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c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway

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Abstract

Sorafenib acquired drug resistance during the treatment of hepatocellular carcinoma (HCC) reduces the efficacy of the drug. The immune escape effect induced by PD-L1 is largely associated with drug resistance of HCC. However, the regulated mechanism of PD-L1 is unclear. This research aimed to clarify the control mechanism of PD-L1. c-Met was found abnormally highly expressed in Huh-7SR with high PD-L1 expression. In addition, c-Met, as the upstream target molecule of PD-L1, promoted the proliferation and migration of HCC in vitro and in vivo. We also found that c-Met activated the MAPK signaling pathway and the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. In conclusion, c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC. The role of c-Met and PD-L1 in HCC needs to be further studied, but it is a potential target for the treatment of HCC.

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Key messages

  • In the study, it was found that c-Met is also abnormally highly expressed in Huh-7SR with high PD-L1 expression and can promote the development of HCC in vitro and in vivo. PD-L1 and c-Met expression levels are positively correlated.

  • In the follow-up mechanism study, we found that c-Met activated the MAPK signaling pathway and subsequently activated the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression.

  • Our study found that c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The National Natural Science Fund of China (82071862, 81872017), University Natural Science Research Project of Anhui Province (KJ2018ZD011, KJ2020A0340, KJ2019A0093), Anhui Provincial Science and Technology program (202004j07020053), and Research Foundation of the Institute of Environment-friendly Materials and Occupational Health (Wuhu), Anhui University of Science and Technology (ALW2020YF11) funded this research.

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  1. Ruyue Xu, Xinkuang Liu, Amin Li, Li Song, Jiaojiao Liang, and Jiafeng Gao contributed equally to this work.

Authors and Affiliations

  1. Medical School, Anhui University of Science & Technology, Huainan, 232001, China

    Ruyue Xu, Xinkuang Liu, Amin Li, Li Song, Jiaojiao Liang, Jiafeng Gao & Xiaolong Tang

  2. Institute of Environmentally-Friendly Materials and Occupational Health, Anhui University of Science and Technology (Wuhu), Wuhu, 241003, China

    Ruyue Xu, Amin Li, Li Song, Jiaojiao Liang, Jiafeng Gao & Xiaolong Tang

  3. Clinical Laboratory Medicine, First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China

    Xinkuang Liu

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  1. Ruyue Xu
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Contributions

Ruyue Xu, Xinkuang Liu, Yongfang Ma, Amin Li, Li Song, Jiaojiao Liang, and Jiafeng Gao conceived the study and participated in the data analysis and drafting, and wrote the manuscript. Ruyue Xu participated in the design of the study and carried out the animal and cell experiments. Xiaolong Tang conceived and designed the study. All authors read and approved the final manuscript.

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Correspondence to Xiaolong Tang.

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Xu, R., Liu, X., Li, A. et al. c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway. J Mol Med 100, 585–598 (2022). https://doi.org/10.1007/s00109-022-02179-2

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