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MicroRNA-129 in Human Cancers: from Tumorigenesis to Clinical Treatment

Gao Y.a · Feng B.a · Han S.a · Lu L.a · Chen Y.a · Chu X.a · Wang R.a · Chen L.a

Author affiliations

aDepartment of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

Corresponding Author

Rui Wang, MD,

Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing

University, No.315 Zhongshan East Road, Nanjing, Jiangsu 210002, (China)

Tel. +86-25-80860072, E-Mail wangrui218@163.com / chenlongbang@yeah.net

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Cell Physiol Biochem 2016;39:2186-2202

Abstract

Emerging evidence has shown that microRNAs (miRNAs) play essential roles in regulating human cancers development and progression. However, the underlying mechanisms remain to be further explored. MiRNAs are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that moderate gene expression primarily at post-transcriptional level. There is a growing body of literature that recognizes the importance of microRNA (miR)-129 during the development of cancers. Aberrant expression of miR-129 has been detected in various types of human cancers and the validated target genes are involved in cancer-related biological processes such as DNA methylation, cell proliferation, apoptosis, cell cycle, and metastasis. In this review, we summarized the roles of miR-129 family members and their target genes in tumorigenesis and clinical treatment of human cancers, highlighting the potential roles of miR-129 as biomarkers for cancer diagnosis and prognosis, and promising tools for cancer treatment.

© 2016 The Author(s) Published by S. Karger AG, Basel


Introduction

Cancer is a principal cause of death throughout the world and remains a momentous threat to human health. Most cancer deaths are due to the development of metastases, which is the culmination of neoplastic progression [1]. However, the underlying mechanisms remain to be further explored. Recently, there has been an increasing emphasis on the role of microRNAs (miRNAs) as biomarkers in diagnosis and prognosis of cancers [2]. Mounting evidence suggests that miRNAs that are aberrantly expressed during tumorigenesis may serve as novel noninvasive and cost-effective screening tools, especially in companion with CT/MRI/ultrasound, for more accurate and specific diagnosis and prognosis of cancers [3,4,5].

MiRNAs are a class of non-coding RNAs that are 20-24 nucleotides in length, carrying out its biological functions by repressing the expression of target genes through base-pairing with endogenous mRNAs. In addition, miRNA genes have been characterized as unique proto-oncogenes or tumor-suppressor genes in carcinogenesis [6]. A miRNA can target multiple mRNAs, and, conversely, an mRNA can be targeted by multiple miRNAs. MiRNAs play energetic roles in regulation of almost every cellular process, including differentiation, epithelial-mesenchymal transition (EMT), proliferation, apoptosis, migration and angiogenesis. Considering their implications in multiple biological processes, further elucidation of the association between miRNAs and tumorigenesis could gain the identification of potential diagnostic and prognostic parameter. Exploring potential miRNAs target genes, clinical applications may achieve greater progress.

Comparative studies indicate that the miR-129 family is composed of two members: miR-129-1 (Gene ID: 406917) located on chromosome 7q32.1 and miR-129-2 (Gene ID: 406918) located on chromosome 11p11.2, which share the same seed sequence ‘‘UUUUUGC''. Also, miR-129-2 but miR-129-1 is located in a CpG island [7]. Remarkably, chromosome 7q32 is a frequently deleted region in various cancers [8]. Human miR-129-1 is among the seven miRNAs recognized in genomic regions near FRA7H, one of the fragile sites in chromosome 7q32 which is frequently deleted in some solid tumors [9]. MiR-129 family members are generally recognized as tumor suppressors with decreased expression in different tumors [10,11,12,13,14,15,16]. However, accumulating evidence indicates that miR-129 could play a dual role in tumorigenesis. In this review, the function of miR-129 and its relation to signaling pathways governing cancer-related phenotypes, such as EMT, proliferation, resistance to apoptosis and invasiveness in different cancers were discussed. The potential roles of miR-129 as biomarkers for cancer diagnosis and prognosis, and promising tools for cancer treatment were also addressed.

Biogenesis of MiR-129

MiRNAs are a large family of small non-coding RNA molecules that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs-miRNAs [17]. MiR-129 is transcribed by RNA polymerase II as part of capped and polyadenylated primary transcript (pri-miR-129) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miR-129 (pre-miR-129), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products [18]. The miR-129-1 precursor can be processed into mature miR-129-5p and miR-129-1-3p. Similar to miR-129-1, two mature miRNAs, miR-129-5p and miR-129-2-3p, which are processed from both 5 prime and 3' prime precursors of its pre-miRNA precursor, respectively (Fig. 1A). Not hard to find their 5' prime product, miR-129-5p, is the same. There is result further confirms that miR-129-5p is the main product and functional form of miR-129 [19]. After unwinding, one strand of the duplex is usually degraded, while the other strand, the mature miR-129, is incorporated into Argonaute and then incorporated into the RNA induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miR-129 and most commonly results in translational inhibition or destabilization of the target mRNA [20]. As shown in Figure, it obtains three main steps for pri-miRNAs to undergo before the production of the mature single-stranded form (Fig. 1B).

