LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability. Issue 1 (24th January 2022)

• Record Type: Journal Article
• Authors: Zhu, Yiran; Zhou, Bingluo; Hu, Xinyang; Ying, Shilong; Zhou, Qiyin; Xu, Wenxia; Feng, Lifeng; Hou, Tianlun; Wang, Xian; Zhu, Liyuan; Jin, Hongchuan
• Is Part Of: Clinical and translational medicine. Volume 12:Issue 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-24
• Subjects: chemoresistance -- c‐Myc -- LINC00942 (LNC942) -- m6A -- Musashi2 (MSI2); Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.703
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: 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 SCF β‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m 6 A)‐dependent manner. As a potential m 6 A recognition protein, MSI2 stabilized c‐Myc mRNA with m 6 A 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. Abstract : 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 m 6 A‐dependent manner. 3. Treatment with MSI2 inhibitor FK228 could overcome LNC942‐induced cisplatin resistance in gastric cancer.