2. Academic Validation
  3. Interferon regulatory factor 1 (IRF-1) downregulates Checkpoint kinase 1 (CHK1) through miR-195 to upregulate apoptosis and PD-L1 expression in Hepatocellular carcinoma (HCC) cells

Interferon regulatory factor 1 (IRF-1) downregulates Checkpoint kinase 1 (CHK1) through miR-195 to upregulate apoptosis and PD-L1 expression in Hepatocellular carcinoma (HCC) cells

  • Br J Cancer. 2021 Jul;125(1):101-111. doi: 10.1038/s41416-021-01337-6.
Yihe Yan  # 1 2,  Leting Zheng  # 3 4,  Qiang Du 3,  Xiao Cui 3,  Kun Dong 3,  Yarong Guo 3,  David A Geller 5
Affiliations

Affiliations

  • 1 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].
  • 2 Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China. [email protected].
  • 3 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 4 Department of Rheumatology and Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
  • 5 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].
  • # Contributed equally.
PMID: 33772151 DOI: 10.1038/s41416-021-01337-6
Abstract

Background: Chk1 is considered an oncogene with overexpression in numerous cancers. However, Chk1 signalling regulation in hepatocellular carcinoma (HCC) remains unclear.

Methods: CHEK1 mRNA, protein, pri-miR-195 and miR-195 expression in HCC tissue was determined by qPCR, WB and IF staining assay. Survival analyses in HCC with high- and low-CHEK1 mRNA expression was performed using TCGA database. Relative luciferase activity was investigated in HCC cells transfected with p-CHEK1 3'UTR. Apoptosis was detected by TUNEL assay. NK and CD8+ T cells were analysed by flow cytometry.

Results: Chk1 is increased in human HCC tumours compared with non-cancerous liver. High Chk1 predicts worse prognosis. IFN-γ suppresses Chk1 via IRF-1 in HCC cells. The molecular mechanism of IRF-1 suppressing Chk1 is post-transcriptional by promoting miR-195 binding to CHEK1 mRNA 3'UTR, which exerts a translational blockade. Upregulated IRF-1 inhibits Chk1, which induces Apoptosis of HCC cells. Likewise, Chk1 inhibition augments cellular Apoptosis in HCC tumours. This effect may be a result of increased tumour NK cell infiltration. However, IRF-1 expression or Chk1 inhibition also upregulates PD-L1 expression via increased STAT3 phosphorylation.

Conclusions: IRF-1 induces miR-195 to suppress Chk1 protein expression. Both increased IRF-1 and decreased Chk1 upregulate cellular Apoptosis and PD-L1 expression in HCC.

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