Fig. 1

The sequences and processing procedure of mature miR-129. (A) Mature miR-129 has different forms, according to which side of the strand they are derived from. And their 5' prime product, miR-129-5p, is based on same sequence. (B) Model for miR-129 processing: Drosha cuts Pri-miRNA into the stem-loop structural pre-miRNA, and then removes the loop region from pre-miRNA by Dicer, leaving the mature sequence.

http://www.karger.com/WebMaterial/ShowPic/524944

The regulatory function of miRNA depends on the complementarity between its seed region (nucleotide positions 2-8) and the target mRNA which can simultaneously regulate several targets with disparate functions, making them fundamental regulators of tumor onset, growth, and progression [21]. Partial or perfect complementarity results in translational repression and mRNA degradation, respectively. MiR-129 can downregulate multiple targets, which often belong to the same metabolic or signaling pathway, through its ability to bind to the 3' untranslated regions (UTRs) of target mRNAs, exerting its effects as a master switch for regulation of gene expression.

The Roles of MiR-129 in Human Cancers

Cancer initiation and progression involve dysregulation of miRNAs that can function as oncogenes or tumor suppressors. MiR-129 family members have been reported to function as both tumor suppressor and oncogene in multiple human cancers. Moreover, there is an evolutionarily conserved signal transduction cascade involved in the control of numerous fundamental cellular processes (Table 1). For instance, miR-129 expression level is much lower in tumor cell lines or primary tumor tissues in colorectal cancer (CRC), neural, pilocytic astrocytoma (PA), pediatric brain tumors, neuroendocrine neoplasms (NEN), etc, in compared with the corresponding controls [16,22,23,24,25,26]. In addition, different mature forms of miR-129 display diverse expressions. Single microRNA RT-qPCR was conducted on ormalin-fixed paraffin-embedded tumor biopsies, confirming higher expression of miR-129-2-3p and in PCFCL as compared to PCLBCL-LT [27]. Yu et al. reported that miR-129-1-3p, miR-129-2-3p, and miR-129-5p expression levels in gastric cancer cells were significantly lower compared with those in normal gastric cells [19]. Importantly, their result indicated that miR-129-1-3p level in male patients was apparent lower than that in female [28]. Conversely, Chen et al. suggested that miR-129-3p, but not miR-129-5p, was frequently attenuated in human clear cell RCC (ccRCC), and chromophobe clear cell RCC (ccRCC) [29].

Table 1

Dysregulation of miR-129 and its common targets in human cancers

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MiR-129 generally functions as a tumor suppressor, however, it has also been presented to be up-regulated laryngeal squamous cell carcinoma and function as an oncogene [30]. By performing an initial genome-wide Solexa survey, Zhi et al. identified that miR-129-5p was significantly upregulated in the serum of acute myeloid leukemia (AML) patients compared with normal controls and underexpressed in human hematopoietic stem cells, with EIF2C3 and CAMTA1 identified as its targets, suggesting that miR-129-5p may act an important role in the genesis of AML [31]. MiR-129 was also identified as highly expressed in retinoblastoma, including hsa-miR-129-1, hsa-miR-129-2 [32]. It was confirmed that hsa-miR-129-5p was overexpressed in tregs, which from HCC patients and healthy controls [33]. In induced pluripotent stem (iPS) cells and retinal pigment epithelium (RPE) derived from induced pluripotent stem cells (iPS-RPE), miR-129-5p was upregulated, which may play a role in promoting differentiation and carcinogenesis [34]. Surprisingly, it was recently noted that diffuse large B cell lymphoma (DLBCL) patients with the GC subtype had higher levels of miR-129 compared to patients with the ABC subtype [35]. These data propose that tumor cells may secrete miR-129 into the extracellular environment via exosomes to diminish the anti-tumorigenic effect within the cells, leading the tumor cells to maintain their oncogenic propensities. The main pathways and functions of miR-129 are shown in Fig. 2.

Fig. 2

The molecular regulatory network of miR-129 in human cancers. The upstream regulation of miR-129 and its direct target genes or indirect downstream players are shown, together with their multiple functions in tumor cells (different colors).

http://www.karger.com/WebMaterial/ShowPic/524943

The Functions and Pathways Involving MiR-129 and Its Targets

DNA Methylation and MiR-129 Expression

Regulation of gene expression happens at both genetic and epigenetic levels. It is widely accepted that epigenetic regulation, including DNA methylation and histone modification, has significant roles in determining miRNA expression. DNA methylation is catalyzed via DNA methyltransferases (DNMTs) by adding a methyl group to the carbon-5 position of cytosine residues at the CpG dinucleotides of CpG islands on promoter or 5' region, leading to the transcriptional repression of downstream gene [36].

