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.
Highlights
Pancreatic cancer is one of the major causes of cancer death worldwide [1] and in the US [2]
Higher level of CRABP-II expression was detected in metastatic lymph nodes [27], suggesting that CRABP-II may contribute to pancreatic ductal adenocarcinoma (PDAC) metastasis
Because CRABP-II is not expressed in normal pancreas, we evaluated the effects of CRABP-II knockout (KO) using CRISPR/Cas9 (Figure 2A)
Summary
Pancreatic cancer is one of the major causes of cancer death worldwide [1] and in the US [2]. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, with an overall 5-year survival rate at around 5% [3]. Identifying new therapeutic targets critically implicated in PDAC progress and metastasis has become a key task for pancreatic cancer researchers. Cellular retinoic acid binding protein II (CRABP-II) is a soluble small protein residing in the cytosol. It belongs to the family of intracellular lipid-binding proteins and binds all-trans retinoic acid (RA), a vitamin A metabolite with powerful transcriptional activities at a sub-nM affinity [4, 5]
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