OPA3 Inhibits the CGAS-STING Pathway Mediated by MtDNA Stress to Promote Colorectal Cancer Progression

Overview

Journal In Vitro Cell Dev Biol Anim

Publisher Springer

Specialties Biology
Cell Biology

Date 2024 Dec 26

PMID 39725842

Authors

Yuqiang Yin

Zhenxin Ma

Siwen Yuan

Kangfeng Xu

Xiaofeng Wang

Affiliations

Soon will be listed here.

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.

References

Abdelmaksoud N, Abulsoud A, Abdelghany T, Elshaer S, Rizk S, Senousy M . Mitochondrial remodeling in colorectal cancer initiation, progression, metastasis, and therapy: A review. Pathol Res Pract. 2023; 246:154509. DOI: 10.1016/j.prp.2023.154509. View

Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini M . Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2020; 22(9):998-1009. DOI: 10.2174/1389450121999201117115717. View

Biller L, Schrag D . Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021; 325(7):669-685. DOI: 10.1001/jama.2021.0106. View

Bychkov I, Itkis Y, Tsygankova P, Krylova T, Mikhaylova S, Klyushnikov S . Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes. Mitochondrion. 2021; 57:205-212. DOI: 10.1016/j.mito.2021.01.004. View

Chen C, Xu P . Cellular functions of cGAS-STING signaling. Trends Cell Biol. 2022; 33(8):630-648. DOI: 10.1016/j.tcb.2022.11.001. View

Dekker E, Tanis P, Vleugels J, Kasi P, Wallace M . Colorectal cancer. Lancet. 2019; 394(10207):1467-1480. DOI: 10.1016/S0140-6736(19)32319-0. View

Gonzalez-Magana A, Blanco F . Human PCNA Structure, Function and Interactions. Biomolecules. 2020; 10(4). PMC: 7225939. DOI: 10.3390/biom10040570. View

Guo W, Liu Y, Ji X, Guo S, Xie F, Chen Y . Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics. 2023; 13(1):324-338. PMC: 9800724. DOI: 10.7150/thno.78718. View

Ha B, Jung S, Shon Y . Effects of proton beam irradiation on mitochondrial biogenesis in a human colorectal adenocarcinoma cell line. Int J Oncol. 2017; 51(3):859-866. DOI: 10.3892/ijo.2017.4067. View

10.

Hopfner K, Hornung V . Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020; 21(9):501-521. DOI: 10.1038/s41580-020-0244-x. View

11.

Huang Y, Lu C, Wang H, Gu L, Fu Y, Li G . DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability. Nat Commun. 2023; 14(1):5246. PMC: 10462666. DOI: 10.1038/s41467-023-40952-0. View

12.

Jin M, Li J, Hu R, Xu B, Huang G, Huang W . Cyclin A2/cyclin-dependent kinase 1-dependent phosphorylation of Top2a is required for S phase entry during retinal development in zebrafish. J Genet Genomics. 2021; 48(1):63-74. DOI: 10.1016/j.jgg.2021.01.001. View

13.

Johdi N, Sukor N . Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol. 2020; 11:1624. PMC: 7530194. DOI: 10.3389/fimmu.2020.01624. View

14.

Ka N, Park M, Kim S, Jeon Y, Hwang S, Kim S . NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling. Cancer Res. 2023; 83(18):3045-3058. PMC: 10538367. DOI: 10.1158/0008-5472.CAN-23-0329. View

15.

Kalpage H, Bazylianska V, Recanati M, Fite A, Liu J, Wan J . Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 2018; 33(2):1540-1553. PMC: 6338631. DOI: 10.1096/fj.201801417R. View

16.

Kaneta A, Nakajima S, Okayama H, Matsumoto T, Saito K, Kikuchi T . Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer. Cancer Immunol Immunother. 2022; 71(11):2765-2776. PMC: 10992387. DOI: 10.1007/s00262-022-03200-w. View

17.

Khorasani M . Role of cGAS-STING in colorectal cancer: A new window for treatment strategies. Cytokine. 2023; 173:156422. DOI: 10.1016/j.cyto.2023.156422. View

18.

Liu M, Du Q, Mao G, Dai N, Zhang F . MYB proto-oncogene like 2 promotes hepatocellular carcinoma growth and glycolysis via binding to the promoter and activating its expression. Bioengineered. 2022; 13(3):5344-5356. PMC: 8973866. DOI: 10.1080/21655979.2021.2017630. View

19.

Liu Y, Huang Y, Xu C, An P, Luo Y, Jiao L . Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases. Int J Mol Sci. 2022; 23(24). PMC: 9788331. DOI: 10.3390/ijms232416053. View

20.

Meng N, Glorieux C, Zhang Y, Liang L, Zeng P, Lu W . Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells. Cancers (Basel). 2019; 12(1). PMC: 7016999. DOI: 10.3390/cancers12010065. View