RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA

Meng Zhang,Ping Wei,Cong Tan,Xiang Du,Yanzi Gu,Senlin Zhao,Xuefeng He,Dawei Li

doi:10.1186/s13046-021-01994-8

Abstract

BackgroundMEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism.MethodsTo investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays.ResultsWe find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3′-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3−/− mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo.ConclusionOur study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

Highlights

MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism
To identify RNA-binding proteins (RBPs) which related with the ability of MEK1-ERK pathway in the progression of CRC, we began by performing high-throughput RNA-sequencing (RNA-seq) of 8 paired CRC with liver metastases samples, including primary tumor tissues(T), normal adjacent tissues(N) and liver metastatic tissues(M).; from this we identified insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) as one of the most dysregulated RBPs in CRC
Elevated insulin-like growth factor mRNA-binding protein 3 (IMP3) expression correlates with poor prognosis in CRC patients To identify key RNA binding proteins involved in the progression of CRC, we began by performing highthroughput RNA-Seq analysis of 8 paired primary CRC and liver metastases samples, including primary tumor tissues(T), normal adjacent tissues(N) and liver metastatic tissues(M)

Summary

Introduction

MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism. Activating mutations of KRAS are found in around 40% of CRC patients [3], RAS signaling triggers multiple downstream pathways, including RAF-MEK1-ERK1 pathway ( known as MAPK (mitogen activated protein kinase pathway) [4]. As the nature of RAS protein, target of RAS remains challenging, some inhibitors have been invented to target RAF and MEK1, there is poorly clinical benefit in monotherapy for the treatment of advanced CRC patients mostly for the feedback reactivation of MEK1/ ERK pathway [5]. Other mechanism might exist which need to be further studied

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Discussion

Conclusion