Oncogenic CD44 is required for pancreatic cancer cell tumorigenesis and CD44 gene knockout is a new strategy for targeted pancreatic cancer therapy

Abstract

CD44 is a cancer stem cell marker and is aberrantly overexpressed in cancer stem/progenitor cells of malignant tumors. Overexpression of CD44 promotes carcinogenesis and is closely associated with poor prognosis in cancer patients, including pancreatic cancer. However, CD44-targeted drug against pancreatic cancer is unavailable in the clinical setting, and the effect of CD44 gene knockout on pancreatic cancer has not yet been reported in the literature. In this study, we investigated the effect of CD44 gene knockout on pancreatic cancer cell tumorigenesis. We found that CD44 genetic disruption notably inhibited pancreatic cancer cell tumorigenesis, migration, and invasion; increased intracellular DNA damage, sensitized pancreatic cancer cells to the anticancer drug cisplatin; and also suppressed tumor growth in xenograft mice. Mechanistically, CD44 genetic disruption suppressed expression of multiple oncogenic genes; particularly, the levels of oncogenic X-inactive specific transcription (Xist) were reduced for 35-fold through diminishing promoter activity, unraveling a novel oncogenic CD44-Xist axis in cancer cells. Additionally, CD44 genetic disruption inhibited the tumorigenic AKT and ERK signaling pathways, and concurrently activated the tumor-suppressive p38 and p53 signaling pathways. Our findings highlight the critical role of CD44 gene in pancreatic cancer and provide a new strategy for targeted pancreatic cancer therapy.