title: REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop.
abstract: Regenerating gene protein (REG) 3A is a 19 kD secretory pancreas protein with pro-growth function. Previously we demonstrated that overexpression of REG3A, acting as a key molecule for up-regulation of the JAK2/STAT3 pathway, contributed to inflammation-related pancreatic cancer (PaC) development. However the exact network associated with REG3A signaling still remains unclear. Here we determined that exposure of human PaC cells to cytokine IL-6 activated the oncogenic JAK2/STAT3 pathway, which directly upregulated REG3A expression, accelerated cell cycle progression by promoting CyclinD1 expression, and enhancing the expression of the anti-apoptosis Bcl family. Importantly, the activation of REG3A would instead enhance the JAK2/STAT3 pathway to constitute a REG3A-JAK2/STAT3 positive feedback loop, which leads to the amplification of the oncogenic effects of IL-6/JAK2/STAT3, a classic pathway linking to inflammation-related tumorigenesis, ultimately resulting in PaC cell over-proliferation and tumor formation both in vitro and in vivo. Moreover, EGFR was found to mediate the REG3A signal for PaC cell growth and JAK2/STAT3 activation, thus functioning as a REG3A receptor. Collectively, our results provide the first evidence for the presence of the synergistic effect of REG3A and IL-6 on PaC development via a REG3A-JAK2/STAT3 positive feedback loop.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan 430030, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Guoxiao
authors.initials: G
authors.lastname: Yin
authors.affiliation: Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, School of Life Science, Wuchang University of Technology, Wuhan 430223, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, School of Life Science, Wuchang University of Technology, Wuhan 430223, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: xiangming@mails.tjmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xiang
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000073718:Pancreatitis-Associated Proteins; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C000612143:Reg3a protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Cell growth; Feedback loop; IL-6; Pancreatic cancer; REG3A