OPA3 inhibits the cGAS-STING pathway mediated by mtDNA stress to promote colorectal cancer progression.

Abstract

Colorectal cancer (CRC) is an extremely harmful malignant tumor. Optic atrophy 3 (OPA3) is highly expressed in multiple tumors, but its action in CRC is still unknown. This research aims to explore the role of OPA3 and its related molecular mechanisms for CRC. Firstly, we overexpressed and knocked down OPA3 to examine its effect on CRC cell (HT29 cell) growth. CRC cell viability, migration, invasion, and levels of proliferation markers and cell cycle-associated proteins were measured. Then, we treated cells with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to explore mitochondrial dysfunction and mtDNA stress in HT29 cells. Next, we overexpressed cGAS and STING to examine their correlation with OPA3. The results showed that OPA3 overexpression enhanced CRC cell viability, migration, invasion, and the levels of PCNA, Cyclin A2, and Cyclin B1. Knockdown of OPA3 had the opposite effects. Moreover, OPA3 knockdown facilitated mitochondrial dysfunction and mtDNA stress in CRC cells. OPA3 overexpression also inhibited CCCP-induced mitochondrial stress disorder. Additionally, OPA3 knockdown elevated the protein levels of p-STING and cGAS and the mRNA level of STING target genes. Furthermore, overexpression of either cGAS or STING partially alleviated the enhancement of HT29 cell proliferation, migration, and invasion mediated by OPA3 overexpression. In conclusion, OPA3 promotes CRC progression via inhibiting the cGAS-STING pathway, which is mediated by mtDNA stress. OPA3 may be a new potential target for CRC.