1. IGFALS suppresses hepatocellular carcinoma progression by stabilizing PPAR-γ.
- Author
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Xu L, Xiong L, Chen Y, Chen J, Liu X, Xu Y, Shen Y, Wang S, Yu S, and Xu X
- Subjects
- Humans, Animals, Mice, Nude, Cell Line, Tumor, Mice, Epithelial-Mesenchymal Transition, Male, Cell Movement, Mice, Inbred BALB C, Xenograft Model Antitumor Assays, Insulin-Like Growth Factor I metabolism, Gene Expression Regulation, Neoplastic, Disease Progression, Insulin-Like Growth Factor II metabolism, Insulin-Like Growth Factor II genetics, Hep G2 Cells, Insulin-Like Growth Factor Binding Protein 3, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms metabolism, Liver Neoplasms pathology, PPAR gamma metabolism, PPAR gamma genetics, Cell Proliferation
- Abstract
IGFALS forms stable ternary complexes with insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins (IGFBP3 and IGFBP5), which prolong the half-lives of IGFs. Through immunohistochemical analysis of 90 pairs of clinical samples and bioinformatics analysis, we observed downregulation of IGFALS in hepatocellular carcinoma tissues, which was associated with poor patient prognosis. This prompted us to explore the specific molecular mechanism of action of IGFALS in the inhibition of hepatocellular carcinoma (HCC), which could be a potential new target for the treatment of HCC. In vitro experiments demonstrated that IGFALS inhibits the proliferation, invasion, and migration of hepatocellular carcinoma cells and suppresses epithelial-mesenchymal transition. Gene Set Enrichment Analysis (GSEA) revealed a positive correlation between IGFALS and the activation of the PPAR pathway. Western blotting, immunofluorescence colocalization, and co-immunoprecipitation assays confirmed that IGFALS binds to PPAR-γ and stabilizes it through deubiquitination. Inhibition of PPAR-γ reversed the anticancer effects of IGFALS. Furthermore, we showed that IGFALS/PPAR-γ upregulates the expression of HMGCS2. The tumor xenograft model supported our findings. Mass spectrometry analysis and co-immunoprecipitation assays indicated that IGFALS promotes the binding of PPAR-γ with USP9X, a deubiquitinating enzyme, thereby facilitating the deubiquitination of PPAR-γ. In conclusion, our findings demonstrate that IGFALS can suppress hepatocellular carcinoma via the PPAR-γ/HMGCS2 pathway., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ximing Xu reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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