STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib.
STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib.
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STOML2通过促进PINK1介导的丝裂原吞噬作用促进肝细胞癌的转移，并调节对Lenvatinib的敏感性。
DOI：
10.1186/s13045-020-01029-3
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发表时间：
2021-01-14
影响因子：
28.5
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zheng Y;Huang C;Lu L;Yu K;Zhao J;Chen M;Liu L;Sun Q;Lin Z;Zheng J;Chen J;Zhang J
线粒体生物发生和线粒体自噬的失调对于维持致癌信号通路至关重要。然而，线粒体自噬促进肝细胞癌（HCC）进展的机制仍然知之甚少。本研究旨在探讨线粒体内膜蛋白STOML 2在肝细胞癌中的表达及其临床意义。通过肝癌组织的基因表达谱鉴定STOML 2，并在组织芯片和细胞系中进行测量。采用功能获得/丧失实验研究STOML 2在肝癌中的生物学功能。采用流式细胞术、Western blotting、激光共聚焦显微镜、透射电子显微镜和免疫共沉淀法检测和分析线粒体自噬。采用ChIP和荧光素酶报告基因分析方法，研究STOML 2与HIF-1α的关系。在体外和体内评估了HCC患者对乐伐替尼的敏感性。与癌旁组织相比，肝癌组织中STOML 2的表达增加。在有转移的肝癌中，这一差异更为显著，并与总生存率差和肝切除术后复发的可能性高相关。STOML 2的上调促进了HCC细胞集落形成、迁移和侵袭。从机制上讲，基于TCGA芯片的分析显示，自噬相关途径在STOML 2高表达的HCC中富集。接下来，STOML 2被证明在细胞应激下与PINK 1相互作用并稳定PINK 1，放大PINK 1-Parkin介导的线粒体自噬，然后促进HCC生长和转移。最有趣的是，在乐伐替尼治疗下，HCC细胞中HIF-1α上调并转录增加STOML 2表达。此外，当STOML 2下调时，发现HCC细胞对乐伐替尼的敏感性更高。乐伐替尼与线粒体自噬抑制剂羟氯喹联合治疗效果最好。我们的研究结果表明，STOML 2可以通过相互作用和稳定PINK 1来放大线粒体自噬，从而促进HCC转移并调节HCC对乐伐替尼的反应。同时阻断血管生成和线粒体自噬的药理学抑制剂的组合可以作为HCC的有效治疗。
Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC. STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo. Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy. Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.
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DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
DOI：
10.1083/jcb.201402054
发表时间：
2014-05-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Okamoto K
通讯作者：
Okamoto K
GEPIA：用于癌症和正常基因表达谱和交互式分析的网络服务器。
影响因子：
14.9
作者：
Tang Z;Li C;Kang B;Gao G;Li C;Zhang Z
通讯作者：
Zhang Z
影响因子：
5.6
作者：
Elefantova K;Lakatos B;Kubickova J;Sulova Z;Breier A
通讯作者：
Breier A
影响因子：
3.7
作者：
Christie DA;Kirchhof MG;Vardhana S;Dustin ML;Madrenas J
通讯作者：
Madrenas J