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METTL16 通过 mA 依赖方式下调 RAB11B-AS1 促进肝癌进展。

METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an mA-dependent manner.

机构信息

Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China.

Department of Interventional Radiology, Changhai Hospital, Naval Medical University, Shanghai, 20043, China.

出版信息

Cell Mol Biol Lett. 2022 May 20;27(1):41. doi: 10.1186/s11658-022-00342-8.

DOI:10.1186/s11658-022-00342-8
PMID:35596159
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9123709/
Abstract

BACKGROUND

The molecular mechanisms driving hepatocellular carcinoma (HCC) remain largely unclear. As one of the major epitranscriptomic modifications, N-methyladenosine (mA) plays key roles in HCC. The aim of this study was to investigate the expression, roles, and mechanisms of action of the RNA methyltransferase methyltransferase-like protein 16 (METTL16) in HCC.

METHODS

The expression of METTL16 and RAB11B-AS1 was determined by RT-qPCR. The regulation of RAB11B-AS1 by METTL16 was investigated by RNA immunoprecipitation (RIP), methylated RIP (MeRIP), and RNA stability assays. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of METTL16 and RAB11B-AS1.

RESULTS

METTL16 was upregulated in HCC, and its increased expression was correlated with poor prognosis of HCC patients. METTL16 promoted HCC cellular proliferation, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumoral growth in vivo. METTL16 directly bound long noncoding RNA (lncRNA) RAB11B-AS1, induced mA modification of RAB11B-AS1, and decreased the stability of RAB11B-AS1 transcript, leading to the downregulation of RAB11B-AS1. Conversely to METTL16, RAB11B-AS1 is downregulated in HCC, and its decreased expression was correlated with poor prognosis of patients with HCC. Furthermore, the expression of RAB11B-AS1 was negatively correlated with METTL16 in HCC tissues. RAB11B-AS1 repressed HCC cellular proliferation, migration, and invasion, promoted HCC cellular apoptosis, and inhibited HCC tumoral growth in vivo. Functional rescue assays revealed that overexpression of RAB11B-AS1 reversed the oncogenic roles of METTL16 in HCC.

CONCLUSIONS

This study identified the METTL16/RAB11B-AS1 regulatory axis in HCC, which represented novel targets for HCC prognosis and treatment.

摘要

背景

驱动肝细胞癌（HCC）的分子机制在很大程度上仍不清楚。作为主要的转录后修饰之一，N6-甲基腺苷（m6A）在 HCC 中发挥关键作用。本研究旨在探讨 RNA 甲基转移酶样蛋白 16（METTL16）在 HCC 中的表达、作用和作用机制。

方法

通过 RT-qPCR 测定 METTL16 和 RAB11B-AS1 的表达。通过 RNA 免疫沉淀（RIP）、甲基化 RIP（MeRIP）和 RNA 稳定性测定研究 METTL16 对 RAB11B-AS1 的调节。进行体外和体内增益和缺失功能测定，以研究 METTL16 和 RAB11B-AS1 的作用。

结果

METTL16 在 HCC 中上调，其表达增加与 HCC 患者的预后不良相关。METTL16 促进 HCC 细胞增殖、迁移和侵袭，抑制 HCC 细胞凋亡，并促进 HCC 肿瘤在体内生长。METTL16 直接结合长链非编码 RNA（lncRNA）RAB11B-AS1，诱导 RAB11B-AS1 的 m6A 修饰，并降低 RAB11B-AS1 转录本的稳定性，导致 RAB11B-AS1 下调。相反，RAB11B-AS1 在 HCC 中下调，其表达减少与 HCC 患者的预后不良相关。此外，RAB11B-AS1 在 HCC 组织中的表达与 METTL16 呈负相关。RAB11B-AS1 抑制 HCC 细胞增殖、迁移和侵袭，促进 HCC 细胞凋亡，并抑制 HCC 肿瘤在体内生长。功能挽救实验表明，过表达 RAB11B-AS1 逆转了 METTL16 在 HCC 中的致癌作用。

结论

本研究鉴定了 HCC 中的 METTL16/RAB11B-AS1 调节轴，为 HCC 的预后和治疗提供了新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bcd/9123709/d40b3c0eeb39/11658_2022_342_Fig8_HTML.jpg
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