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Yap 通过 SIRT1/Mfn2/线粒体自噬调控胃癌的存活和迁移。

Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy.

机构信息

Department of Pathology, Seventh People's Hospital of Shanghai University of TCM, Shanghai 200137, P.R. China.

Department of Pathology, Songjiang Hospital Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai 201600, P.R. China.

出版信息

Oncol Rep. 2018 Apr;39(4):1671-1681. doi: 10.3892/or.2018.6252. Epub 2018 Feb 7.

DOI:10.3892/or.2018.6252
PMID:29436693
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5868403/
Abstract

Gastric cancer is the fifth most common cancer worldwide and Hippo-Yap is the novel signaling pathway which plays an important role in gastric cancer tumor development and progression. However, little insight is available to date regarding the specific role of Yes-associated protein (Yap) in gastric cancer. In the present study, we identified the mechanism through which Yap sustains gastric cancer viability and migration. Yap was greatly upregulated in gastric cancer cells and its expression promoted cellular migration and survival. Functional studies found that knockdown of Yap reduced the mitophagy activity, which subsequently caused mitochondrial apoptosis and cellular oxidative stress. The latter impaired adhesive protein expression, alleviated F-actin expression, blunted lamellipodium formation, leading to inhibition of cancer cell motility. Mechanistically, Yap preserved Sirtuin 1 (SIRT1) activity which manipulated mitofusin 2 (Mfn2) expression and subsequent mitophagy. Loss of Yap reduced SIRT1 expression and inhibited Mfn2-mediated mitophagy. Collectively, our results identified Hippo-Yap as a tumor promoter in gastric cancer that was mediated via activation of the SIRT1/Mfn2/mitophagy axis, with potential applications to gastric cancer therapy involving cancer survival and migration.

摘要

胃癌是全球第五大常见癌症，Hippo-Yap 是一种新型信号通路，在胃癌肿瘤发生和发展中发挥重要作用。然而，目前对于 Yes 相关蛋白（Yap）在胃癌中的具体作用知之甚少。在本研究中，我们确定了 Yap 维持胃癌活力和迁移的机制。Yap 在胃癌细胞中大量上调，其表达促进了细胞迁移和存活。功能研究发现，下调 Yap 减少了线粒体自噬活性，随后导致线粒体凋亡和细胞氧化应激。后者会降低黏附蛋白的表达，减少 F-肌动蛋白的表达，削弱片状伪足的形成，从而抑制癌细胞的运动性。在机制上，Yap 保持了 Sirtuin 1（SIRT1）的活性，从而操纵了线粒体融合蛋白 2（Mfn2）的表达和随后的线粒体自噬。Yap 的缺失会降低 SIRT1 的表达，并抑制 Mfn2 介导的线粒体自噬。总之，我们的研究结果表明，Hippo-Yap 是胃癌的一种肿瘤促进因子，其作用机制是通过激活 SIRT1/Mfn2/线粒体自噬轴，这可能为涉及癌症存活和迁移的胃癌治疗提供新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/b83539041291/OR-39-04-1671-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/5f58d4c7e672/OR-39-04-1671-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/11c2b3477f05/OR-39-04-1671-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/2fa69f3aa1eb/OR-39-04-1671-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/6ab2c8aeb319/OR-39-04-1671-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/785afd103ab4/OR-39-04-1671-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/b83539041291/OR-39-04-1671-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/5f58d4c7e672/OR-39-04-1671-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/11c2b3477f05/OR-39-04-1671-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/2fa69f3aa1eb/OR-39-04-1671-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/6ab2c8aeb319/OR-39-04-1671-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/785afd103ab4/OR-39-04-1671-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b517/5868403/b83539041291/OR-39-04-1671-g05.jpg

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