CRABP-II enhances pancreatic cancer cell migration and invasion by stabilizing interleukin 8 expression.
CRABP-II enhances pancreatic cancer cell migration and invasion by stabilizing interleukin 8 expression.
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DOI：
10.18632/oncotarget.14194
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发表时间：
2017-08-08
期刊：
影响因子：
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通讯作者：
Zhou L
中科院分区：
文献类型：
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作者：
Yu S;Parameswaran N;Li M;Wang Y;Jackson MW;Liu H;Xin W;Zhou L
我们前期的研究表明，细胞视黄酸结合蛋白II（CRABP-II）在胰腺导管腺癌（PDAC）和癌前病变中过度表达，但在正常胰腺组织中未检测到。在这项研究中，我们发现通过 CRISPR/Cas9 删除 PDAC 细胞中的 CRABP-II 不会影响癌细胞增殖，但会减少细胞迁移和侵袭。基因表达微阵列分析显示，IL-8是CRABP-II缺失后表达下调的最主要基因之一，而IL-8的两个靶标MMP-2和MMP-14的表达也显着下调。此外，我们发现CRABP-II能够与HuR形成复合物，该复合物与IL-8信使RNA（mRNA）的3'UTR结合并增强IL-8 mRNA的稳定性。在CRABP-II敲除细胞中异位表达flag-CRABP-II能够挽救IL-8、MMP-2/MMP-14的表达并恢复细胞迁移。使用原位异种移植模型，我们进一步证明 CRABP-II 缺失会损害肿瘤向附近淋巴结的转移。综上所述，我们的结果揭示了一条将 CRABP-II 表达与增强的 PDAC 转移联系起来的新途径，因此我们建议 CRABP-II 可以作为新的 PDAC 治疗靶点。
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.