MiR-129-2 was reported to be dysregulated and heavily methylated in several types of cancers, including gastric, colorectal, lymphocytic leukaemia, endometrial, and liver cancer [37,38,39,40,41,42]. One investigation showed that miR-129-2 was frequently hypermethylated in HCC cells and clinical samples, offering a potential methylation marker for HCC diagnosis [10]. Another study identified the down-regulated expression of miR-129-2 in HCC tissues in a manner reversely correlated with the level of miR-129-2 methylation. SOX4 was proved to be a target of miR-129-2 and its overexpression in HCC tissues was associated with the epigenetic silencing of miR-129-2. In addition, SOX4 can heighten β-catenin/TCF activity by increasing β-catenin level in HepG2 cells [42]. At the same year, hsa-miR-129-2 was reported to be unequivocally hyper-methylated in HCC lines in comparison to immortalized hepatocytes and normal healthy liver samples [43]. Furthermore, in undifferentiated gastric cancer, miR-129 was down regulated [44]. It was demonstrated that miR-129-2 methylation could not only down-regulate the expression of its corresponding miRNA but also cause overexpression of SOX4, one of the targets of miR-129-2 in gastric cancer [37]. Meanwhile, Wu et al. found that the promoter region of miR-129-5p was even more hyper-methylated in gastric cancer multi-drug resistant (MDR) cell lines compared with the parent gastric cancer cell lines [14]. Using bioinformatics analysis and report gene assays, three members of MDR-related ABC transporters (ABCB1, ABCC5 and ABCG1) were discovered to be direct targets of miR-129-5p [14]. In endometrial cancer, reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA de-methylation resulted in decreased SOX4 expression [40]. Pronina et al. demonstrated, for the first time, the frequent hypermethylation of the miR-129-2 and SEMA3B genes in breast and ovarian cancers [45]. Seven cancer-associated genes located in 3p hot spots, including CHL1, NKIRAS1, RARB (isoform 2), GPX1, RHOA, SEMA3B, and RASSF1 (isoform A) were analyzed in breast and ovarian cancers. It was found that the level of miR-129-2 precursor was negatively correlated with the expression of its possible targets (RASSF1 (A), GPX1), but the methylation status of the miR-129-2 gene revealed a positive association with the expression of the same genes [45]. In addition, the hypermethylation of the CpG island upstream of miR-129-2 in glioma patients led to the down-regulation of miR-129-2 by targeting HMGB1. Besides, demethylation of miR-129-2 by 5-Aza-dC treatment augmented miR-129-2 expression in glioma cells [46]. Several other studies also demonstrated that the downregulation of miR-129-2 was generally through chromatin remodeling and DNA methylation in glioma cells, and miR-129-2 expression could be restored upon treatment with trichostatin A (a histone deadetylase inhibitor) [47]. By using bioinformatical prediction, three CPG islands in the region of miR-129-5p promoter were detected, and meaningfully higher expression of miR-129-5p and lower methylation level of miR-129-2 gene in osteosarcoma cells treated with 5-Aza-2- deoxycytidine (a potent DNA demethylating agent) than in those untreated cells were perceived. Demethylation of miR-129-2 gene could up-regulate the expression of miR-129-5p. Similar findings were reported in esophageal squamous cell carcinoma. Low-level expression of miR-129-3p in carcinoma was consistent with its hyper-methylation. Re-expression of miR-129-3p was achieved after treatment with 5-aza-2'-deoxycyti- dine in the EC9706 cell line, confirming the role of methylation of the 5' CpG region in regulating miR-129-3p expression [7]. Later on, Xiao et al. speculated that DNA methylation alters the expression of miR-129 in lung cancer and miR-129 was conferred the tumour suppressive potential [48]. Tan et al. reported that the promoter region of miR-129-5p could be potentially targeted by p53, whose malfunction was frequently detected in human cancers [49]. Meanwhile, multi-CpG-rich loci of TRPM3 promoter were retrieved by the UCSC genome browser, recommending that miR-129-5p downregulation might be associated with genomic methylation. Moreover, methylation of hsa-miR-129-2 CpG island was frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa [38]. Thus, the methylation of promoter CpG islands and the interaction between miR-129 and target mRNAs were considered two crucial epigenetic mechanisms for inducing gene and pathway deregulation in cancers.

