Tan Langping, Ye Xiao, Zhou Yu, Yu Min, Fu Zhiqiang, Chen Ruiwan, Zhuang Baoxiong, Zeng Bing, Ye Huilin, Gao Wenchao, Lin Qing, Li Zhihua, Zhou Quanbo, Chen Rufu
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.
J Transl Med. 2014 Apr 7;12:92. doi: 10.1186/1479-5876-12-92.
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.
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.
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.
MIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in β-cells.
了解胰腺癌相关糖尿病（PCDM）的致病机制可能有助于从新发糖尿病患者群体中找到胰腺癌（PC）早期诊断的生物标志物。在本研究中，我们试图确定巨噬细胞迁移抑制因子（MIF）在PCDM发病机制中的作用。
通过免疫组织化学和定量逆转录聚合酶链反应检测石蜡包埋的人PC样本、慢性胰腺炎标本和正常胰腺中MIF的蛋白质和mRNA水平。我们测量了PC患者和对照组血清中MIF的水平。体外研究了MIF过表达对小鼠胰岛和β细胞（HIT-T15）胰岛素分泌功能的生物学影响。
与慢性胰腺炎或正常胰腺标本相比，胰腺癌组织中MIF表达显著增加。胰岛和HIT-T15细胞与PC细胞间接共培养或用其条件培养基处理后，胰岛素分泌功能均受损。稳定敲低MIF可显著降低PC细胞的致糖尿病作用，而在HPDE6细胞中敲入MIF则对胰岛和HIT-T15细胞的胰岛素分泌功能表现出强烈的抑制作用。MIF通过抑制Ca⁺电流、降低L型Ca⁺通道α1亚基蛋白表达水平和增强p-Src活性来损害β细胞功能。与其他组相比，新发糖尿病相关PC患者的血清MIF平均水平显著更高。
胰腺癌患者中MIF上调，导致β细胞胰岛素分泌功能障碍。
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