TMEM268缺失通過下調ITGB4信號通路抑制胃癌細胞生長

2018年9月，北京大學基礎醫學院免疫學教研室；北京大學國家衛生健康委醫學免疫學重點實驗室；北京大學中國人類疾病基因組學研究中心；北京大學中國醫藥衛生分析中心；中國科學院理化技術研究所光化學轉化與光電材料中國重點實驗室；北京大學**醫院中國臨床檢驗科；中國化學與分子工程學院；北京大學基因組學創新中心(Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, People’s Republic of China) Yingyu Chen老師研究團隊在《Cell Death & Differentiation》上發表論文：

“Deletion of TMEM268 inhibits growth of gastric cancer cells by downregulating the ITGB4 signaling pathway”

“TMEM268缺失通過下調ITGB4信號通路抑制胃癌細胞生長”

Abstract：

Transmembrane protein 268 (TMEM268) encodes a novel human protein of previously unknown function. This study analyzed the biological activities and molecular mechanisms of TMEM268 in vivo and in vitro. We found that TMEM268 deletion decreases cell viability, proliferation, and cell adhesion as well as causing S-phase cell cycle arrest and disrupts cytoskeleton remolding. Xenograft tumor mouse model studies showed that TMEM268 deletion inhibits the tumorigenesis of BGC823 gastric cancer cells. In addition, TMEM268-deleted BGC823 cells failed to colonize the lungs after intravenous injection and to form metastatic engraftment in the peritoneum. Molecular mechanism studies showed a C-terminal interaction between TMEM268 and integrin subunit β4 (ITGB4). TMEM268 knockout promotes ITGB4 ubiquitin-mediated degradation, increasing the instability of ITGB4 and filamin A (FLNA). The reduced ITGB4 protein levels result in the disassociation of the ITGB4/PLEC complex and cytoskeleton remodeling. This study for the first time demonstrates that TMEM268 plays a positive role in the regulation of ITGB4 homeostasis. The above results may provide a new perspective that targeting the TMEM268/ITGB4 signaling axis for the treatment of gastric cancer, which deserves further investigation in the future.

摘要：

跨膜蛋白268 (TMEM268)編碼一種新的功能未知的人類蛋白。本研究分析了TMEM268在體內和體外的生物活性和分子機制。科研人員發現TMEM268缺失會降低細胞活力、增殖和細胞粘附，并導致s期細胞周期停滯，破壞細胞骨架重塑。異種移植腫瘤小鼠模型研究表明，TMEM268缺失抑制BGC823胃癌細胞的腫瘤發生。此外，tmem268缺失的BGC823細胞在靜脈注射后不能在肺部定植，也不能在腹膜形成轉移性移植物。分子機制研究表明，TMEM268與整合素亞基β4 (ITGB4)之間存在c端相互作用。TMEM268敲除促進ITGB4泛素介導的降解，增加ITGB4和絲狀蛋白A (FLNA)的不穩定性。ITGB4蛋白水平的降低導致ITGB4/PLEC復合物的分離和細胞骨架重塑。本研究**證實TMEM268在ITGB4穩態調控中發揮積極作用。上述結果可能為靶向TMEM268/ITGB4信號軸治療胃癌提供了新的視角，值得未來進一步研究。

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