Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis

Xisheng Liu,Ying Lu,Xiao Peng,Fangming Zhu,Xiaole Meng,Zhihai Peng,Hongze Sun,Qianlan Yao,Xueni Liu,Huamei Tang,Zhongyi Ding,Bin Li,Dan Li

doi:10.1038/s41419-021-03672-1

Abstract

Increasing evidence suggests that global downregulation of miRNA expression is a hallmark of human cancer, potentially due to defects in the miRNA processing machinery. In this study, we found that the protein expression of Argonaute 2 (AGO2), a key regulator of miRNA processing, was downregulated in colorectal cancer (CRC) tissues, which was also consistent with the findings of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Furthermore, the correlation between the levels of AGO2 and epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) indicated that reduced levels of AGO2 promoted EMT in CRC. Low expression of AGO2 was an indicator of a poor prognosis among CRC patients. Knockdown of AGO2 in CRC cells promoted migration, invasion and metastasis formation in vitro and in vivo but had no influence on proliferation. To provide detailed insight into the regulatory roles of AGO2, we performed integrated transcriptomic, quantitative proteomic and microRNA sequencing (miRNA-seq) analyses of AGO2 knockdown cells and the corresponding wild-type cells and identified neuropilin 1 (NRP1) as a new substrate of AGO2 via miR-185-3p. Our data provided evidence that knockdown of AGO2 resulted in a reduction of miR-185-3p expression, leading to the upregulation of the expression of NRP1, which is a direct target of miR-185-3p, and elevated CRC cell metastatic capacity. Inhibition of NRP1 or treatment with a miR-185-3p mimic successfully rescued the phenotypes of impaired AGO2, which suggested that therapeutically targeting the AGO2/miR-185-3p/NRP1 axis may be a potential treatment approach for CRC.

Highlights

Colorectal cancer (CRC) is the world’s fourth most deadly cancer, with almost 900,000 deaths occurring per year[1]
We observed a reduction in Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC) complex, in CRC tumor tissues compared to their normal counterparts
We found that the expression level of AGO2 had no influence on the proliferation of CRC cells, impaired AGO2 promoted the migration and invasion of CRC cells in vitro and in vivo

Summary

Introduction

Colorectal cancer (CRC) is the world’s fourth most deadly cancer, with almost 900,000 deaths occurring per year[1]. Mounting evidence suggests that microRNAs (miRNAs) play a critical role in tumorigenesis. Most types of tumors show a global reduction in miRNA expression, which is closely associated with cancer development[4]. These findings indicate that some specific miRNAs serve as oncogenes, miRNAs generally play an essential role in tumor suppression. The global reduction of miRNAs in cancers does not coincide with reductions in their primary transcripts[5], which suggests that altered regulation of the miRNA-processing machine may be responsible for Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion