Hypoxia-induced RNASEH2A limits activation of cGAS-STING signaling in HCC and predicts poor prognosis.

Background: Hypoxia is a hallmark of solid cancers, including hepatocellular carcinoma (HCC). There is scarce information about how hypoxia avoids immunologic stress and maintains a cancer-promoting microenvironment.

Methods: The Cancer Genome Atlas, RNA-seq data, and Oncomine database were used to discover the correlation of with tumor progression; then expression of mRNA and protein were detected in HCC tissues and cells subjected to hypoxia or with the treatment of CoCl via real-time quantitative polymerase chain reaction and immunochemistry assays. Finally, the effect of RNASEH2A on cell proliferation and the involved signaling pathway was explored further.

Results: RNASEH2A was positively correlated with tumor grade, size, vascular invasion, and poor prognosis. The expression of mRNA and protein were increased and dependent on hypoxia-inducible factor 2α in HCC tissues and cell lines. Knockout of in HCC cells greatly reduced cell proliferation and induced the transcription of multiple cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) targeted type 1 interferon-related genes, including , and , which suggests knockout of may produce immunologic stress and tumor suppressive effects.

Conclusions: RNASEH2A plays a critical role and potentially predicts patient outcomes in HCC, which uncovers a new mechanism that RNASEH2A contributes to limit immunologic stress of cancer cells in the context of hypoxia.