Mitochondrial micropeptide STMP1 enhances mitochondrial fission to promote tumor metastasis.
Mitochondrial micropeptide STMP1 enhances mitochondrial fission to promote tumor metastasis.
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DOI：
10.1158/0008-5472.can-21-3910
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发表时间：
2022-05
期刊：
影响因子：
11.2
通讯作者：
Chen Xie;Feng-Yi Wang;Ye Sang;B. Chen;Jia-Hui Huang;Feng He;Hui Li;Ying Zhu;Xingguo Liu;Shi‐Mei Zhuang;Jian-Hong Fang
中科院分区：
文献类型：
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作者：
Chen Xie;Feng-Yi Wang;Ye Sang;B. Chen;Jia-Hui Huang;Feng He;Hui Li;Ying Zhu;Xingguo Liu;Shi‐Mei Zhuang;Jian-Hong Fang
微肽是最近发现的一类在各种细胞过程中发挥重要作用的分子，包括分化、增殖和凋亡。在这里，我们试图识别癌症相关的微肽，并揭示其机制功能。一种定位于线粒体内膜的名为短跨膜蛋白1（STMP 1）的微肽被鉴定为在各种癌症类型中上调，并与肝细胞癌的转移和复发相关。功能获得和功能丧失的研究都表明，STMP 1增加了动力蛋白相关蛋白1（DRP1）的激活，以促进线粒体分裂和增强肿瘤细胞的迁移。STMP 1沉默抑制异种移植小鼠模型中的体内肿瘤转移。STMP 1的过表达导致线粒体重新分布到细胞的前缘，并增强板状伪足的形成。用DRP1抑制剂治疗废除了STMP1对线粒体分裂、板状伪足形成和肿瘤细胞体外迁移以及体内转移的促进作用。此外，STMP 1与肌球蛋白重链9（MYH 9）（非肌肉肌球蛋白II的亚基）相互作用，并且沉默MYH 9废除了STMP 1诱导的DRP 1激活、线粒体分裂和细胞迁移。总的来说，这项研究将STMP 1鉴定为转移的关键调节因子和线粒体裂变蛋白机制的新单位，为治疗转移提供了潜在的治疗靶点。
Micropeptides are a recently discovered class of molecules that play vital roles in various cellular processes, including differentiation, proliferation, and apoptosis. Here, we sought to identify cancer-associated micropeptides and to uncover their mechanistic functions. A micropeptide named short trans-membrane protein 1 (STMP1) that localizes at the inner mitochondrial membrane was identified to be upregulated in various cancer types and associated with metastasis and recurrence of hepatocellular carcinoma. Both gain- and loss-of-function studies revealed that STMP1 increased dynamin-related protein 1 (DRP1) activation to promote mitochondrial fission and enhanced migration of tumor cells. STMP1 silencing inhibited in vivo tumor metastasis in xenograft mouse models. Overexpression of STMP1 led to redistribution of mitochondria to the leading edge of cells and enhanced lamellipodia formation. Treatment with a DRP1 inhibitor abrogated the promotive effect of STMP1 on mitochondrial fission, lamellipodia formation, and tumor cell migration in vitro and metastasis in vivo. Furthermore, STMP1 interacted with myosin heavy chain 9 (MYH9), the subunit of non-muscle myosin II, and silencing MYH9 abrogated STMP1-induced DRP1 activation, mitochondrial fission, and cell migration. Collectively, this study identifies STMP1 as a critical regulator of metastasis and a novel unit of the mitochondrial fission protein machinery, providing a potential therapeutic target for treating metastases.