The microRNA miR-33a suppresses IL-6-induced tumor progression by binding Twist in gallbladder cancer.

Mingdi Zhang,Zhiwei Quan,Mingzhe Ma,Di Zhou,Mingzhe Weng,Zhaohui Tang,Bingfeng Chu,Wei Gong,Yiyu Qin,Bin Zuo,Fei Ma,Yong Yang,Yong Zhang,Alex Jiang

doi:10.18632/oncotarget.12693

Mingdi Zhang, Zhiwei Quan + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.12693

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Journal: Oncotarget	Publication Date: Oct 15, 2016
Citations: 29	License type: cc-by

Affiliation: Shanghai Jiao Tong University, Western University

Abstract

Cytokine is a key molecular link between chronic inflammation and gallbladder cancer (GBC) progression. The potential mechanism of cytokine-associated modulation of microRNAs (miRNAs) expression in GBC progression is not fully understood. In this study, we investigated the biological effects and prognostic significance of interleukin-6 (IL-6) -induced miRNAs in the development of GBC. We identify that inflammatory cytokine, IL-6 promotes proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GBC both in vitro and in vivo. Among all the changed miRNAs in miRNA profiling, miR-33a expression was significantly decreased in IL-6 treated GBC cell lines, as well as in GBC tissues compared with case-matched normal tissues and cholecystitis tissues. In turn, miR-33a suppresses IL-6−induced tumor metastasis by directly binding Twist which was identified as an EMT marker. High expression of miR-33a suppressed xenograft tumor growth and dissemination in nude mice. The downregulation of miR-33a was closely associated with advanced clinical stage, lymph node metastasis, and poor clinical outcomes in patients with GBC. miR-33a acts as a tumor suppressor miRNA in GBC progression and may be considered for the development of potential therapeutics against GBC.

Highlights

Gallbladder cancer (GBC) is a rare neoplasm with an incidence of 2.5 in 100 000 individuals [1, 2]
Cell counting kit-8 (CCK-8) assay indicated that gallbladder cancer (GBC) cell proliferation was significantly promoted by IL-6 at lower concentrations (< 100 ng/ml) but was gradually decreased at the higher concentrations over 100 ng/ml (Supplementary Figure S1A)
As Twist has been identified to be activated in EMTmediated metastasis, we explored the function of Twist in IL-6-induced GBC metastasis

Summary

Introduction

Gallbladder cancer (GBC) is a rare neoplasm with an incidence of 2.5 in 100 000 individuals [1, 2]. Decreased miR-33a is associated with poor prognosis in GBC samples, which in turn promotes the metastasis of GBC both in vitro and in vivo by directly binding Twist. Western blotting (Figure 3A) and IF staining (Supplementary Figure S2A) showed that Twist protein level was significantly increased in IL-6 treated group compared with control cells.

Results

Conclusion