Published online Aug 7, 2025. doi: 10.3748/wjg.v31.i29.106895
Revised: April 15, 2025
Accepted: July 14, 2025
Published online: August 7, 2025
Processing time: 146 Days and 22.4 Hours
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.
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.
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.
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.
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.
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.