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Journal of Translational Medicine

, 12:92

Disease Biomarkers

Abstract

BackgroundUnderstanding the pathogenic mechanism of pancreatic cancer associated diabetes PCDM might help yield biomarkers for the early diagnosis of pancreatic cancer PC from population with new-onset diabetes. In the current study, we sought to determine the role of macrophage migration inhibitory factor MIF in PCDM pathogenesis.

MethodsThe protein and mRNA levels of MIF in paraffin-embedded human PC samples, chronic pancreatitis specimens, and normal pancreas were measured by immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction. We measured serum levels of MIF in PC patients and controls. The biologic impacts of MIF overexpression on insulin secretion function of mice islets and β cells HIT-T15 were investigated in vitro.

ResultsMIF expression was significantly increased in pancreatic cancer tissues compared with chronic pancreatitis or normal pancreas specimens. The insulin secretion function of both islets and HIT-T15 cells was impaired by indirect co-cultured with PC cells or treated with conditioned media from them. Stable MIF knock-down significantly decreased the diabetogenic effect of PC cells, while MIF knock-in HPDE6 cells demonstrated a strong inhibitory effect on insulin secretion function of islets and HIT-T15 cells. MIF impaired βcell function by depressing the Ca currents, decreasing L-type Ca channel α1 subunit protein expression level, and enhancing p-Src activity. Mean serum level of MIF was significant higher in new-onset diabetes associated PC patients in comparison with other groups.

ConclusionsMIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in β-cells.

KeywordsPancreatic cancer Diabetes mellitus Macrophage Migration Inhibitory Factor Biomarker Diagnosis AbbreviationsPCPancreatic cancer

DMDiabetes mellitus

MIFMacrophage migration inhibitory factor

rMIFRecombinant macrophage migration inhibitory factor

rMIFancreatic cancer associated diabetes mellitus

T1DMType 1 diabetes mellitus

T2DMType 2 diabetes mellitus

GDMGestational diabetes mellitus

VDCCVoltage-dependent Ca2+ channel

L-VDCCL-type Voltage-dependent Ca2+ channel

LCCL-type Ca2+ channel

LCCα1L-type Ca2+ channel subunit α1.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-12-92 contains supplementary material, which is available to authorized users.

Langping Tan, Xiao Ye contributed equally to this work.

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Autor: Langping Tan - Xiao Ye - Yu Zhou - Min Yu - Zhiqiang Fu - Ruiwan Chen - Baoxiong Zhuang - Bing Zeng - Huilin Ye - Wenchao

Fuente: https://link.springer.com/







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