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.
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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.
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.
TCS is an inventor of Galectin-1 inhibitor LLS30, and a scientific founder of Kibio Inc. which plans to develop the LLS30.
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Tsai, YT., Li, CY., Huang, YH. et al. Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts. Oncogene 41, 3011–3023 (2022). https://doi.org/10.1038/s41388-022-02309-7