Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2025; 31(29): 106895
Published online Aug 7, 2025. doi: 10.3748/wjg.v31.i29.106895
Flotillin-1 promotes the progression of hepatocellular carcinoma by activating TFE3-mediated Golgi stress response via inhibition of mTORC1/2
Liang Zhang, Cheng-Zhi Bai, Jia-Yan Shan, Hong-Li Xue, Shu-Mei Zheng, Ya-Lun Chen, Shan-Hong Tang
Liang Zhang, Cheng-Zhi Bai, Jia-Yan Shan, Hong-Li Xue, Shu-Mei Zheng, Shan-Hong Tang, Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Cheng-Zhi Bai, Jia-Yan Shan, School of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
Ya-Lun Chen, Department of Geriatric Medicine, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
Co-first authors: Liang Zhang and Cheng-Zhi Bai.
Co-corresponding authors: Ya-Lun Chen and Shan-Hong Tang.
Author contributions: Chen YL and Tang SH designed the research study and contributed new reagents and analytic tools, they are the corresponding authors of this manuscript; Zhang L, Bai CZ, Shan JY, Xue HL, and Zheng SM performed the research; Zhang L and Bai CZ analyzed the data and wrote the manuscript, they are the co-first authors of this manuscript; and all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82203806; and the General Hospital of Western Theater Command Project Funding, No. 2024-YGJC-B10.
Institutional review board statement: The study was carried out in accordance with relevant guidelines and regulations. This present study was approved by the Institution Ethics Committee of the General Hospital of Western Theater Command (Approval No. 2020ky031).
Institutional animal care and use committee statement: The study was reviewed and approved by the Institution Ethics Committee of the General Hospital of Western Theater Command (Approval No. 2024EC5-ky039).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shan-Hong Tang, MD, PhD, Professor, Department of Gastroenterology, The General Hospital of Western Theater Command, No. 270 Rongdu Avenue, Jinniu District, Chengdu 610083, Sichuan Province, China. shanhongtang@163.com
Received: March 11, 2025
Revised: April 15, 2025
Accepted: July 14, 2025
Published online: August 7, 2025
Processing time: 147 Days and 6.8 Hours
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.

Keywords: Hepatocellular carcinoma; Flotillin-1; Transcription factor E3; Golgi stress; Proliferation

Core Tip: Research has found a close correlation between Golgi apparatus function and the survival of cancer cells. This study elucidates that elevated expression of flotillin-1 (FLOT1) promotes the proliferation, migration, and invasion capabilities of hepatocellular carcinoma (HCC), as well as the mechanism by which FLOT1 inhibits mechanistic target of rapamycin complex 1/2 by ubiquitination, leading to the dephosphorylation and nuclear translocation of the transcription factor transcription factor E3, thereby activating the Golgi stress response and further promoting the malignant biological behavior of HCC. These findings underscore the potential of the lipid raft protein FLOT1 as a promising therapeutic target for HCC treatment in clinical practice.