Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
Document Type
Article
Publication Date
5-1-2022
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.
Keywords
Factor receptor 1, Disintegrin, Sorafenib
Publication Title
Oncogene
Recommended Citation
Tsai, Yao-Tsung; Li, Chih-Yi; Huang, Yen-Hua; Chang, Te-Sheng; Lin, Chung-Yen; Chuang, Chia-Hsien; Wang, Chih-Yang; Anuraga, Gangga; Chang, Tzu-Hao; Shih, Tsung-Chieh; Lin, Zu-Yau; Chen, Yuh-Ling; Chung, Ivy; Lee, Kuen-Haur; Chang, Che-Chang; Sung, Shian-Ying; Yang, Kai-Huei; Tsui, Wan-Lin; Yap, Chee-Voon; and Wu, Ming-Heng, "Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts" (2022). Research Publications (2021 to 2025). 109.
https://knova.um.edu.my/research_publications_2021_2025/109
Divisions
fac_med
Funders
Chang Gung Memorial Hospital
Volume
41
Issue
21
Publisher
Springer Nature
Publisher Location
CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND