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Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis

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Abstract

Background

Regenerating islet-derived 3 (Reg3) is abnormally expressed in several human digestive system diseases, including chronic pancreatitis (CP) and pancreatic cancer (PC).

Aim

The purpose of this study was to clarify the mechanism of the enhanced expression of Reg3 in inflammation-induced PC.

Methods

C57BL/6 mice were treated with caerulein for 6 weeks to induce CP and then injected with pReg3g—a lentivirus system encoding for murine Reg3g—accompanied by dimethylbenzanthracene to induce PC. We detected pancreatic histopathological characteristics, tumor-related gene expression, inflammation-associated pathway activation, serum biochemical indicators, and immunological cell activities.

Results

The mice that developed CP after caerulein treatment were marked by pronounced histologic lesions, elevated serum amylase levels, and activation of inflammation-related pathways. Mice given a high dose of pReg3g developed PC by 16 weeks, with recognizable tumors in the pancreas. While, both the low and high doses of pReg3g produced higher transcription of c-fos, k-ras, cytokeratin-19, and proliferating cell nuclear antigen, and a lower expression of caspase-3 compared to pNEG controls. Additionally, the higher dose of pReg3g increased the expressions of pSTAT3, NFκB (p65), and SOCS3 methylation during PC development. In addition, mice treated with pReg3g displayed higher levels of serum IL10 and TGFβ and suppressed T lymphocyte proliferation and DC function.

Conclusion

The comprehensive analysis suggests enhanced Reg3g expression exacerbates PC in inflammation-associated cancer progression. Reg3g appears to promote CP-related PC in mice through multiple mechanisms, involving enhanced transcription of pancreatic tumor markers, repression of anti-tumor immunity, and activation of STAT3/p65 signal transduction pathways.

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Abbreviations

Reg3g:

Regenerating islet-derived 3-gamma

pReg3g :

pEZ-Lv201-Reg3g

pNEG :

pEZ-Lv201-NEG

AP:

Acute pancreatitis

CP:

Chronic pancreatitis

PC:

Pancreatic cancer

IL10:

Interleukin-10

STAT3:

Signal transducer and activator of transcription 3

NFκB:

Nuclear factor kappa B

TGFβ:

Transforming growth factor

SOCS3:

Suppressor of cytokine signaling 3

DNMT1:

DNA (cytosine-5)-methyltransferase 1

DMBA:

Dimethylbenzanthracene

HFD:

High fat diet

ELISA:

Enzyme-linked immunoassay

MSP:

Methylation-specific PCR

RT-PCR:

Real-time polymerase chain reaction

MLR:

Mixed lymphocyte reaction

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Acknowledgments

This work was supported by the National Natual Science Foundation of China (Nos. 91229114 and 81273521).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Guoxiao Yin, Jiao Du, Hui Cao, Xiulan Liu, Qianqian Xu & Ming Xiang

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  1. Guoxiao Yin
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  2. Jiao Du
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  3. Hui Cao
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  4. Xiulan Liu
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Correspondence to Ming Xiang.

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Yin, G., Du, J., Cao, H. et al. Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis. Dig Dis Sci 60, 3656–3668 (2015). https://doi.org/10.1007/s10620-015-3787-5

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  • DOI: https://doi.org/10.1007/s10620-015-3787-5

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