RNA编辑酶ADAR1参与导管内乳头状黏液性肿瘤相关的癌变

Background: Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing subtype of the pancreatic cyst lesions arising from the pancreatic duct system. IPMN is a potential precursor of pancreatic cancer and surgical decision-making is guided by “high-risk stigmata” and “worrisome features” according to international evidence-based Kyoto guidelines for the management of IPMN. However, these criteria can be insufficient for the prediction of invasive intraductal papillary mucinous carcinoma (IPMC). Adenosine-to-inosine (A-to-I) RNA editing, which is regulated by adenosine deaminase acting on RNA (ADAR) was reported to induce the posttranscriptional modification of oncogenes. However, the significance of RNA editing in IPMN remains unclear. We investigated whether ADAR1 expression increases with pathological progression in IPMN and whether higher expression is associated with adverse clinical outcomes. Methods: We analyzed gene profiling dataset from IPMN tissue samples in silico discovery from GEO (Gene Expression Omnibus). AS a clinical validation analysis, we analyzed 102 IPMN patients who received surgical resection in our institution. Functional analysis was evaluated in ASAN-PaCa cell lines using small interfering RNA (siRNA) transfection. Results: The mRNA expression data were obtained from a publicly available GEO dataset, comprising samples from 7 normal main pancreatic ducts, 6 low-grade intraductal papillary mucinous neoplasms (LGD-IPMNs), 7 high-grade IPMNs (HGD-IPMNs), and 3 invasive intraductal papillary mucinous carcinomas (IPMCs). Compared to normal epithelial cells, the expression of ADAR1 were elevated in LGD-IPMNs, HGD-IPMNs, and invasive IPMC samples (p=0.0383, 0.0383, and 0.0227, respectively). Among the participants in our hospital, 44 had LGD-IPMNs, 29 had HGD-IPMNs, and 29 had invasive IPMC. ADAR1 expression was significantly higher in the HGD-IPMNs and invasive IPMCs than in the LGD-IPMNs (p<0.01 for both). We observed a shorter OS and DFS in the high ADAR1 group (OS: p = 0.0279, DFS: p = 0.0163). In univariate Cox regression, high ADAR1 expression was significantly associated with shorter OS and DFS (OS HR=2.63, p=0.034; DFS HR=2.83, p=0.021). In multivariate analysis, ADAR1 remained an independent prognostic factor for both OS and DFS (OS HR=2.45, p=0.042; DFS HR=2.66, p=0.033). In comparison with control cells, ADAR1 knockdown cells exhibited significantly reduced proliferative activity (p<0.01) and decreased invasion potential, indicating that ADAR1 contributes to both cell growth and invasiveness in vitro. Conclusion: IPMC showed frequent ADAR1 overexpression, and higher ADAR1 expression was associated with poorer prognosis. These findings suggest that elevated ADAR1 expression may be involved in IPMN carcinogenesis and could potentially serve as a biomarker for clinical application.