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Th22/IL-22 mediates the progression of HBV-related hepatocellular carcinoma via STAT3

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Abstract

T helper cell 22 are abundant in Hepatitis B Virus-related hepatocellular carcinoma tissue, and the main cytokine interleukin 22 produced by Th22 cells is closely related to the initiation and development of HCC. Understanding the role of Th22/IL-22 in the progression of HBV-related HCC will facilitate new therapeutic development. Th22 cells were isolated from peripheral blood of healthy donors and co-cultured with HBV positive HepG2.2.15 cells. IL-22 secretion and HepG2.2.15 cell proliferation and apoptosis were monitored. Expressions of p-STAT3, Cyclin D1, Bcl-2, and cleaved caspase 3 were detected by Western blot analysis. Th22 cells significantly promoted the proliferation and inhibited the apoptosis of HepG2.2.15 cells; up-regulated expression of p-STAT3, Cyclin D1 and Bcl-2, and down-regulated cleaved caspase 3 in HepG2.2.15 cells. These effects were significantly attenuated when IL-22 and STAT3 was knockdown in Th22 and HepG2.2.15 cells, respectively. Our data suggests that HBV induces host Th22 cells to overexpress IL-22, which in turn triggers over-activation of STAT3 and its downstream signaling proteins to promote HCC progression.

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Data availability

The datasets generated and analyzed during the study are available from the corresponding author on request.

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Funding

This work was supported by the Natural Science Foundation of China (No. 81760514) and Youth Science Fund of Jiangxi Provincial Science and Technology Department (No. 20161BAB215252).

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  1. Jia Zhang and Zhou Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, People’s Republic of China

    Jia Zhang, Lingpeng Liu, Mingwen Huang & Yong Huang

  2. Department of Internal Medicine, Jiangxi Provincial Chest Hospital, Nanchang, Jiangxi, 330006, People’s Republic of China

    Zhou Liu

Authors
  1. Jia Zhang
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  2. Zhou Liu
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  3. Lingpeng Liu
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  4. Mingwen Huang
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  5. Yong Huang
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Correspondence to Yong Huang.

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10616_2021_517_MOESM1_ESM.tif

Supplementary file1—Figure S1 The identification of Th22 cells. After PBMCs were sorted by magnetic beads, flow cytometry was used to identify the proportions of CD4, IL-22, IFN-γ and IL-17 expressing cells in the isolated cells. ELISpot was used to detect the expression of IL-22 in the isolated cells. (A) Flow cytometry of CD4 positive cells in sorted cells. (B) Flow cytometry of IL-22 positive cells in isolated cells. (C) Flow cytometry of IFN-γ positive cells in isolated cells. (D) Flow cytometry of IL-17 positive cells in isolated cells. (E-F) The isolated cells were stimulated for 4 h with 50 ng/ml phorbol 12-myristate 13-acetate and 1mg/ml ionomycin (Sigma-Aldrich) and ELISpot was used to observe the production of IL-22. The representative image of IL-22 ELISpot in negative control was shown in E and the representative image of IL-22 ELISpot after incubating with Th22 cells isolated from PBMCs was shown in F. (TIF 1001 kb)

10616_2021_517_MOESM2_ESM.tif

Supplementary file2—Figure S2 Effects of shIL-22 and shSTAT3 on proteins expression of IL-22 and STAT3 in Th22 and HepG2.2.15 cells, respectively. (A) Th22 cells were infected with shNC/shIL-22 recombinant adenovirus. After 48h, phorbol 12-myristate 13-acetate plus ionomycin was used to stimulate Th22 cells for 4h to produce IL-22. Western blotting was used to detect the IL-22 protein expression level in Th22 cells. (B) HepG2.2.15 cells were infected with shNC/shSTAT3 recombinant adenovirus. After 48h, Western blotting was used to detect the STAT3 protein expression level in HepG2.2.15 cells. Data are presented as the means ± standard error of the mean for six independent experiments. *P <0.05 vs. shNC group. (TIF 1124 kb)

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Zhang, J., Liu, Z., Liu, L. et al. Th22/IL-22 mediates the progression of HBV-related hepatocellular carcinoma via STAT3. Cytotechnology 74, 203–216 (2022). https://doi.org/10.1007/s10616-021-00517-9

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