CDCA8/SNAI2 Complex Activates CD44 to Promote Proliferation and Invasion of Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: There is an urgent need to find an effective therapeutic target for pancreatic cancer owing to late diagnosis, tumor metastasis, and current ineffective targeted drugs. We aimed to identified potential targets for the treatment of pancreatic cancer. In this study, the specific mechanism by which the CDCA8 contributes to pancreatic cancer progression via the activation of CD44 was clarified, and CDCA8 knockdown inhibited the proliferation and metastasis of pancreatic cancer. This finding may provide a promising target for future targeted therapies of pancreatic cancer. ABSTRACT: (1) Background: Recently, cell division cycle associated 8 (CDCA8) was found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to explore the specific mechanism of action of CDCA8 in PDAC progression. (2) Methods: All human PDAC samples and clinical data were collected from Huashan Hospital, Fudan University. All experimental studies were carried out using many in vitro and in vivo assays, including lentiviral transfection, real-time quantitative polymerase chain reaction (qPCR), western blotting, co-immunoprecipitation (Co-IP), chromatin IP (ChIP)-qPCR, dual-luciferase reporter, and in vivo imaging assays. (3) Results: Clinical data analysis of human PDAC samples revealed that CDCA8 overexpression were positively and negatively associated with tumor grade (p = 0.007) and overall survival (p = 0.045), respectively. CDCA8 knockdown inhibited PDAC proliferation and invasion in in vitro and in vivo assays. CD44 was also up-regulated by CDCA8 during PDAC progression. CDCA8 could be combined with SNAI2 to form a CDCA8/SNAI2 complex to integrate with the CD44 promoter as indicated through ChIP-qPCR and dual-luciferase reporter assays. (4) Conclusion: We showed that CDCA8-CD44 axis plays a key role in the proliferation and invasion of PDAC, which provides a potential target for treatment.