Fan Yue, Xu Li-Li, Shi Chen-Ye, Wei Wei, Wang Dan-Song, Cai Ding-Fang
Department of Integrated TCM &Western Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Sci Rep. 2016 Mar 15;6:22793. doi: 10.1038/srep22793.
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454-overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC.
胰腺导管腺癌（PDAC）是一种具有极高致死率的高恶性肿瘤。我们最近报道，缺氧诱导因子1（HIF-1）靶向巯基氧化酶1以促进PDAC细胞的生长和侵袭。在此，我们分析了PDAC细胞中另一个HIF-1靶点基质细胞衍生因子-1（SDF-1）的调控情况。与正常人类胰腺（NT）相比，我们在PDAC中检测到显著更多的CD68 +巨噬细胞。由于巨噬细胞通过其CXCR4的表达响应SDF-1而被招募到组织中，因此我们检测了PDAC标本中的SDF-1水平。令人惊讶的是，与NT相比，PDAC中SDF-1蛋白而非mRNA显著增加。此外，发现一种靶向SDF-1的微小RNA miR-454在PDAC中减少。启动子荧光素酶测定证实，miR-454与SDF-1 mRNA的3'-UTR结合可抑制SDF-1蛋白翻译。在transwell迁移实验中，骨髓来源的巨噬细胞与miR-454修饰的PDAC细胞共培养表明，巨噬细胞向miR-454过表达的PDAC细胞迁移较少，而向miR-454缺失的细胞迁移较多。植入miR-454缺失的PDAC细胞比对照生长明显更快，而植入miR-454过表达的PDAC细胞比对照生长明显更慢。总之，我们的数据表明miR-454可能在PDAC生长调控中调节SDF-1。
