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

ABSTRACT: 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 ? 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 ?cell function by depressing the Ca? currents, decreasing L-type Ca? channel ?1 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 ?-cells.

SUBMITTER: Tan L 

PROVIDER: S-EPMC4022046 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature