@article{0e16687a508d40ef8d30130c388c9409,
title = "Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts",
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 β-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-α → 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.",
author = "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 Gangga Anuraga and Chang, {Tzu Hao} and Shih, {Tsung Chieh} and Lin, {Zu Yau} and Chen, {Yuh Ling} and Ivy Chung 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}",
note = "Funding Information: We thank the National RNAi Core Facility at Academia Sinica, Taiwan for providing shRNA reagents and related services. We thank the Image and Bioinformatics Core Facility of Taipei Medical University for confocal microscopy and the microarray analysis. Human samples were from the Human Tumor Tissue Bank, Chang Gung Memorial Hospital (Chiayi, Taiwan). This work was financially supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Funding Information: We thank the National RNAi Core Facility at Academia Sinica, Taiwan for providing shRNA reagents and related services. We thank the Image and Bioinformatics Core Facility of Taipei Medical University for confocal microscopy and the microarray analysis. Human samples were from the Human Tumor Tissue Bank, Chang Gung Memorial Hospital (Chiayi, Taiwan). This work was financially supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Funding Information: This work was supported by grants MOST 107-2314-B-038-062, MOST 107-2320-B-038-062, MOST 108-2314-B-038-007, MOST 109-2314-B-038-134, MOST 110-2320-B-038-018, and MOST 110-2314-B-038-133 from the Ministry of Science and Technology, Taiwan; grants DP2-110-21121-01-T-03-01, DP2-109-21121-01-T-03-01, DP2-108-21121-01-T-02-04, and DP2-107-21121-T-02 from the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan; grants NHRI-EX109-10918BI, NHRI-EX110-10918BI and NHRI-EX111-10918BI from the National Health Research Institutes, Taiwan; and SATU Joint Research Grant ST039-2020. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = may,
day = "20",
doi = "10.1038/s41388-022-02309-7",
language = "English (US)",
volume = "41",
pages = "3011--3023",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "21",
}