BackgroundColorectal cancer (CRC) is one of the most common malignancies in the world. microRNA-140-5p (miR-140) has been shown to be involved in cartilage development and osteoarthritis (OA) pathogenesis. Some contradictions still exist concerning the role of miR-140 in tumor progression and metastasis, and the underlying mechanism is uncertain.MethodsImmunohistochemistry was performed to determine the expressions of ADAMTS5 and IGFBP5 in CRC tissues. Human CRC cell lines HCT116 and RKO were transfected with miR-140 mimic, inhibitor, or small interfering RNA (siRNA) against ADAMTS5 or IGFBP5, respectively, using oligofectamine or lipofectamine 2000. Scratch-wound assay and transwell migration and invasion assays were used to evaluate the effects of miR-140 on the capabilities of migration and invasion. The levels of miR-140 and ADAMTS5 and IGFBP5 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of ADAMTS5 and IGFBP5 proteins.ResultsmiR-140 was significantly reduced, whereas ADAMTS5 and IGFBP5 were upregulated, in the human CRC tissues compared to the corresponding normal colorectal mucosa. miR-140 downregulation and ADAMTS5 or IGFBP5 overexpression were associated with the advanced TNM stage and distant metastasis of CRC. There was a reverse correlation between miR-140 levels and ADAMTS5 and IGFBP5 expression in CRC tissues. ADAMTS5 and IGFBP5 were downregulated by miR-140 at both the protein and mRNA levels in the CRC cell lines. The gain-of- and loss-of-function studies showed that miR-140 inhibited CRC cell migratory and invasive capacities at least partially via downregulating the expression of ADAMTS5 and IGFBP5.ConclusionsThese findings suggest that miR-140 suppresses CRC progression and metastasis, possibly through downregulating ADAMTS5 and IGFBP5. miR-140 might be a potential therapeutic candidate for the treatment of CRC.
MicroRNA-140, a cartilage-specific microRNA, has recently been implicated in the cancer progression. However, the comprehensive role of miR-140 in the invasion and metastasis of colorectal cancer (CRC) is still not fully understood. In this study, we confirmed that miR-140 downregulates SMAD family member 3 (Smad3), which is a key downstream effector of the TGF-β signaling pathway, at the translational level in the CRC cell lines. Ectopic expression of miR-140 inhibits the process of epithelial-mesenchymal transition (EMT), at least partially through targeting Smad3, and induces the suppression of migratory and invasive capacities of CRC cells in vitro. miR-140 also attenuates CRC cell proliferation possibly via downregulating Samd3. Furthermore, overexpression of miR-140 inhibits the tumor formation and metastasis of CRC in vivo, and silenced Smad3 has the similar effect. Additionally, miR-140 expression is decreased in the clinical primary CRC specimens and appears as a progressive reduction in the metastatic specimens, whereas Smad3 is overexpressed in the CRC samples. Taken together, our findings suggest that miR-140 might be a key suppressor of CRC progression and metastasis through inhibiting EMT process by targeting Smad3. miR-140 may represent a novel candidate for CRC treatment.
Abstract. microRNAs (miRNAs) have been proven to play key regulatory roles in hepatocarcinogenesis. In the present study, the possible role of microRNA-450a (miR-450a) in hepatocarcinogenesis was investigated. Our study revealed that miR-450a was significantly down-regulated in hepatocellular carcinoma (HCC) tissues compared with that in normal liver (NL) and para-tumorous (PT) tissues, and miR-450a expression in HepG2 cells was significantly lower than that in L02 cells. Both the mRNA and protein levels of the miR-450a potential target gene, DNA methyltransferase 3a (DNMT3a), were obviously higher in HCC compared with levels in the NL and PT tissues. We further identified DNMT3a as the direct target gene for miR-450a, and ectopic miR-450a expression in HepG2 cells caused the down-regulation of DNMT3a and an inhibition of cell proliferation. Taken together, these findings suggest that miR-450a plays an important regulatory role in hepatocarcinogenesis through inhibition of DNMT3a expression, and miR-450a may be a potential target for the treatment of HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, especially in East Asia, including China. However, the pathogenesis of hepatocarcinogenesis is far from clear. microRNAs (miRNAs) are a type of highly conserved non-coding small RNAs which regulate gene expression at the post-transcriptional level. It is now clear that miRNAs can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, and apoptotic and viral infection. Recently, miRNAs have been found to play pivotal roles in many malignancies including HCC development (1-9). The presence of a molecular prognostic miRNA signature in primary HCC clinical specimens has also been confirmed by several recent studies (4,6,7,(10)(11)(12), and many miRNAs have been found to play important regulatory roles in hepatocarcinogenesis.Our previous study found that miRNA-602 has an important regulatory activity in HBV-mediated hepatocarcinogenesis by inhibiting the tumor-suppressive gene RASSF1A from very early stages of chronic HBV hepatitis to HBV-positive cirrhosis to HCC (13). In this study, the expression of miRNA-450a and its potential target, DNA methyltransferase 3a (DNMT3a), was investigated in HCC. Materials and methodsPatients and cell lines. Histologically normal liver samples were obtained by biopsy during surgery from eight patients with gallbladder stones. Thirty-four HCC and corresponding non-malignant para-tumorous specimens were collected by radical hepatectomy. All tissues were obtained with informed consent from the patients, and were verified by biochemistry and pathological examination. The study was approved by the Institutional Review Board of Tongji Medical College, Huazhong University of Science and Technology (China). The cell lines, HepG2 and L02, were cultured in RMPI-1640 with 10% fetal bovine serum.microRNA arrays. miR-450a from 8 normal livers, 34 HCC, and corresponding non-tumor...
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