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METTL14 和 USP38 的反馈回路调节膀胱癌中的细胞迁移、侵袭和 EMT 以及转移。

The feedback loop of METTL14 and USP38 regulates cell migration, invasion and EMT as well as metastasis in bladder cancer.

机构信息

Departments of Urology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China.

出版信息

PLoS Genet. 2022 Oct 26;18(10):e1010366. doi: 10.1371/journal.pgen.1010366. eCollection 2022 Oct.

DOI:10.1371/journal.pgen.1010366
PMID:36288387
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9605029/
Abstract

BACKGROUND

Bladder cancer (BCa) is one of the most prevalent malignancies globally. Previous study has reported the inhibitory effect of methyltransferase-like 14 (METTL14) on BCa tumorigenesis, but its role in the cell migration, invasion and epithelial-mesenchymal transition (EMT) in BCa remains unknown.

MATERIALS AND METHODS

Quantitative real-time PCR (RT-qPCR) and western blot were applied to measure RNA and protein expression respectively. Cell migration, invasion and EMT were evaluated by wound healing, Transwell, and immunofluorescence (IF) assays as well as western blot of EMT-related proteins. In vivo experiments were performed to analyze metastasis of BCa. Mechanism investigation was also conducted to study METTL14-mediated regulation of BCa progression.

RESULTS

METTL14 overexpression prohibits BCa cell migration, invasion in vitro and tumor metastasis in vivo. METTL14 stabilizes USP38 mRNA by inducing N6-methyladenosine (m6A) modification and enhances USP38 mRNA stability in YTHDF2-dependent manner. METTL14 represses BCa cell migration, invasion and EMT via USP38. Additionally, miR-3165 inhibits METTL14 expression to promote BCa progression.

CONCLUSIONS

Our study demonstrated that METTL14 suppresses BCa progression and forms a feedback loop with USP38. In addition, miR-3165 down-regulates METTL14 expression to promote BCa progression. The findings may provide novel insight into the underlying mechanism of METTL14 in BCa progression.

摘要

背景

膀胱癌（BCa）是全球最常见的恶性肿瘤之一。先前的研究已经报道了甲基转移酶样 14（METTL14）对 BCa 肿瘤发生的抑制作用，但它在 BCa 中的细胞迁移、侵袭和上皮间质转化（EMT）中的作用尚不清楚。

材料与方法

采用实时定量 RT-PCR（qRT-PCR）和 Western blot 分别检测 RNA 和蛋白表达。通过划痕愈合、Transwell 以及免疫荧光（IF）和 EMT 相关蛋白的 Western blot 实验评估细胞迁移、侵袭和 EMT。进行体内实验分析 BCa 的转移。还进行了机制研究，以研究 METTL14 介导的 BCa 进展的调节。

结果

METTL14 过表达可抑制 BCa 细胞的体外迁移、侵袭和体内肿瘤转移。METTL14 通过诱导 N6-甲基腺苷（m6A）修饰稳定 USP38 mRNA，并以 YTHDF2 依赖的方式增强 USP38 mRNA 的稳定性。METTL14 通过 USP38 抑制 BCa 细胞迁移、侵袭和 EMT。此外，miR-3165 通过抑制 METTL14 的表达促进 BCa 的进展。

结论

本研究表明 METTL14 抑制 BCa 进展，并与 USP38 形成反馈回路。此外，miR-3165 通过下调 METTL14 的表达促进 BCa 的进展。这些发现可能为 METTL14 在 BCa 进展中的潜在机制提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/aa382e940191/pgen.1010366.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/5ad24870d312/pgen.1010366.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/268ebcc88692/pgen.1010366.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/7f84c8414b69/pgen.1010366.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/1b697ac63552/pgen.1010366.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/78b2a09ff2e9/pgen.1010366.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/4b9f0dd2291d/pgen.1010366.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/aa382e940191/pgen.1010366.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/5ad24870d312/pgen.1010366.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/268ebcc88692/pgen.1010366.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/7f84c8414b69/pgen.1010366.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/1b697ac63552/pgen.1010366.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/78b2a09ff2e9/pgen.1010366.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/4b9f0dd2291d/pgen.1010366.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e238/9605029/aa382e940191/pgen.1010366.g007.jpg

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