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
Menée à l'aide de données du projet "The Cancer Genome Atlas" et à l'aide d'échantillons tissulaires de carcinomes hépatocellulaires, cette étude met en évidence un mécanisme par lequel le facteur IRF-1, en réduisant l'expression de la kinase CHK1 via le microARN miR-195, augmente l'apoptose des cellules cancéreuses et l'expression de PDL-1 par ces dernières
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.