Tumor suppressive microRNA138 contributes to cell migration and invasion through its targeting of vimentin in renal cell carcinoma. Int J Oncol

Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
International Journal of Oncology (Impact Factor: 3.03). 07/2012; 41(3):805-17. DOI: 10.3892/ijo.2012.1543
Source: PubMed


Many studies have recently suggested that microRNAs (miRNAs) contribute to the development of various types of human cancers as well as to their invasive and metastatic capacities. Previously, our miRNA expression signature of renal cell carcinoma (RCC) revealed that microRNA‑138 (miR‑138) was significantly reduced in cancer cells. The aim of the present study was to investigate the functional significance of miR‑138 and to identify its target genes in RCC cells. Restoration of mature miR‑138 in two RCC cell lines (A498 and 786‑O) caused changes in the bleb-like cell morphology, characteristics of the epithelial-mesenchymal transition (EMT). Restoration also significantly inhibited migration and invasion in the two RCC cell lines, suggesting that miR‑138 functions as a tumor suppressor. Genome-wide gene expression analysis (miR‑138 transfectants and RCC clinical specimens) and TargetScan database studies showed that vimentin (VIM) is a promising candidate target gene of miR‑138. It is well known that VIM is one of the most widely expressed mammalian intermediate filament proteins. Recent studies showed that VIM functions in cell adhesion, migration, survival and cell signaling processes via dynamic assembly/disassembly in cancer cells. We focused on VIM and investigated whether VIM was regulated by tumor suppressive miR‑138 and contributed to cancer cell migration and invasion in RCC cells. Restoration of miR‑138 in RCC cell lines suppressed VIM expression at both the mRNA and protein levels. Silencing studies of VIM in RCC cell lines demonstrated significant inhibition of cell migration and invasion activities in si-VIM transfectants. In clinical specimens of RCC, the expression levels of VIM were significantly upregulated in cancer tissues compared to adjacent non-cancerous tissues. Furthermore, immunohistochemistry showed that VIM expression levels in RCC specimens were significantly higher than those in normal renal tissues. These data suggest that VIM may function as an oncogene and is regulated by tumor suppressive miR‑138. The existence of a tumor suppressive miR‑138-mediated oncogenic pathway provides new insights into the potential mechanisms of RCC oncogenesis and metastasis.

Download full-text


Available from: Nijiro Nohata
  • Source
    • "Additionally, vimentin was a sensitive and specific marker for conventional renal cell carcinoma. Vimentin contributes to cancer cell migration, invasion, and metastasis (Yamasaki et al., 2012). The JAK2/STAT3/vimentin signaling pathway participates in regulating the proliferation and migration of human colon cancer cells (Xu et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS); and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity.
    Full-text · Article · Sep 2014 · Toxicology and Applied Pharmacology
  • Source
    • "Another important example of down-regulation of tumor-suppressor-miRNAs is miR-138 that targets vimentin (78). Vimentin participates to cancer cell migration, metastasis, and invasion and it is overexpressed in human specimens of RCC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor formation is a complex process that occurs in different steps and involves many cell types, including tumor cells, endothelial cells, and inflammatory cells, which interact to promote growth of the tumor mass and metastasization. Epigenetic alterations occurring in transformed cells result in de-regulation of miRNA expression (a class of small non-coding RNA that regulates multiple functions), which contributes to tumorigenesis. The specific miRNAs, which have an aberrant expression in tumors, are defined as oncomiRNAs, and may be either over- or under-expressed, but down-regulation is most commonly observed. Renal cell carcinoma (RCC) is a frequent form of urologic tumor, associated with an alteration of multiple signaling pathways. Many molecules involved in the progression of RCCs, such as HIF, VEGF, or mammalian target of rapamycin, are possible targets of de-regulated miRNAs. Within tumor mass, the cancer stem cell (CSC) population is a fundamental component that promotes tumor growth. The CSC hypothesis postulates that CSCs have the unique ability to self-renew and to maintain tumor growth and metastasis. CSCs present in RCC were shown to express the mesenchymal stem cell marker CD105 and to exhibit self-renewal and clonogenic properties, as well as the ability to generate serially transplantable tumors. The phenotype of CSC has been related to the potential to undergo the epithelial-mesenchymal transition, which has been linked to the expression pattern of tumorigenic miRNAs or down-regulation of anti-tumor miRNAs. In addition, the pattern of circulating miRNAs may allow discrimination between healthy and tumor patients. Therefore, a miRNA signature may be used as a tumor biomarker for cancer diagnosis, as well as to classify the risk of relapse and metastasis, and for a guide for therapy.
    Full-text · Article · Mar 2014 · Frontiers in Oncology
  • Source
    • "Furthermore, MiR-17-3p [88], as well as miR-124 and miR-203 [89], repressed vimentin expression by targeting its 3′UTR. miR-138 suppressed cell migration and invasion by directly targeting vimentin in renal cell carcinoma [90] and squamous cell carcinoma cells [91]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease.
    Full-text · Article · Mar 2014 · Journal of Hematology & Oncology
Show more