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

Abstract

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 RNASEH2A with tumor progression; then expression of RNASEH2A mRNA and protein were detected in HCC tissues and cells subjected to hypoxia or with the treatment of CoCl2 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 RNASEH2A mRNA and protein were increased and dependent on hypoxia-inducible factor 2α in HCC tissues and cell lines. Knockout of RNASEH2A 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 IFIT1, USP18, and CXCL10, which suggests knockout of RNASEH2A 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.

• Authors: Fengbo Zhao, Aifen Liu, Xiu Gong, Hao Chen, Jinhuan Wei, Bin Chen, Shiyin Chen, Riyun Yang, Yihui Fan, Renfang Mao
• Journal: Tumori (Tumori) Vol. 108 Issue 1 Pg. 63-76 (Feb 2022) ISSN: 2038-2529 [Electronic] United States
• PMID: 34165025 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• CXCL10 protein, human
• Chemokine CXCL10
• IFIT1 protein, human
• Membrane Proteins
• RNA-Binding Proteins
• STING1 protein, human
• Nucleotidyltransferases
• cGAS protein, human
• ribonuclease HII
• Ribonuclease H
• USP18 protein, human
• Ubiquitin Thiolesterase

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Carcinoma, Hepatocellular (genetics, immunology, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Chemokine CXCL10 (genetics)
• Female
• Gene Expression Regulation, Neoplastic (immunology)
• Gene Knockout Techniques
• Hep G2 Cells
• Humans
• Liver Neoplasms (genetics, immunology, pathology)
• Male
• Membrane Proteins (genetics)
• Nucleotidyltransferases (genetics)
• Prognosis
• RNA-Binding Proteins (genetics)
• Ribonuclease H (genetics)
• Signal Transduction (genetics)
• Tumor Hypoxia (genetics)
• Tumor Microenvironment (immunology)
• Ubiquitin Thiolesterase (genetics)