HnRNPK/miR-223/FBXW7 feedback cascade promotes pancreatic cancer cell growth and invasion

Abstract

Several studies have identified miR-223 critically involved in various types of cancer, including pancreatic ductal adenocarcinoma (PDAC). However, its action and regulatory mechanisms in PDAC remains largely unclear. In this study, we found that the expression levels of miR-223 were increased in clinical samples with PDAC (81.6%). The upregulation of miR-223 increases the proliferation, migration, and invasive abilities of PDAC cells in vitro and in vivo. Mechanistically, miR-223 directly targeted FBXW7 and overexpression of FBXW7 reverted miR-223- induced drastic proliferation in PDAC cells. Interestingly, miR-223 promoter was found to form a coprecipitable complex with hnRNPK, and siRNA knockdown of hnRNPK in PDAC cells reduced the levels of miR-223. These results show that hnRNPK is a cellular protein that binds and affects the accumulation of miR-223 in PDAC. Furthermore, FBXW7 interacts with hnRNPK and promotes its degradation, which requires phosphorylation of hnRNPK at threonine 1695 by GSK3. Consistently, we observed an inverse expression pattern between FBXW7 and miR-223, whereas a positive expression pattern between miR-223 and hnRNPK was found in human PDAC tissues. These data unveiled an important new miR-223/FBXW7/HnRNPK feedback cascade in human PDAC.