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Int J Biol Sci 2024; 20(7):2763-2778. doi:10.7150/ijbs.93075 This issue Cite

Research Paper

Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma

Zhi-Yong Liu1,2*, Xia-Hui Lin1,2*, Hong-Ying Guo1,2*, Xuan Shi1,2, Dan-Ying Zhang1,2, Jia-Lei Sun1,2, Guang-Cong Zhang1,2, Ru-Chen Xu1,2, Fu Wang1,2, Xiang-Nan Yu1,2, Dou Wang3, Shu-Qiang Weng1,2, Xi-Zhong Shen1,2,4, Tao-Tao Liu1,2, Ling Dong1,2✉, Ji-Min Zhu1,2✉

1. Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
2. Shanghai Institute of Liver Diseases, Shanghai 200030, China.
3. Department of Gastroenterology, Shigatse People's Hospital, Shigatse, Tibet 857000, China.
4. Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai 200030, China.
* These authors contributed equally.

✉ Corresponding authors: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China; E-mail addresses: dong.lingsh.cn (LD) and zhu.jiminsh.cn (JMZ).

Citation:
Liu ZY, Lin XH, Guo HY, Shi X, Zhang DY, Sun JL, Zhang GC, Xu RC, Wang F, Yu XN, Wang D, Weng SQ, Shen XZ, Liu TT, Dong L, Zhu JM. Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma. Int J Biol Sci 2024; 20(7):2763-2778. doi:10.7150/ijbs.93075. https://www.ijbs.com/v20p2763.htm
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Abstract

Graphic abstract

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting β-catenin/TGF-β1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Keywords: ALDH2, Metabolic disturbance, TNFRSF18 (GITR), Regulatory T cells, Liver cancer

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APA
Liu, Z.Y., Lin, X.H., Guo, H.Y., Shi, X., Zhang, D.Y., Sun, J.L., Zhang, G.C., Xu, R.C., Wang, F., Yu, X.N., Wang, D., Weng, S.Q., Shen, X.Z., Liu, T.T., Dong, L., Zhu, J.M. (2024). Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma. International Journal of Biological Sciences, 20(7), 2763-2778. https://doi.org/10.7150/ijbs.93075.

ACS
Liu, Z.Y.; Lin, X.H.; Guo, H.Y.; Shi, X.; Zhang, D.Y.; Sun, J.L.; Zhang, G.C.; Xu, R.C.; Wang, F.; Yu, X.N.; Wang, D.; Weng, S.Q.; Shen, X.Z.; Liu, T.T.; Dong, L.; Zhu, J.M. Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma. Int. J. Biol. Sci. 2024, 20 (7), 2763-2778. DOI: 10.7150/ijbs.93075.

NLM
Liu ZY, Lin XH, Guo HY, Shi X, Zhang DY, Sun JL, Zhang GC, Xu RC, Wang F, Yu XN, Wang D, Weng SQ, Shen XZ, Liu TT, Dong L, Zhu JM. Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma. Int J Biol Sci 2024; 20(7):2763-2778. doi:10.7150/ijbs.93075. https://www.ijbs.com/v20p2763.htm

CSE
Liu ZY, Lin XH, Guo HY, Shi X, Zhang DY, Sun JL, Zhang GC, Xu RC, Wang F, Yu XN, Wang D, Weng SQ, Shen XZ, Liu TT, Dong L, Zhu JM. 2024. Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma. Int J Biol Sci. 20(7):2763-2778.

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