Flotillin-1 promotes the progression of hepatocellular carcinoma by activating TFE3-mediated Golgi stress response via inhibition of mTORC1/2.

IF 5.4 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Liang Zhang, Cheng-Zhi Bai, Jia-Yan Shan, Hong-Li Xue, Shu-Mei Zheng, Ya-Lun Chen, Shan-Hong Tang
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引用次数: 0

Abstract

Background: It is critical to explore effective therapeutic targets for improving the survival rate of patients with hepatocellular carcinoma (HCC). Although many studies have focused on flotillin-1 (FLOT1) as a lipid raft-associated protein that regulates the activation of some proteins or kinases to promote tumor cell survival and proliferation, few studies have explored the regulation of Golgi apparatus function.

Aim: To investigate the molecular mechanism through which FLOT1 activates the Golgi stress response downstream of transcription factor E3 (TFE3), thereby promoting the progression of HCC.

Methods: FLOT1 expression in HCC tissue, HCC cell lines, and nude mouse tumor models was assessed. The impact of FLOT1 silencing or its overexpression on the proliferation of HCC cells was studied. CCK-8, flow cytometry, and transwell assays were used to assess the proliferation, cell cycle, migration, and invasion abilities of HCC cells. A dual-luciferase reporter assay was used to study the effect of FLOT1 on the transcriptional activity of the downstream Golgi apparatus stress element promoter of TFE3. Western blotting, co-immunoprecipitation, and immunofluorescence staining were employed to detect relevant proteins.

Results: High FLOT1 expression was correlated with a poor prognosis in patients with HCC. The knockdown of FLOT1 suppressed the proliferation, migration, and invasion of HCC cells and promoted their apoptosis. Xenograft assays revealed that FLOT1 knockdown inhibited HCC tumorigenesis in vivo. Mechanistically, FLOT1 inhibited the expression of mechanistic target of rapamycin complex 1/2 proteins through ubiquitination and downstream effector p-S6 kinase-T389, leading to the dephosphorylation and nuclear translocation of TFE3 and promotion of Golgi stress-mediated responses, ultimately resulting in HCC progression.

Conclusion: FLOT1 recruits and inhibits mechanistic target of rapamycin complex 1/2, causing dephosphorylation and TFE3 nuclear translocation, thereby activating the Golgi stress response and further promoting the proliferation, migration, and invasion capabilities of HCC cells. These results underscore the potential of FLOT1 as a promising therapeutic target for HCC.

flotilin -1通过抑制mTORC1/2激活tfe3介导的高尔基应激反应,从而促进肝细胞癌的进展。
背景:探索有效的治疗靶点是提高肝细胞癌(HCC)患者生存率的关键。虽然许多研究都关注flotilin -1 (FLOT1)作为一种脂筏相关蛋白,通过调节一些蛋白或激酶的激活来促进肿瘤细胞的存活和增殖,但很少有研究探讨高尔基体功能的调节。目的:探讨FLOT1激活转录因子E3 (TFE3)下游高尔基应激反应,从而促进HCC进展的分子机制。方法:观察FLOT1在肝癌组织、肝癌细胞系和裸鼠肿瘤模型中的表达。研究了FLOT1沉默或过表达对HCC细胞增殖的影响。CCK-8、流式细胞术和transwell检测用于评估HCC细胞的增殖、细胞周期、迁移和侵袭能力。采用双荧光素酶报告试验研究了FLOT1对下游高尔基体应激元件启动子TFE3转录活性的影响。Western blotting、共免疫沉淀、免疫荧光染色检测相关蛋白。结果:HCC患者中FLOT1高表达与预后不良相关。FLOT1基因的下调抑制了肝癌细胞的增殖、迁移和侵袭,促进了肝癌细胞的凋亡。异种移植实验显示,FLOT1基因敲除抑制了体内HCC的肿瘤发生。在机制上,FLOT1通过泛素化和下游效应物p-S6激酶- t389抑制雷帕霉素复合物1/2蛋白的机制靶点的表达,导致TFE3的去磷酸化和核易位,促进高尔基应力介导的应答,最终导致HCC进展。结论:FLOT1招募并抑制雷帕霉素复合体1/2的机制靶点,引起去磷酸化和TFE3核易位,从而激活高尔基应激反应,进一步促进HCC细胞的增殖、迁移和侵袭能力。这些结果强调了FLOT1作为HCC治疗靶点的潜力。
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来源期刊
World Journal of Gastroenterology
World Journal of Gastroenterology 医学-胃肠肝病学
CiteScore
7.80
自引率
4.70%
发文量
464
审稿时长
2.4 months
期刊介绍: The primary aims of the WJG are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in gastroenterology and hepatology.
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