MiR-129 and EMT

During the EMT process, the molecular repertoire of epithelial cells experience dramatic changes, such as cell-cell contacts or polarity, and adopt a mesenchymal phenotype of enlarged migratory behavior. Growing evidence has validated that EMT contributes to cancer development, metastasis and drug resistance [50]. The molecular mechanisms of EMT involve various aspects, including miRNAs. One systematic investigation presented that MCRS1 was directly and negatively regulated by miR-129. MCRS1 overexpression, which was specifically inhibited by miR-129, promoted EMT and metastasis in NSCLC [51]. Yu et al. found that down-regulation of miR-129-5p via the Twist1-Snail feedback loop stimulates the EMT and is associated with poor prognosis in breast cancer [13]. To sum up, in-depth understanding about the mechanisms how miR-129 affecting cancer cell phenotypes can be advantageous to harvest clarification of tumor progression.

MiR-129 and Cell Proliferation

One of the most significant characteristics of cancer cells is uncontrolled cell proliferation. Recent studies have shown that miR-129 have important roles in cell proliferation. It was reported that miR-129 levels were much depressed in cancer cell lines or primary tumors derived from gastric, neural, or colorectal tissue than that in corresponding normal tissues [16,23 ,44,52]. In glioma cells, miR-129-2 could function as a tumor suppressor by targeting HMGB1. Reintroducing of miR-129-2 suppressed cell growth [46]. Consistently, restoration of miR-129-2 restrained glioma cell proliferation partially through repressing of some major oncogenic genes, such as PDGFRa and Foxp1 [47]. Importantly, inhibition of autophagic flux induced by miR-129 or E2F7 rescued the glioma cell proliferation. Xiong et al. suggested that miR-129 or E2F7 had this antiproliferative function partially via inducing Beclin-1-mediated autophagy [53]. Furthermore, overexpression of miR-129-2 in HepG2 decreased cell proliferation and clonogenicity, while co-expression with SOX4 could partially reverse those antitumor effects [42]. SOX4 belongs to the SRY-related HMG-box (SOX) transcription factor family and is critically involved in controlling cell fate and differentiation in major developmental processes. SOX4 upregulation may be a critical determinant of cancer progression [54,55]. In addition, strong evidence was found that miR-129-2 could suppress proliferation of esophageal carcinoma cells through downregulation of SOX4 [56].

Levels of miR-129 appear to be associated with the differentiation status of tumors. For example, miR-129 expression was depressed in nonfunctioning pituitary tumors than in the more differentiated growth hormone-secreting pituitary adenomas [57]. Ectopic overexpression of miR-129-5p remarkably reduced the proliferation activity of endometrial cancer cells and bladder cancer cells [40]. Coincidentally, miR-129 exerted significant growth inhibition and provoked cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines [11]. Another recent study showed that transfection of miR-129-5p significantly diminished the proliferation of endometrial cancer cells [40]. A novel regulatory mechanism of NTS/NTSR1, an upstream signaling of miRNAs and c-Myc, was detected in glioblastoma progression. Glioma cell proliferation was impaired with inhibition of the NTSR1 function or the upregulation of miR-129-3p [58]. One study by Tan et al. indicated that miR-129-5p directly repressed YAP and TAZ expression, inactivated TEA domain (TEAD) and led to the subsequent inhibition of ovarian cancer cell proliferation, survival and tumorigenicity [49]. Interestingly, miR-129-5p was found to be involved in downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A, suppressing the growth of LSCC by targeting APC [30]. Shen et al. proved that miR-129-5p could directly inhibit STAT3 expression and play an important role in the proliferation of LSCC [59]. According to the Cell Titer-Glo assay, overexpression of hsa-miR-129 caused meaningful reduction in cell proliferation in glioma cell lines [60]. Similarly, Kouhkan et al. demonstrated that miR-129-1 could impede the proliferation of GBM cells in vitro[61]. Another study indicated that miR-129-1-3p promoted cell growth of human gastric cancer cell lines by targeting PDCD2 [62], which could function as a tumor suppressor gene and inhibit cell proliferation in lymphomas [63]. MiR-129 was found commonly down-regulated in HCC with ability of suppressing HCC cell proliferation. As the target gene of miR-129, PAK5, was frequently up-regulated and could promote cell viability [64]. Ectopic expression of miR-129-5p significantly suppressed cell viability in MTC cells through decreasing the phosphorylated AKT. Furthermore, miR-129-5p pointedly decreased MTC cell growth in vivo, in parallel with the inhibited level of REar-ranged during Transfection (RET) protein [65]. In NEN, knockdown of EGR1 and G3BP1 mimicked the growth inhibition induced by miR-129-5p [26]. Above-mentioned findings indicate that miR-129 plays an indispensable role in cell proliferation. Dysregulation of miR-129 in cancers affects cell proliferation by targeting diverse genes and regulates the balance of interactions in cell growth.

