CRABP-II enhances pancreatic cancer cell migration and invasion by stabilizing interleukin 8 expression

// Shuiliang Yu 1 , Neetha Parameswaran 1 , Ming Li 2 , Yiwei Wang 1 , Mark W. Jackson 1 , Huiping Liu 1 , Wei Xin 1, 3 and Lan Zhou 1, 3 1 Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA 2 Biostatistics and Bioinformatics Core Facility, Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA 3 Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio, USA Correspondence to: Lan Zhou, email: lan.zhou@case.edu Keywords: pancreatic cancer, CRABP-II, IL-8, MMP-2/MMP-14, metastasis Received: September 09, 2016     Accepted: November 19, 2016     Published: December 26, 2016 ABSTRACT Our previous study shows that cellular retinoic acid binding protein II (CRABP-II) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and pre-cancerous lesions, but not detected in normal pancreatic tissues. In this study, we show that deletion of CRABP-II in PDAC cells by CRISPR/Cas9 does not affect cancer cell proliferation, but decreases cell migration and invasion. Gene expression microarray analysis reveals that IL-8 is one of the top genes whose expression is down-regulated upon CRABP-II deletion, while expression of MMP-2 and MMP-14, two targets of IL-8 are also significantly down-regulated. Moreover, we found that CRABP-II is able to form a complex with HuR, which binds to the 3’UTR of IL-8 messenger RNA (mRNA) and enhances IL-8 mRNA stability. Ectopic expression of flag-CRABP-II in CRABP-II knockout cells is able to rescue the expression of IL-8, MMP-2/MMP-14 and recovers cell migration. Using the orthotopic xenograft model, we further demonstrate that CRABP-II deletion impairs tumor metastasis to nearby lymph nodes. Taken together, our results reveal a novel pathway linking CRABP-II expression to enhanced PDAC metastasis, and hence we propose CRABP-II may serve as a new PDAC therapeutic target.