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

Oncogene volume 41, pages 3011–3023 (2022)Cite this article

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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.

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Fig. 1: Gal-1 is a CAF marker and is correlated with the poor prognosis of hepatocellular carcinoma (HCC) patients.
Fig. 2: Knockdown of Gal-1 in HSCs and CAFs inhibits the invasive and stemness-like properties of hepatocellular carcinoma (HCC) cells.
Fig. 3: Plasminogen activator inhibitor-2 (PAI-2)/serpin family B member 2 (SERPINB2) is a critical downstream gene of Gal-1.
Fig. 4: Gal-1 regulates PAI-2/SERPINB2 through the JNK/c-Jun/ATF2 signaling axis.
Fig. 5: Targeting Gal-1 induces ADAM17-dependent TNFR1 shedding.
Fig. 6: Knockdown of Gal-1 in carcinoma-associated fibroblasts (CAFs) inhibits CAF-promoted hepatocellular carcinoma (HCC) progression and reprograms the inflammatory microenvironment.
Fig. 7: A proposed model depicting the role of Gal-1 in tumor-stroma crosstalk in HCC.

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Acknowledgements

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

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.

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Author notes

  1. These authors contributed equally: Yao-Tsung Tsai, Chih-Yi Li.

Authors and Affiliations

  1. International PhD Program for Translational Science, Taipei Medical University, Taipei, Taiwan

    Yao-Tsung Tsai, Chih-Yi Li, Che-Chang Chang, Shian-Ying Sung, Kai-Huei Yang, Wan-Lin Tsui, Chee-Voon Yap & Ming-Heng Wu

  2. Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan

    Yao-Tsung Tsai, Chih-Yi Li, Yen-Hua Huang, Che-Chang Chang, Shian-Ying Sung, Kai-Huei Yang, Wan-Lin Tsui, Chee-Voon Yap & Ming-Heng Wu

  3. Department of Biochemistry and Molecular Cell Biology, Taipei Medical University, Taipei, Taiwan

    Yen-Hua Huang

  4. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yen-Hua Huang

  5. Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan

    Yen-Hua Huang & Ming-Heng Wu

  6. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Te-Sheng Chang

  7. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Te-Sheng Chang

  8. Institute of Information Science, Academia Sinica, Taipei, Taiwan

    Chung-Yen Lin & Chia-Hsien Chuang

  9. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

    Chih-Yang Wang, Gangga Anuraga & Kuen-Haur Lee

  10. Graduate Institute of Biomedical Informatics, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan

    Tzu-Hao Chang

  11. Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA

    Tsung-Chieh Shih

  12. Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Zu-Yau Lin

  13. Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Zu-Yau Lin

  14. Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yuh-Ling Chen

  15. Universiti Malaya Cancer Research Institute, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia

    Ivy Chung

  16. Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia

    Ivy Chung

  17. TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan

    Ming-Heng Wu

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  1. Yao-Tsung Tsai
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Contributions

Conception and design: MHW. Development of methodology: MHW, YTT, and CYL. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): YHH, TSC, CYL, ZYL, and YLC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): CHC, CYW, THC, SYS, KHY, WLT, GA, CVY, and MHW. Writing, review, and/or revision of the manuscript: IC, KHL, CCC and MHW. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): ZYL, YLC, and TCS. Study supervision: MHW.

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Correspondence to Ming-Heng Wu.

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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

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