MiR-129 and Cell Cycle

The cell cycle is a vital procedure by which a single-celled fertilized egg develops into a mature organism. Each stage of the cell cycle has a dissimilar set of specialized biochemical processes that prepare the cell for initiation of cell division. There is no doubt that if one phase get too far off track from the natural circadian rhythm it will throw our body out of disorder involved in cancers. Wu et al. found that lentiviral-mediated overexpression of miR-129 in lung epithelial cells resulted in significant G1 phase arrest that eventually led to cell death by targeting Cdk6, a cell cycle-associated protein involved in G1-S transition [66]. By targeting SOX4 proto-oncogene, increased miR-129-2 function was sufficient to overwhelm HCC cancer cell proliferation by inducing G1 arrest [42]. It was also suggested that increased miR-129 level resulted in significant G0/G1 phase arrest in gastric cancer cells. Interestingly expression of SOX4 was inversely associated with that of miR-129-2-3p and miR-129-5p but not of miR-129-1-3p [19]. Xiao et al. proposed that lung cancer cells were profoundly arrested at G2/M phase of cell cycle after miR-129 overexpression through inactivation of CDK1 [48]. In addition, the effects of miR-129-5p overexpression on the cell cycle progression in LSCC cells were also investigated. It was found that the number of Hep-2 cells in the G2/M phase was declined compared to the control cells at 24h post-transfection, suggesting an increase in the number of cancer cells entering the S phase [59]. Overexpression of STAT3 could trigger disorders of the cell cycle, resulting in cell transformation due to the upregulation of cyclinD1 [67]. Recently, it was reported that miR-129-1 could act as a tumor suppressor and induce cell cycle arrest of GBM cancer cells through targeting IGF2BP3, MAPK1 and CDK6 [61]. Meanwhile, ectopic expression of miR-129 is found to induce cell-cycle arrest in CRC cells [16]. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion. It is clear that miR-129 plays an important part in tumorigenesis and contributes to destroy the cell cycle.

MiR-129 and Apoptosis

Cellular senescence and apoptosis act as barriers to cancer progression. Cells would be induced apoptosis if the intracellular environment were persistent disordered or extremely worse. The ability of cancer cells to escape from apoptosis is complex. As mentioned above, SOX4 was one of the direct target genes of miR-129-2 in gastric and endometrial cancers and was considered as an oncogene because its overexpression increased the transforming ability in immortalized prostate cell. SOX4 knockdown and/or restoration of miR-129-2 reduced cancer cell viability with increased apoptosis in both adenoid cystic carcinoma [68] and gastric cancer cells [37]. MiR-129-2 was also reported to be downregulated in human glioma cancer, partially due to its DNA promoter hypermethylation. Overexpression of miR-129-2 promoted cell apoptosis at least partially through targeting the oncogene HMGB1 [46]. It was demonstrated that the apoptosis rate of cancer cells could be increased when STAT3 expression was decreased as a result of upregulation of miR-129-5p in LSCC cells [59]. MiR-129-5p could also induce cell apoptosis of MTC cells in vitro, suggesting a possible tumor suppressive role of miR-129-5p [65]. In colorectal cancer, Karaayvaz et al. discovered a novel mechanism mediated by miR-129 to trigger apoptosis by suppressing a key anti-apoptotic protein, B-cell lymphoma 2 (BCL2) [16], which was a central player in apoptosis of eukaryotic cells favoring survival by inhibiting cell death [69]. It was further found that piceatannol could stimulate the expression of miR-129, trigger down-regulation of Bcl-2, up-regulation of Bax and activation of caspase-3, and ultimately induce the apoptosis in CRC cells [70]. MiR-129-5p was also reported to inhibit the expression of VCP directly and play an important role in cell apoptosis of HCC [71]. Luo et al. observed that miR-129-5p could enhance radio-sensitivity of breast cancer cells through apoptosis promotion [72].

