TGF-β1 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m6A modification

  • Cell Death Dis. 2024 Jun 17;15(6):422. doi: 10.1038/s41419-024-06800-9.
Zhenheng Wu  #  1  2  3  4 ,  Qiming Ke  #  1  2  3  4 ,  Lei Jiang  1  2 ,  Haijie Hong  1  2 ,  Wei Pan  1  2 ,  Wen Chen  1  2 ,  Xiahenazi Abudukeremu  1  2 ,  Feifei She  5  6 ,  Yanling Chen  7  8  9  10
Affiliations
  • 1. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China.
  • 2. Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China.
  • 3. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China.
  • 4. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China.
  • 5. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China. [email protected].
  • 6. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China. [email protected].
  • 7. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China. [email protected].
  • 8. Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China. [email protected].
  • 9. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China. [email protected].
  • 10. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China. [email protected].
  • # Contributed equally.
PMID: 38886389 DOI: 10.1038/s41419-024-06800-9
Abstract

TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (m6A) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-β1 with mRNA m6A modification, especially the effect of mRNA translation efficiency associated with m6A modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-β1 expression in GBC. Overexpression of FOXA1 inhibited TGF-β1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-β1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-β1 promoted m6A modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-β1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting m6A modification on the CDS region of FOXA1 mRNA. Moreover, TGF-β1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-β1 in regulating TGF-β1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through m6A modification.

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