406947

MIR155

BACKGROUND & AIMS: epithelial-mesenchymal transition (EMT) process and extracellular signal-regulated kinase 1 (ERK1) signalling pathway play pivotal roles in hepatic stellate cell (HSC) activation, which is associated with the altered expression patterns of microRNAs (miRNAs). miR-155 is considered a typical multifunctional miRNA to regulate many biological processes. However, little attention has been given to the contributions of miR-155 to simultaneous regulation of EMT process and ERK1 pathway during HSC activation. METHODS: Differential expression of miR-155 was assessed in activated HSC, sera and liver tissues from cirrhotic patients. Whether miR-155 could directly interact with 3'-untranslated region (3'-UTR) of T cell factor 4 (TCF4) and angiotensin II receptor type 1 (AGTR1) respectively was detected by luciferase reporter assay. The effects of enhanced miR-155 on EMT process and ERK1 pathway, cell apoptosis in HSC activation were also evaluated. RESULTS: A significant decrease in miR-155 expression was observed in activated HSC, sera or liver tissues of cirrhotic patients. MiR-155 was found to simultaneously interact with 3'-UTR of TCF4 and AGTR1 mRNAs, which are known as important regulators associated with EMT and ERK1 pathway repectively. Inhibiting miR-155 expression could stimulate the EMT state and ERK1 pathway activity, thus contributing to HSC activation. Forced miR-155 expression markedly decreased the mesenchymal markers and phosphorylated ERK1 level, and enhanced E-cadherin expression, leading to the synchronous inhibitory effect on EMT and ERK1 pathway and inducing HSC apoptosis. CONCLUSIONS: Our results implicate that miR-155 plays an important role in regulating the pathological network involving EMT process and ERK1 pathway during HSC activation.CI - (c) 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

It has been shown that acquisition of epithelial-mesenchymal transition (EMT) and induction of cancer stem cell (CSC)-like properties contribute to metastasis of cancers in many studies; however, the molecular mechanisms underlying EMT and CSC phenotypes in liver cancer cells remain to be elucidated. MiR-155 is an important microRNA associated with tumour progression. Here, we report that miR-155 regulates not only the epithelial-mesenchymal transition but also the stem-like transition in liver cancer cells. Utilizing quantitative RT-PCR, we found that the expression of miR-155 is positively related to the levels of CD90, CD133 and Oct4 in enriched spheres. Up-regulated miR-155 significantly increases the population of stem-like CSCs among liver cancer cells and the ability to form tumour spheres. Additionally, miR-155 overexpression in cells significantly increases cell motility and invasion, as well as the epithelial-mesenchymal transition process. Conversely, suppression of miR-155 in cells had an opposite effect, which was partially rescued by the down-regulation of TP53INP1. Collectively, miR-155 promotes liver cancer cell EMT and CSCs, in part, via silencing TP53INP1. In addition, we found that TGF-beta1 indirectly regulates TP53INP1 expression via miR-155 in liver cancer cells. Taken together, our findings suggest that miR-155 regulates TP53INP1 expression, to induce the epithelial-mesenchymal transition and acquisition of a stem cell phenotype.CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved.

Hypoxia has been considered to be a significant microenvironmental factor in promoting renal fibrosis, which causes progressive kidney disease and renal allograft failure. Previous studies have demonstrated versatile functions of miR155 in hypoxia and fibrosis of the lung and liver. However, it is unclear whether miR155 is able to regulate renal fibrosis and what the detailed mechanisms of this may be. In the current study, we focused on the interaction of miR155/hypoxiainducible factor 1 alpha (HIF1alpha) and the effects of miR155 on fibrosis in hypoxic HK2 cells. Analysis of the expression of miR155 and fibrosisassociated cytokines revealed upregulated miR155, increased transforming growth factor beta 1 (TGFbeta1) and alphasmooth muscle actin, and decreased Ecadherin in hypoxic HK2 cells. Further study demonstrated that miR155 played a positive role in regulating HIF1alpha and vice versa. Moreover, the data illustrated the synergistic effects of upregulated miR155 on fibrosis by gainoffunction and lossoffunction methods in hypoxic HK2 cells. Notably, the results also revealed that miR155 had the ability to modulate TGFbeta1 and the process of epithelialmesenchymal transition (EMT). In conclusion, this study not only demonstrated that hypoxiainduced miR155 was a profibrotic cytokine which was positively regulated by HIF1alpha, but also revealed that miR155 promoted the fibrosis of proximal tubule cells by regulating both TGFbeta1 and the process of EMT under hypoxia.

Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in hepatocellular carcinoma (HCC). The protein kinase Akt is considered to be the primary effector of PI3K, but there is evidence to suggest that serum and glucocorticoid kinase 3 (SGK3) acts in an Akt-independent manner downstream of PI3K. In this report, we found that SGK3 promotes epithelial-mesenchymal transition (EMT) and reduces phosphorylation-dependent degradation of beta-catenin in HCC cells. We determined that miR-155, previously shown to promote EMT, stimulates the expression of SGK3 by targeting and repressing P85alpha, thereby removing its inhibitory effect on PI3K-AKT signaling. These findings suggest that miR-155 promotes EMT and metastatic properties in HCC cells through activation of PI3K/SGK3/beta-catenin signaling pathways.

BACKGROUND We investigated whether microRNA-155-5p is involved in the differentiation of bone marrow mesenchymal stem cells (BMSCs) into alveolar type II epithelial (AT II) cells by regulating the Wnt signaling pathway, thus participating in the development of acute respiratory distress syndrome (ARDS). MATERIAL AND METHODS Serum levels of microRNA-155-5p in 50 ARDS patients and 50 normal controls were detected by quantitative real-time PCR (qRT-PCR). Marrow mesenchymal stem cells (MCSs) were isolated from mouse bone marrow and identified by flow cytometry. Subsequently, the effect of microRNA-155-5p on differentiation of BMSCs into AT II cells was evaluated by detecting the expression levels of AT II-specific genes. The expression levels of proteins in the Wnt signaling pathway after overexpression or knockdown of microRNA-155-5p were detected by Western blot. RESULTS Serum levels of microRNA-155-5p in ARDS patients were significantly higher than that in normal controls. expression levels of AT II-specific genes were enhanced after downregulating microRNA-155-5p in BMSCs. MicroRNA-155-5p overexpression showed the opposite result. Furthermore, microRNA-155-5p inhibited the expression levels of proteins in the Wnt signaling pathway. CONCLUSIONS MicroRNA-155-5p can attenuate the differentiation of BMSCs into AT II cells by inhibiting the Wnt signaling pathway, thus promoting the progression of ARDS.

Paclitaxel is a firstline chemotherapeutic agent for gastric cancer; however, resistance limits its effectiveness. Investigation into the underlying mechanisms of paclitaxel resistance is urgently required. In the present study, a paclitaxelresistant gastric cancer cell line (MGC803R) was generated with a morphological phenotype of epithelialtomesenchymal transition (EMT) and increased expression levels of microRNA (miR)1555p. MGC803R cellderived exosomes were effectively taken up by paclitaxelsensitive MGC803S cells, which exhibited EMT and chemoresistance phenotypes. miR1555p was enriched in MGC803Rexosomes and could be delivered into MGC803S cells. miR1555p overexpression in MGC803S cells via transfection with mimics resulted in similar phenotypic effects as treatment with MGC803R exosome and increased miR1555p content in MGC803S exosomes, which then capable of inducing the malignant phenotype in the sensitive cells. GATA binding protein 3 (GATA3) and tumor protein p53inducible nuclear protein 1 (TP53INP1) were identified as targets of miR1555p. Exosomal miR1555p inhibited these targets by directly targeting their 3' untranslated regions. Knockdown of miR1555p was observed to reverse the EMT and chemoresistant phenotypes of MGC803R cells, potentially via GATA3 and TP53INP1 upregulation, which inhibited MGC803Rexosomes from inducing the malignant phenotype. These results demonstrated that exosomal delivery of miR1555p may induce EMT and chemoresistant phenotypes from paclitaxelresistant gastric cancer cells to the sensitive cells, which may be mediated by GATA3 and TP53INP1 suppression. Targeting miR1555p may thus be a promising strategy to overcome paclitaxel resistance in gastric cancer.