Chronic Pancreatitis and Pancreatic Cancer: Prediction and Mechanism
Chronic Pancreatitis and Pancreatic Cancer: Prediction and Mechanism
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DOI：
10.1016/j.cgh.2009.07.042
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发表时间：
2009-11-01
影响因子：
12.6
通讯作者：
Satoh, Kennichi
中科院分区：
文献类型：
--
作者：
Shimosegawa, Tooru;Kume, Kiyoshi;Satoh, Kennichi
我们研究了156例散发性胰腺癌（PCa）和8例胰腺癌伴慢性胰腺炎（CPPCa）患者以及527例健康受试者的SPINK 1突变。结果显示，8例CPPCa患者中3例（37.5%）存在SPINK 1基因N34 S突变。另外，156例散发性PCa患者中分别有3例（1.9%）和1例（0.6%）存在N34 S和IVS 3 + 2 T>C突变。联合频率为2.5%，显著高于健康受试者（0.38%），表明SPINK 1突变是胰腺癌发生的重要危险因素。为探讨散发性PCa与CPPCa的遗传差异，我们对6例CPPCa和15例散发性PCa患者的PCa发病机制进行了研究。检测的因子包括K-ras、p53、smad 4、p-smad 1、CXCL 14、NF-κ B亚单位p65和Wnt 5a等基因。在这些因素的比较检查中没有发现显着差异，表明分子疾病似乎发生类似的CPPCa以及散发性PCa。为了评估纤维化在胰腺癌发生中的作用，我们研究了胰腺星状细胞（PSC），这是主要负责胰腺纤维化，对导管细胞，在体外和体内的影响。在二甲基苯并蒽小鼠模型和人前列腺癌组织中发现癌前导管细胞周围有活化的PSC。与此同时，与PSC条件培养基培养的人胰腺导管上皮细胞显示增加的细胞增殖和集落形成，表明PSC可能促进胰腺导管肿瘤发生。
We investigated the SPINK 1 mutations in 156 sporadic pancreatic cancer (PCa), and 8 pancreatic cancer with chronic pancreatitis (CPPCa) patients, and in 527 healthy subjects. The results demonstrated that 3 of 8 patients with CPPCa (37.5%) had the SPINK 1 gene N34S mutation. In addition, 3 of 156 sporadic PCa patients (1.9%) and 1 of them (0.6%) had the N34S and IVS3+2T>C mutation, respectively. The combined frequency of 2.5% was significantly higher than that of healthy subjects (0.38%), suggesting that the SPINK 1 mutation is an important risk factor for the development of pancreatic cancer. To investigate the genetic difference between sporadic PCa and CPPCa, we investigated several factors involved in the pathogenesis of PCa in 6 CPPCa and 15 sporadic PCa patients. The factors examined were genes inducting K-ras, p53, smad 4, p-smad 1, CXCL 14, NF-kB subunit p65 and Wnt 5a. No significant difference was found in the comparative examination of these factors, suggesting that the molecular disorders appeared to occur similarly in CPPCa as well as sporadic PCa. To assess the role of fibrosis in pancreatic carcinogenesis, we investigated the effects of pancreatic stellate cells (PSCs), which are largely responsible for pancreatic fibrogenesis, on duct cells, in vitro and in vivo. Activated PSCs were found surrounding precancerous duct cells in the tissues of a dimethylbenzanthracene mouse model and those of human PCa. Consistently, human pancreatic epithelial duct cells cultured with PSC conditioned media showed increased cell proliferation and colony formation, suggesting that PSCs may promote pancreatic ductal tumorigenesis.