ITGA2 overexpression inhibits DNA repair and confers sensitivity to radiotherapies in pancreatic cancer. (28th October 2022)

• Record Type: Journal Article
• Authors: Zhou, Chen; Li, Shoukang; Bin, Kaijian; Qin, Gengdu; Pan, Penglin; Ren, Dianyun; Zhao, Yuhan; Xia, Wentao; Chen, Jie; Liu, Jiaying; Wu, Heshui; Zhou, Yingke
• Is Part Of: Cancer letters. Volume 547(2022)
• Publication Date: 2022-10-28
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215855
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a 5-year survival rate of less than 10%, despite the recent advances in chemoradiotherapy. The sensitivity of the PDAC patients to chemoradiotherapy varies widely, especially to radiotherapy, suggesting the need for more elucidation of the underlying mechanisms. In this study, a novel function of the nuclear ITGA2, the alpha subunit of transmembrane collagen receptor integrin alpha-2/beta-1, regulating the DNA damage response (DDR), was identified. First, analyzing The Cancer Genome Atlas (TCGA) PDAC data set indicated that the expression status of ITGA2 was negatively correlated with the genome stability parameters. The study further demonstrated that ITGA2 specially inhibited the activity of the non-homologous end joining (NHEJ) pathway and conferred the sensitivity to radiotherapy in PDAC by restraining the recruitment of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to Ku70/80 heterodimer during DDR. Considering the overexpression of ITGA2 and its associated with the poor prognosis of PDAC patients, this study suggested that the ITGA2 expression status could be used as an indicator for radiotherapy and DNA damage reagents, and the radiotherapy in combination with the overexpression of ITGA2 might be a viable treatment strategy for the PDAC patients. Highlights: ITGA2 expression significantly correlated with the genome stability of pancreatic cancer patients. ITGA2 overexpression impaired the chromosomal stability of pancreatic cancer cells. ITGA2 inhibited DNA repair via the repression of NHEJ pathway. ITGA2 competitively binds to Ku70/80 heterodimer and inhibited the recruitment of DNA-PKcs and the further activation of DNA-PKcs. TM domain of the nuclear ITGA2 mediated its interaction with Ku70/80. Cancer derived ITGA2 overexpression in PDAC conferred the vulnerability to radiotherapy.