Macrophage migration inhibitory factor is overexpressed in pancreatic cancer tissues and impairs insulin secretion function of β-cell.
BACKGROUND
Understanding 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.


METHODS
The 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.


RESULTS
MIF 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.


CONCLUSIONS
MIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in β-cells.
Langping
L
Tan
Xiao
X
Ye
Yu
Y
Zhou
Min
M
Yu
Zhiqiang
Z
Fu
Ruiwan
R
Chen
Baoxiong
B
Zhuang
Bing
B
Zeng
Huilin
H
Ye
Wenchao
W
Gao
Qing
Q
Lin
Zhihua
Z
Li
Department of Pancreaticobiliary Surgery, The Second Affiliated Hospital of Sun Yat-sen University (Sun Yat-sen Memorial Hospital), Sun Yat-sen University, 107 Yan-Jiang Xi Road, Guangzhou 510120, China. zqb_sysu@126.com.
Quanbo
Q
Zhou
Rufu
R
Chen
D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
D007328:Insulin; D008263:Macrophage Migration-Inhibitory Factors