title: MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Integrated TCM &Western Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Integrated TCM &Western Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Chen-Ye
authors.initials: CY
authors.lastname: Shi
authors.affiliation: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Institute for Nutritional Sciences, Shanghai 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Dan-Song
authors.initials: DS
authors.lastname: Wang
authors.affiliation: Department of Integrated TCM &Western Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Ding-Fang
authors.initials: DF
authors.lastname: Cai
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D054377:Chemokine CXCL12; C583712:MIRN454 microRNA, human; D035683:MicroRNAs