HT, Kaern J, et al. miRNA profiling along tumour progression in ovarian carcinoma. J Cell Mol Med, 2011,15:1593–1602.
Liu Z, Liu J, Segura MF, et al. miR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma. J Pathol, 2012,228:204–215.
Wang YQ, Guo RD, Guo RM, et al. MicroRNA-182 promotes cell growth, invasion, and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian carcinomas. J Cell Biochem, 2013,114:1464–1473.
Wang L, Zhu MJ, Ren AM, et al. A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer. PLoS One, 2014,9:e96472.
Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA, 2011, 306:1557–1565.
Qu Y, Li WC, Hellem MR, et al. miR-182 and miR-203 induce mesenchymal to epithelial transition and self-sufficiency of growth signals via repressing SNAI2 in prostate cells. Int J Cancer, 2013,133:544–555.
Chiang CH, Hou MF, Hung WC. Up-regulation of miR-182 by beta-catenin in breast cancer increases tumorigenicity and invasiveness by targeting the matrix metalloproteinase inhibitor RECK. Biochim Biophys Acta, 2013,1830:3067–3076.
Qiu Y, Luo X, Kan T, et al. TGF-beta upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1. Mol Biosyst, 2014,10:679–685.
Donnem T, Fenton CG, Lonvik K, et al. MicroRNA signatures in tumor tissue related to angiogenesis in non-small cell lung cancer. PLoS One, 2012,7:e29671.
Sachdeva M, Mito JK, Lee CL, et al. MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest, 2014,124:4305–4319.
Smirnova L, Grafe A, Seiler A, et al. Regulation of miRNA expression during neural cell specification. Eur J Neurosci, 2005,21:1469–1477.
Lukiw WJ. Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport, 2007,18:297–300.
Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA, 2005,11:241–247.
Corcoran DL, Pandit KV, Gordon B, et al. Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data. PLoS One, 2009,4:e5279.
Monteys AM, Spengler RM, Wan J, et al. Structure and activity of putative intronic miRNA promoters. RNA, 2010,16:495–505.
Muinos-Gimeno M, Montfort M, Bayes M, et al. Design and evaluation of a panel of single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease. Eur J Hum Genet, 2010,18:218–226.
Mi S, Lu J, Sun M, et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci U S A, 2007,104:19971–19976.
Donzelli S, Fontemaggi G, Fazi F, et al. MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. Cell Death Differ, 2012,19:1038–1048.
Karimi M, Conserva F, Mahmoudi S, et al. Extract from Asteraceae Brachylaena ramiflora induces apoptosis preferentially in mutant p53-expressing human tumor cells. Carcinogenesis, 2010,31:1045–1053.
Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A, 2006,103:2257–2261.
Katada T, Ishiguro H, Kuwabara Y, et al. microRNA expression profile in undifferentiated gastric cancer. Int J Oncol, 2009,34:537–542.
Khan AP, Poisson LM, Bhat VB, et al. Quantitative proteomic profiling of prostate cancer reveals a role for miR-128 in prostate cancer. Mol Cell Proteomics, 2010,9:298–312.
Woo HH, Laszlo CF, Greco S, et al. Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Mol Cancer, 2012,11:58.
Qian P, Banerjee A, Wu ZS, et al. Loss of SNAIL regulated miR-128-2 on chromosome 3p22.3 targets multiple stem cell factors to promote transformation of mammary epithelial cells. Cancer Res, 2012,72:6036–6050.
Evangelisti C, Florian MC, Massimi I, et al. miR-128 up-regulation inhibits Reelin and DCX expression and reduces neuroblastoma cell motility and invasiveness. FASEB J, 2009,23:4276–4287.
Shahab SW, Matyunina LV, Hill CG, et al. The effects of microRNA transfections on global patterns of gene expression in ovarian cancer cells are functionally coordinated. BMC Med Genomics, 2012,5:33.
We thank Ms. Ann Sutton in the Department of Scientific Publications at MD Anderson for editing this manuscript. This study was partially supported by the U.S. National Institutes of Health grants (U24 CA143835 to IS and WZ, P50 CA083639 and P50 CA098258 to AKS), MD Anderson support grant (CA016672) to WZ; a grant from the Blanton-Davis Ovarian Cancer Research Program to WZ; grants from the Program for Changjiang Scholars, Innovative Research Team in University (PCSIRT) in China, the National Key Scientific and Technological Project (2011ZX0 9307-001-04), and Tianjin Science and Technology Committee Foundation (09ZCZDSF04700) to KC; a grant from National Nature Science Foundation of China (#81201651) to YS; and a grant from Fondazione CARIPLO (2013-0865) to DM; and the A. Lavoy Moore Endowment Fund to YS and DY.
About this article
Cite this article
Sun, Y., Guo, F., Bagnoli, M. et al. Key nodes of a microRNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer. Chin J Cancer 34, 28–40 (2015). https://doi.org/10.5732/cjc.014.10284
- MicroRNA (miRNA)
- epithelial-to-mesenchymal transition (EMT)