MiR-129 and Metastasis

The process of metastasis involves multiple sequential steps, which undergoes extravasation and initiate either intra-vascular or extra-vascular proliferation at ectopic sites (colonization) in response to local growth factors [73,74,75]. HMGB1 can induce cell growth and migration via its intracellular signaling pathways including NF-κB, MAPK, and ERK. It has been reported that miR-129-2 could directly target HMGB1 and inhibit its expression in glioma cells [46]. Long et al. exhibited a significant negative connection between expression of miR-129-5p and mobility of OS cells, suggesting a pivotal role of miR-129-5p in OS cell migration and invasion [76]. Further studies indicated that the enhanced expression of miR-129-5p could restrain the degradation of IkBa and reduce the migration of HCC cells by suppressing the expression of VCP [71]. Besides, ectopic restoration of miR-129-5p inhibited cellular migration and invasion via direct binding of v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1) [77]. In lung cancers, ectopic expression of miR-129 not only prevented cell migration, but also hampered the cell invasion, in line with the observations after DAC treatment [48]. Upregulation of miR-129-5p suppressed LSCC invasion and migration by affecting STAT3 expression [59]. In esophageal tumor tissues, miR-129-2 overexpression inhibited cell invasion and migration, and deregulation of miR-129-2 resulted in aberrant SOX4 expression. Additionally, miR-129-2 expression was found associated with advanced clinical TNM stage, lymph node metastasis and distal metastasis [56]. Similarly, Zhai et al. proposed that miR-129 could suppress invasion by direct targeting PAK5 [64]. Meanwhile, it was also found that HCC patients with lower expression of miR-129 tended to have more advance stages and there is also noteworthy difference between the miR-129 expression in metastatic tumors and non-metastatic tumors. Dossing et al. reported that down-regulation of PAK5 repressed migration and invasion of glioma cells via Egr1-MMP2 pathway, a testified target of miR-129 [26]. Wang et al. revealed that miR-129-1-3p could inhibit migration by targeting bradykinin receptor B2 (BDKRB2) in gastric cancer [78]. Ectopic expression of miR-129-5p led to suppressed migration in MTC cells, and restoration of RET protein expression counteracted the effects caused by over-expression of miR-129-5p [65]. MiR-129-3p expression differed obviously between malignant and benign kidney tumors. Notably, low miR-129-3p levels were correlated with short disease-free and overall survival. Ectopic expression of miR-129-3p robustly impaired RCC cell invasive and migratory properties. MiR-129-3p exerted its anti-metastatic function through modulating multiple metastasis-related genes, including SOX4, phosphorylation of focal adhesion kinase and MMP-2/9 expression [29]. MMP9 was also proved a target gene of miR-129 to govern metastasis in NSCLC cells [79]. Understanding the mechanisms by which miR-129 is involved in tumorigenesis will lead to new directions of cancer treatment.

MiR-129 and Autophagy

Autophagy is a catabolic biological event characterized by degradation and recycling of cellular compartments for new cell formation, which progress cell survival in response to stresses, such as starvation, hypoxia etc. harsh environment, toxin exposure and nutrient deprivation [80]. However, many cases of autophagy can lead to autophagy cell death. Recently, autophagy has been publicized to play a critical role in tumorigenesis. MiRNAs were identified to modulate cancer chemo- and radio-sensitivity via autophagy [81,82]. It was reported that norcantharidin (NCTD) could suppress miR-129-5p to provoke autophagic cell death and cell proliferation arrest in prostate cancer cells, which may increase cell autophagy via Beclin-1 as an initial cellular response to the toxicity of NCTD [83]. MiR-129-5p overexpression induced higher level of autophagy and lower response to irradiation with HMGB1 as a direct functional target in breast cancer cells [72]. In glioma cells, forced expression of miR-129 could trigger autophagic flux by depressing Notch-1 [84] and subsequently restrain the activity of mammalian target of rapamycin (mTOR) and upregulate Beclin-1. Likewise, E2F transcription factor 7 (E2F7) could also induce autophagic flux by upregulating Beclin-1 and mediating miR-129-induced autophagy. Furthermore, knockdown of Notch-1 could upregulate the expression of E2F7. In brief, these findings classified an innovative function of miR-129 as an effective inducer of autophagy through a novel Notch-1/E2F7/Beclin-1 axis in glioma [53].

Clinical Implication of MiRNAs in Human Cancers

MiR-129 As A Biomarker for Cancer Diagnosis and Prognosis

The foremost cause of poor prognosis and high recurrence rate of cancer is the high rate of metastasis, calling for novel biomarkers to identify these patients in advance [85,86]. DNA methylation changes have been described to appear early in carcinogenesis and are potentially worthy early indicators of carcinoma. DNA methylation may become a potential indicator in early-stage ESCC by improving the sensitivity, and the sensitivity had not been significantly improved. MiR-129-2 had a higher methylation ratio, indicating its potential as a methylation biomarker in early diagnosis of ESCC [7]. Considering that miR-129-3p was markedly decreased in ccRCC, it may act as a promising diagnostic biomarker for distinguishing ccRCC from benign tumors and normal tissues and an independent prognostic biomarker in ccRCC [29]. As shown in a recent study, the detection of gastric juice miR-129-1-3p and miR-129-2-3p may be an innovative choice for the diagnosis of gastric cancer [28]. Another study delivered latest evidence for a miRNA-driven antitumor effect of HDACi and proposed that miR-129-5p might be valuable in defining susceptible and resistant tumors following the HDACi-induced response in tumor cells [87].

