REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop

Xiulan Liu; Jun Wang; Hongjie Wang; Guoxiao Yin; Yang Liu; Xiang Lei; Ming Xiang

doi:10.1016/j.canlet.2015.03.014

REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop

Cancer Lett. 2015 Jun 28;362(1):45-60. doi: 10.1016/j.canlet.2015.03.014. Epub 2015 Mar 14.

Authors

Xiulan Liu¹, Jun Wang², Hongjie Wang³, Guoxiao Yin¹, Yang Liu⁴, Xiang Lei⁴, Ming Xiang⁵

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² 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.
³ Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida, USA.
⁴ Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, School of Life Science, Wuchang University of Technology, Wuhan 430223, China.
⁵ 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.

PMID: 25779676
DOI: 10.1016/j.canlet.2015.03.014

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.

Keywords: Cell growth; Feedback loop; IL-6; Pancreatic cancer; REG3A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / biosynthesis
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism*
Antigens, Neoplasm / pharmacology
Biomarkers, Tumor / biosynthesis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Biomarkers, Tumor / pharmacology
Cell Growth Processes / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Drug Synergism
ErbB Receptors / metabolism
Feedback, Physiological / drug effects
Female
Heterografts
Humans
Inflammation / chemically induced
Inflammation / metabolism
Inflammation / pathology
Interleukin-6 / genetics
Interleukin-6 / metabolism
Interleukin-6 / pharmacology*
Janus Kinase 2 / metabolism*
Lectins, C-Type / biosynthesis
Lectins, C-Type / genetics
Lectins, C-Type / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology*
Pancreatitis-Associated Proteins
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Random Allocation
Recombinant Proteins / pharmacology
STAT3 Transcription Factor / metabolism*
Signal Transduction / drug effects
Transfection

Substances

Antigens, Neoplasm
Biomarkers, Tumor
Interleukin-6
Lectins, C-Type
Pancreatitis-Associated Proteins
REG3A protein, human
RNA, Small Interfering
Recombinant Proteins
Reg3a protein, mouse
STAT3 Transcription Factor
STAT3 protein, human
EGFR protein, human
ErbB Receptors
JAK2 protein, human
Janus Kinase 2