Trefoil Factor 2 Promotes Cell Proliferation in Pancreatic β-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation
Trefoil Factor 2 Promotes Cell Proliferation in Pancreatic β-Cells through CXCR-4-Mediated ERK1/2 Phosphorylation
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DOI：
10.1210/en.2012-1814
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发表时间：
2013-01-01
期刊：
影响因子：
4.8
通讯作者：
Terauchi, Yasuo
中科院分区：
文献类型：
--
作者：
Orime, Kazuki;Shirakawa, Jun;Terauchi, Yasuo
β细胞质量降低是2型糖尿病的标志，增加胰腺β细胞质量的治疗方法已被期待。近年来，胃肠道肠促胰岛素肽已被证明在胰腺β细胞中发挥细胞增殖作用。三叶因子2 （TFF2）主要表达于胃表面上皮，具有抗凋亡、迁移和增殖的作用。TFF家族在胰腺β细胞中表达，而TFF2在胰腺β细胞中的作用尚不清楚。在这项研究中，我们研究了TFF2促进胰腺β细胞增殖的机制。利用含有TFF2或重组TFF2肽的腺病毒载体，在INS-1细胞、MIN6细胞和小鼠胰岛中评估TFF2对细胞增殖的影响。TFF2的强制表达导致INS-1细胞和胰岛中溴脱氧尿苷（BrdU）掺入增加，而胰岛素分泌没有任何改变。TFF2显著提高胰岛细胞周期蛋白A2、D1、D2、D3和E1的mRNA表达。TFF2肽增加了MIN6细胞ERK1/2磷酸化和BrdU掺入。MAPK激酶抑制剂（U0126）消除了TFF2肽介导的MIN6细胞增殖。cx趋化因子受体-4拮抗剂也阻止了TFF2肽介导的ERK1/2磷酸化增加和BrdU在MIN6细胞中的掺入。这些结果表明，TFF2至少部分通过cx趋化因子受体-4介导的ERK1/2磷酸化参与β细胞增殖，提示TFF2可能是诱导β细胞增殖的新靶点。（journal of Endocrinology, 2013）
Decreased beta-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic beta-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic beta-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic beta-cells, whereas the role of TFF2 in pancreatic beta-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic beta-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in beta-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing beta-cell proliferation. (Endocrinology 154: 54-64, 2013)