Tan et al. demonstrated that downregulation of miR-129-5p highly correlated with ovarian cancer progression with poor prognosis [49]. This finding also uncovered a novel mechanism for YAP/TAZ overexpression, and may suggest new targets for clinical intervention in human cancers. There was also evidence that expression of SOX4 in pancreatic cancers correlated with poor survival, and was strongly associated with co-repressed expression of miRNA-129-2 [88]. It was revealed that miR-129-3p was associated with the International Federation of Gynecology and Obstetrics (FIGO) stage, and lower expression level of mi-129-3p was correlated with a poor prognosis of EOC [89]. MiR-129-5p was involved in the down-regulation of lncRNA-AC130710 expression in gastric cancer cells. As one of lncRNAs, the levels of AC130710 were associated with tumor size, TNM stages, distal metastasis, and tissue CEA expression. So, AC130710 targeting by miR-129-5p played crucial roles during cancer progression and may be a potential tumor marker for gastric cancer [90,91]. Liu et al. revealed that the expression of VCP was directly downregulated by miR-129-5p and this regulation played a critical role in the progression of HCC [71]. Since the level of VCP and miR-129-5p in HCC samples was significantly distinctive from that in adjacent normal tissues, the two molecules may be novel indicators for prediction of the genesis of HCC. Katayama et al. referred miR-129 as a novel candidate for HCC biomarkers regardless of virus infection [92]. Additionally, a negative correlation between miR-129-5p expression levels and ETS1 levels was reported in HCC tissues, suggesting that miR-129-5p could be a helpful prognostic marker and/or therapeutic target in HCC [77]. In particular, the expression level of miRNA-129 differed significantly between the different stages, and a high expression level of miRNA-129 might be associated with the tumor burden, suggesting the potential of miRNA-129 serving as an independent monitoring indicator for the prognosis of ESCC [93,94]. It was also discovered that decreased expression of miR-129-3p was associated with a worse prognosis in renal cell carcinoma [95]. In genomic profiling of miRNAs in bladder cancer, the association between miR-129 expression and poor outcomes was observed. Luciferase assays further demonstrated the direct link between miR-129 and the two putative targets GALNT1 and SOX4. These findings might form a basis for clinical development of new biomarkers for bladder cancer [11]. It was estimated that DLBCL patients with low miRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival compared with patients with high expression. Patients treated with R-CHOP with low miRNA-129-5p expression had a notably shorter overall survival compared to those with high miRNA-129-5p expression [96]. MiR-129-5p expression was observed to be negatively correlated with Twist1 and Snail in breast cancer, and miR-129-5p down-regulation resulted in advanced clinical stage and poor prognosis in patients with breast cancer [13]. Taken together, miR-129 represents a new biomarker for detection and diagnosis of diverse cancers and might serve as a novel prognostic marker.

MiR-129 As A therapeutic target for Human Cancers

Resistance to conventional cancer treatment denotes that innovative approaches are required to improve OS [97]. The mechanisms that have been extensively investigated at both levels of genes and proteins would contribute to improve the clinical treatment [98]. Several reports have shown that miR-129-based therapeutics could help to achieve the multi-targeted anticancer therapeutic strategy. It is reported that miR-129-2 could function as a tumor suppressor in glioma cells and was down-regulated by DNA methylation by directly targeting HMGB1, PDGFRa, and Foxp1, providing a novel therapeutic strategy for treatment of glioma [46,47]. Another study suggested that demethylation of miR-129-2 gene could up-regulate the expression of miR-129-5p and subsequently depress OS metastasis by inhibiting VCP [76]. Huang et al. found that compared with the parent SGC7901/VCR cells, expression of miR-129-5p was restored in SGC7901/VCR gastric cancer multi-drug resistant cell line treated by de-methylation reagent (5-AZA-dC), indicating the important role of hyper-methylation of miR-129-5p CpG island in the development of gastric cancer chemo-resistance by targeting MDR related ABC transporters [40]. NTS/NTSR1 could regulate a broad range of normal physiological processes, and as a down-stream regulator of the NTS/NTSR1/c-Myc/miRNA/CDK axis, miR-129 might be a more ideal target with particular effects for glioblastoma therapy [58]. Understanding the particular role of miR-129- 5p in the pathogenesis of ovarian cancer and activation of the YAP/TAZ signaling pathway promised to spread our knowledge of the biological basis of cancer development, and may also allow the improvement of new therapeutic strategies against ovarian cancer [49]. It was reported that miR-129-5p was down-regulated and could repress RET directly in MTC cells. Increased level of miR-129-5p significantly constrained the expression of RET and phosphorylated AKT, suggesting a tumor suppressor role in medullary thyroid cancers harboring oncogenic [65]. In NSCLC, miR-129 restrained EGFR signaling through PI3K signal transduction cascades to regulate MMP9 expression. Thus, the collection of miR-129, EGFR, and MMP9 performed to be promising therapeutic targets for blocking the metastasis of NSCLC [79].

