Journal Article

LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability

Feng, Lifeng, Ying, Shilong, Zhou, Qiyin, Xu, Wenxia, Jin, Hongchuan, Zhu, Yiran, Zhou, Bingluo, Hou, Tianlun, Wang, Xian, Hu, Xinyang, Zhu, Liyuan

2022

Overview

Background Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non‐coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP‐based chemotherapy in GC remain under‐investigated. This study was designed to explore the critical chemoresistance‐related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC. Methods Chemoresistance‐related lncRNAs were identified through microarray and verified through a quantitative real‐time polymerase chain reaction (qRT‐PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull‐down assays. Co‐immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post‐modification. The effects of LINC00942 (LNC942) and MSI2 on DDP‐based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo. Results LNC942 was found to be up‐regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up‐regulated the MSI2 expression by preventing its interaction with SCFβ‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m6A)‐dependent manner. As a potential m6A recognition protein, MSI2 stabilized c‐Myc mRNA with m6A modifications. Moreover, inhibition of the LNC942‐MSI2‐c‐Myc axis was found to restore chemosensitivity both in vitro and in vivo. Conclusions These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942‐MSI2‐c‐Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance. 1. LNC942 is a vital chemoresistant‐related lncRNA in gastric cancer. 2. LNC942 prevents β‐Trcp‐mediated MSI2 degradation. Then, MSI2 recognizes and stabilizes the c‐Myc mRNA in an m6A‐dependent manner. 3. Treatment with MSI2 inhibitor FK228 could overcome LNC942‐induced cisplatin resistance in gastric cancer.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Antibodies / Apoptosis / chemoresistance / Chemotherapy / Cisplatin - metabolism / Cisplatin - therapeutic use / Clinical medicine / c‐Myc / Drug Resistance - drug effects / Gastric cancer / Genes, myc - drug effects / Genes, myc - physiology / Humans / LINC00942 (LNC942) / m6A / Medical prognosis / Musashi2 (MSI2) / Plasmids / Proteins / Reagents / RNA, Long Noncoding - agonists / RNA, Long Noncoding - genetics / RNA, Long Noncoding - therapeutic use / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - genetics / RNA-Binding Proteins - pharmacology / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics