407015

MIR26A1

BACKGROUND: Our previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). The direct roles of miR-26a on tumor cell invasion remain poorly understood. In this study, we aim to explore the mechanism of miR-26a in modulating epithelial-mesenchymal transition (EMT) in HCC. METHODS: In vitro cell morphology and cell migration were compared between the hepatoma cell lines HCCLM3 and HepG2, which were established in the previous study. Overexpression and down-regulation of miR-26a were induced in these cell lines, and Western blot and immunofluorescence assays were used to detect the expression of EMT markers. Xenograft nude mouse models were used to observe tumor growth and pulmonary metastasis. Immunohistochemical assays were conducted to study the relationships between miR-26a expression and enhancer of zeste homolog 2 (EZH2) and E-cadherin expression in human HCC samples. RESULTS: Down-regulation of miR-26a in HCCLM3 and HepG2 cells resulted in an EMT-like cell morphology and high motility in vitro and increased in tumor growth and pulmonary metastasis in vivo. Through down-regulation of EZH2 expression and up-regulation of E-cadherin expression, miR-26a inhibited the EMT process in vitro and in vivo. Luciferase reporter assay showed that miR-26a directly interacted with EZH2 messenger RNA (mRNA). Furthermore, the expression of miR-26a was positively correlated with E-cadherin expression and inversely correlated with EZH2 expression in human HCC tissue. CONCLUSIONS: miR-26a inhibited the EMT process in HCC by down-regulating EZH2 expression.

UNLABELLED: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with unknown cause or cure. Although some microRNAs (miRNAs), such as miR-26a and let-7d, have been confirmed, the contribution to the pathophysiological processes of IPF, the roles of miRNAs and intrinsic links between them in fibrotic lung diseases are not yet well understood. In this study, we found that Lin28B could induce the process of epithelial-mesenchymal transition (EMT) by inhibiting let-7d, whereas inhibition of Lin28B mitigated TGF-beta1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of miR-26a could simultaneously enhance the expression of let-7d in A549 cells, and further study confirmed that Lin28B was one of the direct targets of miR-26a, which mediates, at least in part, the regulatory effects of miR-26a on the biogenesis of let-7d. Finally, we constructed a regulatory network among miRNAs involved in the progression of IPF. Taken together, our study deciphered the essential role of Lin28B in the pathogenesis of EMT, and unraveled a novel mechanism that miR-26a is a modulator of let-7d. This study also defines the miRNAs network involved in IPF, which may have implications for developing new strategies for pulmonary fibrosis. KEY MESSAGE: Upregulation of Lin28B contributes to idiopathic pulmonary fibrosis. Lin28B causes epithelial-mesenchymal transition (EMT) by inhibition of let-7d. Lin28B is one of the targets of microRNA-26a. miR-26a enhances the expression of let-7d via targeting regulation of Lin28B. A regulatory network among miRNAs involved in the progression of IPF.

OBJECTIVE: To determine the role of miR-26a-5p in tumor invasion and metastasis in hepatocellular carcinoma (HCC). METHODS: We evaluated miR-26a-5p expression in HCC tissues by quantitative PCR and then analyzed its clinical significance using a Cox regression model. Transwell and nude mouse models were used to examine tumor metastasis in vitro and in vivo, respectively. The relationship between miR-26a-5p and epithelial-mesenchymal transition was also investigated by q-PCR and western blot. RESULTS: Strong downregulation of miR-26a-5p was observed in tumor tissues compared to paired adjacent normal tissues. Moreover, patients with low miR-26a-5p expression had a significantly poorer prognosis than those with high expression. The multivariate analysis indicated that miR-26a-5p expression was an independent prognostic indicator. The experimental transwell model and athymic mouse model revealed that miR-26a-5p depressed tumor metastasis in vitro and in vivo, respectively. In addition, the decreased miR-26a-5p level observed in HCC was associated with reduced E-cadherin expression and upregulation of vimentin, which affects the molecular mechanism of EMT. CONCLUSION: Downregulation of miR-26a-5p promotes tumor metastasis by targeting EMT and influences the prognosis of HCC patients. Therefore, miR-26a-5p has potential as a new biomarker and therapeutic target.

BACKGROUND/AIMS: Accumulating evidence revealed that microRNAs (miRNAs) have been demonstrated as critical molecules in tumor development and progression. MiR-26a, located in a fragile chromosomal region associated with various human cancer, has been reported to be involved in regulating various cellular process, such as proliferation, apoptosis and invasion through targeting multiple oncogene. Docetaxel-mediated chemotherapy has been applied in improving the survival and prognosis of patients with advanced lung adenocarcinoma (LAD). However, chemoresistance remains a major impediment to clinical application of this agent. It has been presented that decreased miR-26a expression lead to cisplatin resistance and promoted growth and migration in human lung cancer. Enhancer of zeste homolog 2 (EZH2) is the target of miR-26a. The present study aimed to investigate the function of miR-26a/EZH2 in the acquisition of malignant behaviors of LAD. METHODS: MiR-26a and EZH2 expression levels in the dcetaxel-insensitive groups (n = 19) and the docetaxel-sensitive groups (n = 18) were assessed by qRT-PCR. Colony formation assay, flow cytometric analysis, wound healing assay, cell transwell assays and western blotting were performed to assess the effects of miR-26a on proliferation, apoptosis and epithelial-to-mesenchymal (EMT) phenotypes in docetaxel resistant LAD cells in vitro. Xenograft transplantation, immunohistochemistry, tunel assays and western blotting assays were employed to demonstrate the role of miR-26a in docetaxel resistant LAD cells in vivo. The expression level of EZH2 in docetaxel-resistant LAD cells and corresponding parental cells was detected by qRT-PCR and western blotting. The relationship between miR-26a and EZH2 was confirmed by luciferase reporter assay. And rescue assays were performed to further confirm that miRNA-26a contributes to the acquisition of malignant behaviors of docetaxel-resistant LAD cells through targeting EZH2. RESULTS: MiR-26a was significantly down-regulated in the dcetaxel-insensitive groups (n = 19) compared with the docetaxel-sensitive groups (n = 18) assessed by qRT-PCR. MiR-26a decreased the proliferation, increased the apoptosis rate and reversed EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro. EZH2 was confirmed as target of miR-26a. Rescue assays further verified that the function of miR-26a exerts in docetaxel-resistant LAD cells is through targeting EZH2. CONCLUSIONS: Our data revealed that overexpression of miR-26a in docetaxel-resistant LAD cells could decrease the proliferation, increase the apoptosis rate and reverse EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro and such function is partially exerted via downregulating EZH2. MiR-26a/EZH2 signal pathway makes contribute to the malignant phenotype of docetaxel-resistant of LAD cells which indicated that miR-26a exerts pivotal functions in the molecular etiology of chemoresistant lung adenocarcinoma.CI - (c) 2017 The Author(s) Published by S. Karger AG, Basel.