Journal Article

MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells

Yeh, Da-Wei, Chen, Lin, Zheng, Mengmei, Narayanan, Padmini, Tahara, Stanley M, Siddique, Hifzur R, Machida, Tatsuya, Punj, Vasu, Zhao, Xuyao, Feldman, Douglas E, Kou, Yi, Machida, Keigo, Choi, Hye Yeon

2023

Overview

RNA-binding protein Musashi 2 (MSI2) is elevated in several cancers and is linked to poor prognosis. Here, we tested if MSI2 promotes MYC and viral mRNA translation to induce self-renewal via an internal ribosome entry sequence (IRES). We performed RIP-seq using anti-MSI2 antibody in tumor-initiating stem-like cells (TICs). MSI2 binds the internal ribosome entry site (IRES)-containing oncogene mRNAs including MYC, JUN and VEGFA as well as HCV IRES to increase their synthesis and promote self-renewal and tumor-initiation at the post-transcriptional level. MSI2 binds a lncRNA to interfere with processing of a miRNA that reduced MYC translation in basal conditions. Deregulation of this integrated MSI2-lncRNA-MYC regulatory loop drives self-renewal and tumorigenesis through increased IRES-dependent translation of MYC mRNA. Overexpression of MSI2 in TICs promoted their self-renewal and tumor-initiation properties. Inhibition of MSI2-RNA binding reduced HCV IRES activity, viral replication and liver hyperplasia in humanized mice predisposed by virus infection and alcohol high-cholesterol high-fat diet. Together MSI2, integrating the MYC oncogenic pathway, can be employed as a therapeutic target in the treatment of HCC patients.

• Publisher: Springer Nature B.V
• Subject: Apoptosis / Cholesterol / Genomes / Hepatitis C / High cholesterol diet / High fat diet / Hyperplasia / Internal ribosome entry site / Liver cancer / Medical prognosis / miRNA / Myc protein / Non-coding RNA / Oncogenes / Post-transcription / Proteins / Replication initiation / RNA-binding protein / Therapeutic targets / Transcription initiation / Translation / Tumorigenesis / Tumors