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

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

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 be...

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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/
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spelling	my.um.eprints.428782023-10-06T07:23:25Z http://eprints.um.edu.my/42878/ Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts 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 R Medicine RM Therapeutics. Pharmacology 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. Springer Nature 2022-05 Article PeerReviewed 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 <https://doi.org/10.1038/s41388-022-02309-7>. 10.1038/s41388-022-02309-7
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	R Medicine RM Therapeutics. Pharmacology
spellingShingle	R Medicine RM Therapeutics. Pharmacology 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 Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
description	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.
format	Article
author	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
author_facet	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
author_sort	Tsai, Yao-Tsung
title	Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
title_short	Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
title_full	Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
title_fullStr	Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
title_full_unstemmed	Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts
title_sort	galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing tnfr1 protein stability and signaling in carcinoma-associated fibroblasts
publisher	Springer Nature
publishDate	2022
url	http://eprints.um.edu.my/42878/
_version_	1781704655809544192
score	13.211869

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

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