Tsai, Yao-Tsung and Li, Chih-Yi and Huang, Yen-Hua and Chang, Te-Sheng and Lin, Chung-Yen and Chuang, Chia-Hsien and Wang, Chih-Yang and Anuraga, Gangga and Chang, Tzu-Hao and Shih, Tsung-Chieh and Lin, Zu-Yau and Chen, Yuh-Ling and Chung, Ivy and Lee, Kuen-Haur and Chang, Che-Chang and Sung, Shian-Ying and Yang, Kai-Huei and Tsui, Wan-Lin and Yap, Chee-Voon and Wu, Ming-Heng (2022) Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts. Oncogene, 41 (21). pp. 3011-3023. ISSN 0950-9232, DOI https://doi.org/10.1038/s41388-022-02309-7.
Full text not available from this repository.Abstract
Most cases of hepatocellular carcinoma (HCC) arise with the fibrotic microenvironment where hepatic stellate cells (HSCs) and carcinoma-associated fibroblasts (CAFs) are critical components in HCC progression. Therefore, CAF normalization could be a feasible therapy for HCC. Galectin-1 (Gal-1), a beta-galactoside-binding lectin, is critical for HSC activation and liver fibrosis. However, few studies has evaluated the pathological role of Gal-1 in HCC stroma and its role in hepatic CAF is unclear. Here we showed that Gal-1 mainly expressed in HCC stroma, but not cancer cells. High expression of Gal-1 is correlated with CAF markers and poor prognoses of HCC patients. In co-culture systems, targeting Gal-1 in CAFs or HSCs, using small hairpin (sh)RNAs or an therapeutic inhibitor (LLS30), downregulated plasminogen activator inhibitor-2 (PAI-2) production which suppressed cancer stem-like cell properties and invasion ability of HCC in a paracrine manner. The Gal-1-targeting effect was mediated by increased a disintegrin and metalloprotease 17 (ADAM17)-dependent TNF-receptor 1 (TNFR1) shedding/cleavage which inhibited the TNF-alpha -> JNK -> c-Jun/ATF2 signaling axis of pro-inflammatory gene transcription. Silencing Gal-1 in CAFs inhibited CAF-augmented HCC progression and reprogrammed the CAF-mediated inflammatory responses in a co-injection xenograft model. Taken together, the findings uncover a crucial role of Gal-1 in CAFs that orchestrates an inflammatory CSC niche supporting HCC progression and demonstrate that targeting Gal-1 could be a potential therapy for fibrosis-related HCC.
| Item Type: | Article |
|---|---|
| Funders: | Chang Gung Memorial Hospital |
| Uncontrolled Keywords: | Factor receptor 1; Disintegrin; Sorafenib |
| Subjects: | R Medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 06 Oct 2023 07:23 |
| Last Modified: | 06 Oct 2023 07:23 |
| URI: | http://eprints.um.edu.my/id/eprint/42878 |
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