LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c-Myc mRNA stability.
LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c-Myc mRNA stability.
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LncRNA LINC00942 通过抑制 MSI2 降解来增强 c–Myc mRNA 稳定性，从而促进胃癌的化疗耐药性
DOI：
10.1002/ctm2.703
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发表时间：
2022-01
影响因子：
10.6
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Zhu Y;Zhou B;Hu X;Ying S;Zhou Q;Xu W;Feng L;Hou T;Wang X;Zhu L;Jin H
对顺铂（DDP）的化疗耐药仍然是晚期胃癌（GC）治疗的主要挑战。尽管越来越多的证据表明长链非编码 RNA (lncRNA) 的失调与化疗耐药之间存在关联，但 lncRNA 在调节 GC 中基于 DDP 的化疗中的调节功能和复杂性仍未得到充分研究。本研究旨在探索GC中关键的化疗耐药相关lncRNA，并为化疗耐药的GC患者确定新的治疗靶点。通过微阵列鉴定与化疗耐药相关的lncRNA，并通过定量实时聚合酶链反应（qRT-PCR）进行验证。通过人类蛋白质组阵列鉴定了 lncRNA 结合的蛋白质，并通过 RNA 免疫沉淀 (RIP) 和 RNA Pull-down 测定进行验证。进行免疫共沉淀和泛素化检测以探索 Musashi2 (MSI2) 修饰后的分子机制。通过 MTS、细胞凋亡测定和体内异种移植肿瘤形成研究了 LINC00942 (LNC942) 和 MSI2 对 DDP 化疗的影响。 LNC942被发现在化疗耐药的GC细胞中表达上调，其高表达与GC患者的不良预后呈正相关。功能研究表明，LNC942 通过损害细胞凋亡和诱导干细胞赋予 GC 细胞化学抗性。从机械角度来看，LNC942 通过阻止 MSI2 与 SCFβ-TRCP E3 泛素连接酶的相互作用来上调 MSI2 表达，最终抑制泛素化。然后，LNC942 以 N6-甲基腺苷 (m6A) 依赖性方式稳定 c-Myc mRNA。作为一种潜在的 m6A 识别蛋白，MSI2 通过 m6A 修饰稳定了 c-Myc mRNA。此外，抑制 LNC942-MSI2-c-Myc 轴被发现可以恢复体外和体内的化学敏感性。这些结果揭示了 LNC942 在 GC 中的化疗耐药加速功能，并且破坏 LNC942-MSI2-c-Myc 轴可能成为化疗耐药的 GC 患者的一种新的治疗策略。 1. LNC942是胃癌中重要的耐药相关lncRNA。 2. LNC942 防止 β-Trcp 介导的 MSI2 降解。然后，MSI2 以 m6A 依赖性方式识别并稳定 c-Myc mRNA。 3. MSI2抑制剂FK228治疗可以克服LNC942诱导的胃癌顺铂耐药性。
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. 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. 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. 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.
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影响因子：
11.5
作者：
Phu Hung Nguyen;Giraud, Julie;Varon, Christine
通讯作者：
Varon, Christine
影响因子：
56.9
作者：
Kapranov, Philipp;Cheng, Jill;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
影响因子：
51.1
作者：
Kang, Yoon-Koo;Chin, Keisho;Boku, Narikazu
通讯作者：
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Musashi 2通过LIN28A激活促进肝癌干细胞的干性和化疗耐药性
影响因子：
9.7
作者：
Fang, Tian;Lv, Hongwei;Wang, Hongyang
通讯作者：
Wang, Hongyang
DOI：
10.1038/s41580-020-00315-9
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Statello L;Guo CJ;Chen LL;Huarte M
通讯作者：
Huarte M