Expression of matrix metalloproteinases (MMPs) during hamster pancreatic duct carcinogenesis, detection of serum MMPs in tumor-bearing hamster and chemopreventive effect of hamster pancreatic cancer

基质金属蛋白酶(MMPs)在仓鼠胰管癌变过程中的表达、荷瘤地鼠血清MMPs的检测及对仓鼠胰腺癌的化学预防作用

• 批准号: 11671291
• 负责人: TSUNODA Tsukasa
• 金额: $ 2.05万
• 依托单位: KAWASAKI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671291/
• 关键词: Rapid production model for hamster pancreatic cancer; Matrix metalloproteinase (MMP); Gelatin zymography; Chemoprevention; OPB-3206; Immunohistochemistry; Serum; MMP; ハムスター; matrix metalloproteinase(MMP); tissue inhibitor of MMP(TIMP); 免疫染色; 血

In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a rapid production model for pancreatic duct carcinomas in hamsters initiated with N-nitrosobis (2-oxopropyl) amine (BOP) was investigated. Northern analysis revealed MMP-2 and MMP-9 mRNAs to be overexpressed in pancreatic duct carcinomas. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in primary tumors. Moreover we also invetigated that sera from hamsters with transplantable hamster pancreatic duct carcinoma (HPDt) possessed serum MMP-2 levels five times higher than the control sera as determined by gelatin zymographic analysis.In our rapid production model, 0.1% and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that over expression of MMP-2 and MMP-9 are involved in the development of pancreatic duct adenocarcinomas and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. Serum MMPs may be useful markers for monitoring patients with pancreatic adenocarcinoma. OPB-3206 may be candidate chemopreventive agent for pancreatic ductal adenocarcinomas.

为了评价金属蛋白酶活性变化在胰腺癌发生中的意义，研究了基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）在N-亚硝基双（2-氧代丙基）胺（BOP）引发的仓鼠胰腺导管癌快速产生模型中的表达。北方分析显示MMP-2和MMP-9 mRNA在胰管癌中过表达。免疫组化显示，MMP-2水平升高在早期导管上皮增生中明显，从非典型增生到癌染色增加。明胶酶谱显示在原发性肿瘤中proMMP-2而不是proMMP-9明显活化。此外，我们还研究了移植性仓鼠胰腺导管癌（HPDt）血清中MMP-2的水平，明胶酶谱分析表明，血清MMP-2水平比对照血清高5倍。在两个周期的增加压力48天后在饮食中给予的剂量降低了癌的发生率和数量。明胶酶谱显示OPB-3206抑制胰腺癌组织中proMMP-2的活化。提示MMP-2和MMP-9的过度表达参与了胰管腺癌的发生发展过程，且MMP-2在蛋白水平的表达出现在胰管癌发生的早期阶段。血清MMPs可作为胰腺癌患者病情监测的有效指标。OPB-3206可能是胰腺导管腺癌的候选化学预防剂。

项目成果

Katsumichi Iki: "Minimal pulmonary embolism detected after abdominal insufflation for laparoscopic cholecystectomy"Surgery. 127・6. 719 (2000)

Katsumichi Iki：“腹腔镜胆囊切除术中腹部充气后检测到的最小肺栓塞”127・6（2000）。

伊木勝道: "虫垂が嵌頓した大腿ヘルニアの一例"兵庫県医師会医学雑誌. 43・1. 26-28 (2000)

Katsumichi Iki：“伴有阑尾嵌顿的股疝一例”兵库县医学会医学杂志43·1（2000年）。

Atsushi Urakami, et al: "A pitfall of MRCP for preoperative cholangiography : Report of a case"The American Journal of Gastroenterological. 95(6). 1601-1602 (2000)

Atsushi Urakami 等人：“MRCP 术前胆管造影的陷阱：病例报告”美国胃肠病学杂志。

Tsukasa Tsunoda, et al.: "Staging and TNM classification for carcinoma of the pancreas (in Japanese)"KAN TAN SUI. 41(4). 663-672 (2000)

Tsukasa Tsunoda 等人：“胰腺癌的分期和 TNM 分类（日语）”KAN TAN SUI。

Katsumichi Iki: "Expression of matrix metalloproteinases (MMPs) during hamster pancreatic duct carcinogenesis and detection of serum MMPs in tumor-bearing hamsters (in Japanese)"Kawasaki Igakkai Shi. 25(1). 1-10 (1999)

Katsumichi Iki：“仓鼠胰管癌变过程中基质金属蛋白酶（MMP）的表达以及荷瘤仓鼠血清 MMP 的检测（日语）”川崎 Igakkai Shi。