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.
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