Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts

• Main Authors: 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, Wu, Ming-Heng
• Format: Article
• Published: Springer Nature 2022
• Subjects: R Medicine; RM Therapeutics. Pharmacology
• Online Access: http://eprints.um.edu.my/42878/
• Institution: Universiti Malaya

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.