MiR-361-3p regulates ERK1/2-induced EMT via DUSP2 mRNA degradation in pancreatic ductal adenocarcinoma

Jisheng Hu,Yongwei Wang,Yilong Li,Huan Liu,Guanqun Li,Xinjian Lv,Rui Kong,Bei Sun,Fengyu Tian,Le Li,Hongze Chen,Guangquan Zhang,Hua Chen

doi:10.1038/s41419-018-0839-8

Abstract

Metastasis remains one of the most intractable challenges in pancreatic ductal adenocarcinoma (PDAC) biology, and epithelial-to-mesenchymal transition (EMT) is essential to the epithelium-originated solid tumor metastasis cascade. Emerging evidence demonstrates that aberrant miRNA expression is involved in pancreatic cancer progression. We found that miR-361-3p was associated with an advanced stage of PDAC and poor prognosis. Hence, the effect of miR-361-3p on metastasis of PDAC cells was evaluated using Transwell assay and wound healing assay in vitro as well as orthotopic and liver metastasis pancreatic cancer models in vivo. Overexpression of miR-361-3p promoted pancreatic cancer cell migration and invasion in vitro, and miR-361-3p-elevated PDAC cells were prone to generating metastatic nodules in vivo. However, miR-361-3p showed no significant effect on the proliferation of PDAC cells in vivo or in vitro. Further study demonstrated that miR-361-3p could enhance EMT and ERK pathway activation, and ERK inhibitor could attenuate miR-361-3p-induced EMT. Luciferase assays, qPCR, and western blot and Ago2 co-immunoprecipitation were performed to identify the direct target of miR-361-3p. Mechanistic investigations identified DUSP2 as a direct target of miR-361-3p, and DUSP2 was revealed to be involved in miR-361-3p-induced EMT by directly leading to the inactivation of the ERK pathway. Moreover, we found that miR-361-3p-induced EMT was dependent on Ago2, the core component of RNA-induced silencing complex, while enforced expression of Ago2 enhanced the miR-361-3p-induced effect by promoting interference efficacy and specificity rather than regulating miR-361-3p stability and biogenesis. Thus, this study revealed that miR-361-3p functions as an oncomiR for promoting metastasis and identified the miR-361-3p/DUSP2/ERK axis as a novel EMT axis dependent on Ago2 in PDAC.

Highlights

Despite tremendous effort and huge investment to improve the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC), PDAC remains one of most lethal malignant tumors, with only an 8% 5-year overall survival rate[1]
These findings indicate that the extracellular signalregulated kinases (ERK) pathway may function as an MicroRNAs are a family of endogenous small non-coding RNAs of 19–25 nt that negatively regulate gene expression in a sequence-specific manner at the post-transcriptional level[16]
These results indicate that miR-3613p may induce pancreatic cancer cell metastasis and predict a poor prognosis

Summary

Introduction

Despite tremendous effort and huge investment to improve the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC), PDAC remains one of most lethal malignant tumors, with only an 8% 5-year overall survival rate[1]. Hu et al Cell Death and Disease (2018)9:807 progress as a crucial role function in pancreatic cancer metastasis[5,6]. Twist[2], all major developmental signaling pathways have been implicated in some aspect of the EMT program[7,8]; among these, the transforming growth factor-β (TGF-β) signaling pathway has a predominant role[9]. ERK pathway activation triggered by RAS or RAF contributes to EMT13,14, and ERK1/2 blockade restrains EMT in lung cancer cells[15]. These findings indicate that the ERK pathway may function as an EMT inducer

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Results

Conclusion