Oncotarget

Research Papers:

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

Shuiliang Yu, Neetha Parameswaran, Ming Li, Yiwei Wang, Mark W. Jackson, Huiping Liu, Wei Xin and Lan Zhou _

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Oncotarget. 2017; 8:52432-52444. https://doi.org/10.18632/oncotarget.14194

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Abstract

Shuiliang Yu1, Neetha Parameswaran1, Ming Li2, Yiwei Wang1, Mark W. Jackson1, Huiping Liu1, Wei Xin1,3 and Lan Zhou1,3

1Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA

2Biostatistics and Bioinformatics Core Facility, Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

3Department 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.


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