MicroRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways.

Zexi Chen,Meizhang Li,Shanshan Yang,Qin Yang,Xiuyu Yang,Haijing Yu,Ran Wei,Yan Li,Qinghua Cui,Jiaqi Zhou,Kun Yao,Min Yu,Bing Han

doi:10.18632/oncotarget.15114

MicroRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways.

Zexi Chen, Meizhang Li + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.15114

Copy DOI

Journal: Oncotarget	Publication Date: Feb 6, 2017
Citations: 48	License type: cc-by

Affiliation: Yunnan University

Abstract

MicroRNA-375 is involved in many types of alimentary system cancers. Our previous studies showed that microRNA-375 was significantly down-regulated in carcinoma tissues compared with para-carcinoma tissues, which strongly indicates that microRNA-375 might suppress the occurrence and development of colorectal cancer. However, the mechanism underlying the microRNA-375 regulation in colorectal cancer remains unclear. In this study, we first sorted out jak2, map3k8 and atg7 as microRNA-375 targeted genes from multiple databases, and found that jak2, map3k8 and their downstream genes stat3 and erk were up-regulated in carcinoma tissues. Secondly, we over-expressed microRNA-375 in colorectal cancer cell lines (HCT116, Caco2 and HT29). Our results showed that in microRNA-375 over-expressing cells, JAK2/STAT3 and MAP3K8/ERK proteins were down-regulated, cell proliferation was inhibited, cell migration rate did not change. There was no significant difference on ATG7 expression between the control group and microRNA-375 over-expressing HT29/Caco2 cells, whereas microRNA-375 down-regulated ATG7 specifically in HCT116 cells. Finally, we demonstrated that expressing microRNA-375 suppressed tumor formation in nude mice. In conclusion, microRNA-375 might function as a tumor-repressive gene to inhibit cell proliferation, mainly through targeting both JAK2/STAT3 and MAP3K8/ERK signaling pathways in colorectal cancer. These findings suggest miR-375 as a promising diagnostic marker and a therapeutic drug for colorectal cancer.

Highlights

Colorectal cancer (CRC), including colon cancer and rectal cancer, is one of the most common human malignant cancers and the leading cause of death worldwide
We first sorted out jak2, map3k8 and atg7 as microRNA-375 targeted genes from multiple databases, and found that jak2, map3k8 and their downstream genes stat3 and erk were up-regulated in carcinoma tissues
The jak2 and map3k8 genes belong to jak2/ stast3 and mapk/erk signaling pathways respectively, atg7 relates to autophagy pathway, and these pathways were reported to modulate tumor growth or metastasis

Summary

Introduction

Colorectal cancer (CRC), including colon cancer and rectal cancer, is one of the most common human malignant cancers and the leading cause of death worldwide. Diagnosis and treatment can markedly raise the survival rate of CRC patients from 15% to 90% [1]. MiRNAs could suppress target gene expression at post-transcriptional level by binding to the 3’UTR of target mRNAs [2]. Their expression patterns have been used to diagnose various types of cancer [3,4,5]. MicroRNA-375 (miR-375) located in chromosome 2 functions as a cancer suppressor, which showed significant lower levels in alimentary canal cancers, such as esophageal squamous cancer, gastric cancer, liver cancer and pancreatic cancer [9,10,11]. Over-expression of miR-375 suppresses the expression of aeg-1, induces apoptosis and inhibits migration of the liver cancer cells [11]. miR-375 can suppress cell growth by arresting cancer cells in G0 phase in pancreatic cancer [12]

Methods

Results

Conclusion