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Liver-specific overexpression of Gab2 accelerates hepatocellular carcinoma progression by activating immunosuppression of myeloid-derived suppressor cells

Oncogene volume 41, pages 3316–3327 (2022)Cite this article

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A Correction to this article was published on 06 May 2022

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Abstract

GRB2-associated-binding protein 2 (Gab2) deletion has a preventive effect of on chronic liver inflammation and hepatocellular carcinoma. This study was aimed to elaborate Gab2-initiated immunoregulation during hepatocarcinogenesis. Compared to wild-type group, liver-specific overexpression of Gab2 mice (L-Gab2) displayed early hepatocarcinogenesis after 5-month diethylnitrosamine (DEN) induction, and accelerated tumor growth after 9-month DEN challenge. More myeloid-derived suppressor cells (MDSCs) were observed in DEN-challenged L-Gab2 mice than that in DEN-treated wild-type mice. Additionally, MDSCs activation-induced tumor angiogenesis capability and immunosuppression function were exceedingly activated in DEN-exposed L-Gab2 mice, which reflected in the increased platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial growth factor (VEGF), and the decreased cytotoxic T lymphocytes. Mechanistically, DEN-challenged L-Gab2 mice produced more IL-6, and IL-6 depletion significantly deprived Gab2-overexpression-mediated tumor-promotion phenomena, accompanied by the impairment of MDSCs-initiated immunosuppression function. MDSCs isolated from IL-6-depleted L-Gab2 mice or inactivating MDSCs partly restored the immune function of cytotoxic T cells. Of note, MDSCs gene signatures had a significant association with the increased Gab2 or IL6 in hepatoma specimens. Collectively, L-Gab2 mice accelerated hepatoma progression possibly through activating IL-6-initiated the activation of MDSCs. This study provides a novel insights for exploring the role of Gab2 in autoimmune tolerance during hepatocarcinogenesis.

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Fig. 1: Effects of Gab2 overexpression on early hepatocarcinogenesis.
Fig. 2: Effects of Gab2 overexpression on tumor growth.
Fig. 3: Measurement of MDSCs accumulation and activity in WT and L-Gab2 mice.
Fig. 4: Role of IL-6 knockdown on tumor growth in L-Gab2 mice.
Fig. 5: Role of IL-6 knockdown on MDSCs activation in L-Gab2 mice.
Fig. 6: Association analysis among Gab2, MDSCs and IL-6 in human liver cancer specimens.

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Acknowledgements

We thank the Gene Expression Profiling Interactive Analysis 2.0 online database (GEPIA2). This work was supported by the grants from Natural Science Foundation of China (81802332 and 82103189), Natural Science Foundation of Fujian Province (2020J05302 and 2021J011358), Science Foundation of the Fujian provincial Commission of Health and Family Planning (2021GGB026) and Natural Science Basic Research Program of Shaanxi Province (2021JQ-780).

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  1. These authors contributed equally: Shuai Chen, Jianghong Cheng.

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, PR China

    Shuai Chen & Xianyang Luo

  2. Xi’an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi’an Medical University, Xi’an, 710021, China

    Jianghong Cheng

  3. School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, 361005, China

    Yanhong Zhong, Ruimin Liu & Zhongxian Lu

  4. Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, 361003, China

    Xianyang Luo

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Contributions

ZL and XL designed the study; SC and JC performed research and drafted the paper; YZ and RL participated in the exploration of MDSCs function and helped in histology and IHC staining; SC and JC performed clinical correlation analysis; SC and RL contributed to the statistical analysis, and all authors polished and approved the final paper.

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Correspondence to Zhongxian Lu or Xianyang Luo.

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Chen, S., Cheng, J., Zhong, Y. et al. Liver-specific overexpression of Gab2 accelerates hepatocellular carcinoma progression by activating immunosuppression of myeloid-derived suppressor cells. Oncogene 41, 3316–3327 (2022). https://doi.org/10.1038/s41388-022-02298-7

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