It was recently found that three members of MDR related ABC transporters (ABCB1, ABCC5 and ABCG1) were targeted by miR-129-5p, which was hyper-methylated in gastric cancer MDR cell lines. Thus, hyper-methylation of miR-129-5p CpG island might be a potential therapeutic target in preventing the chemo-resistance of gastric cancer [40]. MiR-129 was also reported to sensitize colorectal carcinoma cells to 5-FU treatment by decreasing the expression of BCL2 [99]. Notably, miR-129 levels were dramatically diminished in stage 3 and stage 4 cancers, which illustrated that loss of miR-129 expression was significantly connected with the progression of CRC [16]. It has been proved that upregulation of E2F family proteins contributed to 5-FU resistance [100]. As 5-FU-based chemotherapy was still the main treatment option for advanced metastatic CRC, E2F3 suppressed by miR-129 could offer a new modulation strategy to overwhelmed chemoresistance [16]. Zhang et al. demonstrated that restoration of CP110 expression in breast cancer cells by miR-129 overexpression rendered the cells sensitive to docetaxel treatment [12]. Another study discovered the ability of piceatannol to depress colorectal cancer growth and clarified the participation of miR-129 in the anti-cancer action of piceatannol. The findings further suggested that piceatannol could be considered as a hopeful anticancer agent for CRC [70]. As mentioned previously, the miR-129-5p/HMGB1 axis could regulate irradiation-induced autophagy and might be a principal pathway in regulating radiosensitivity of breast cancer [72]. The results suggested that miR-129 could serve not only as prognostic biomarkers for cancer treatment but also as interventional agents to modulate desired chemo- or radiosensitivity of tumor cells.

Conclusion and Future Directions

Numerous studies have been committed to discover cancer pathogenesis and investigate efficient treatment strategies [101,102]. In the past decade, miR-129 family members have emerged as notable players involved in carcinogenesis. Data from current reports also support this speculation. This gathering evidence indicates that miR-129 is an effective tumor suppressor in numerous cancers, despite its oncogenic function in some cases. To the best of our knowledge, this is the first review that systematically and mainly focuses on the role of miR-129 in cancer development and clinical applications.

Collective studies recommend functional links between miR-129 and the expression of its targets in diverse tumors cells. Ectopic expression of miR-129 and its subtypes are related with process and prognosis of cancers. Since its location in cancer-associated genomic regions, miR-129 plays a controversial role in various cancers. Whatever the oncogenic or tumor-suppressive role of miR-129, miR-129-1-3p, miR-129-2-3p and miR-129-5p, aberrant expression both participate in carcinogenesis and represent significant untapped biomarkers in the diagnostic and prognostic of various cancers, as well as potential targets of miR-129-mediated therapies. Knowledge about the functional roles of specific miR-129 is steadily increasing; however, knowledge is still missing for a large part of the actual benefit to our clinic patients. Fortunately, miR-129 can improve the sensitivity of cancer cells to chemotherapy agents, implying that a novel strategy for overwhelming chemoresistance may be promising. Ideally, miR-129 could be a therapeutic tool, due to its ability to target numerous genes. Besides, most probable miR-129-target gene pairs might have similar functional effects. It is recognized that it is difficult to identify the downstream targets of miR-129. Thus, it is necessary to appreciate that the importance of miR-129 co-regulation network on various signal pathways, which might help in designing more specific therapeutic targets and drugs. In brief, further experiments are needed to study the functional relevance of miR-129 in cancers and whether more detailed mechanisms in cancers by regulated expression of miR129 and its subtypes might be of therapeutic benefit.

Acknowledgements

The work was supported by grants from the National Natural Science Foundation of China (No.81172335, 81472266, and 81301913), the Excellent Youth Foundation of Jiangsu Province, China (BK20140032), and the Natural Science Foundation of Jiangsu Province, China (BK20130698).

Disclosure Statement

The authors declare that they have no conflicts of interest related to this work.


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Author Contacts

Rui Wang, MD,

Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing

University, No.315 Zhongshan East Road, Nanjing, Jiangsu 210002, (China)

Tel. +86-25-80860072, E-Mail wangrui218@163.com / chenlongbang@yeah.net


Article / Publication Details

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Abstract of Review

Accepted: September 05, 2016
Published online: November 02, 2016
Issue release date: November 2016

Number of Print Pages: 17
Number of Figures: 2
Number of Tables: 1

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: https://www.karger.com/CPB


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