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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancy and has with a 5-year survival of less than 5% [1]
QRTPCR analysis revealed that pancreatic ductal adenocarcinoma (PDAC) patients had > 1.5-fold greater concentrations of serum miR-223 than duodenal adenocarcinoma patients or healthy controls (P
We found that miR-223 was relatively higher in a series of tested human PDAC cell lines as compared with that found in normal human pancreatic duct epithelial cells (Figure 1E)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancy and has with a 5-year survival of less than 5% [1] This poor survival rate has not improved in the last decades. Deciphering the potential mechanisms underlying PDAC invasion and metastasis is of paramount importance and likely to contribute to the development of effective therapeutics for treating PDAC patients. Another reason of this dismal prognosis is the lack of sensitive and specific biomarkers for PDAC, which adds to the existing problems of increasing incidence and poor prognosis of this lethal disease, because early detection of pancreatic intraepithelial neoplasia or mucinous neoplasms would be the best option to improve patient survival. There is an immediate need to identify new targets for the treatment of PDAC in general and this aggressive subtype in particular
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
