15-羟基前列腺素脱氢酶与胃癌发生关系的研究

Study on the Relationship of NAD+-dependent 15-Hydroxyprostaglandin Dehydrogenase and Gastric Carcinogenesis

背景:NAD+依赖性15-羟基前列腺素脱氢酶(15-PGDH)是前列腺素和相关廿烷类生物降解、灭活的关键酶,其表达缺失或减低可能与一些恶性肿瘤的发生、发展密切相关。目的:探讨15-PGDH在胃癌组织和癌旁组织中的表达及其与临床病理特征的关系,初步评价15-PGDH在胃癌发生、发展中的作用及其意义。方法:随机收集30例胃癌患者的癌组织、癌旁3cm和6cm的对照组织,以及10例胃息肉、萎缩性胃炎和健康志愿者正常胃黏膜组织标本,以免疫组化和Westernblot法检测15-PGDH蛋白表达,半定量逆转录聚合酶链反应(RT-PCR)法检测其mRNA表达,并分析其临床病理特征。结果:癌组织中15-PGDH蛋白和mRNA表达显著低于癌旁3cm、癌旁6cm对照组织和正常胃黏膜(P均<0.01),约1/3癌组织中15-PGDH表达缺失,胃息肉和萎缩性胃炎组织显著低于正常胃黏膜(P均<0.01);癌组织中15-PGDH蛋白表达量较癌旁3cm和6cm对照组织分别平均降低5.7倍和8.3倍,胃息肉和萎缩性胃炎组织较正常胃组织分别平均降低2.0倍和2.1倍;黏液腺癌中15-PGDH蛋白量显著低于高分化腺癌(P<0.05),印戒细胞癌中15-PGDH蛋白和mRNA的表达均缺失;伴有远处转移组15-PGDH蛋白和mRNA表达显著低于无远处转移组(P<0.05和P<0.01);Ⅳ期胃癌组织15-PGDH蛋白表达量显著低于Ⅰ期(P<0.01),其mRNA表达在Ⅲ、Ⅳ期胃癌组织中显著低于Ⅰ、Ⅱ期胃癌(P均<0.01)。结论:15-PGDH在胃癌组织中表达减少甚至缺失,在癌旁组织和胃癌前状态中表达减少;15-PGDH表达缺失或减少可能是胃癌发生、发展,以及胃癌浸润转移的重要机制之一。

Background： NAD^＋-dependent 15-hydroxyprostaglandin dehydrogenase （15-PGDH） is a key enzyme in degradation and biological inactivation of prostaglandins and the correlative twenty-alkyl. Recent studies showed that deletion or lack of 15-PGDH expression played a key role in the development and progression of some malignant tumors. Aims： To investigate the expression of 15-PGDH in gastric cancer, precancerous state and its possible implications. Methods： The protein and mRNA expressions of 15-PGDH were determined by immunohistochemistry, Western blot and semiquantitative reverse transcriptase polymerase chain reaction （RT-PCR）, respectively, in 30 gastric cancerous tissue, paracancerous mucosae 3 cm and 6 cm distant from the tumors, 10 gastric polyps, 10 atrophic gastritis and 10 normal gastric mucosa specimens, respectively. Results： The levels of 15-PGDH protein and mRNA in gastric cancers were significantly lower than those in the paracancerous tissue 3 cm and 6 cm distant from the normal mucosae and normal gastric tissues （P all 〈0.01）. Both of them in the gastric polyps and atrophic gastritis were significantly lower than those in the normal mucosa （P all 〈0.01）. 15-PGDH expression was undetectable in 1/3 tumors. Western blot demonstrated that an average of 5.7-fold and 8.3-fold less of PGDH expression in cancerous tissue versus 3 cm and 6 cm paracancerous tissue distant from the cancer. There were 2.0-fold and 2.1-fold less in the gastric polyp and atrophic gastritis than those in the normal mucosa. Loss of 15-PGDH expression at protein and mRNA levels was significantly different among the various pathologic types （only at protein level P〈0.05）, between those with and without distant metastasis （at protein level P〈0.05, at mRNA level P〈0.01） and among those of different TNM stages （both P〈0.01）. Conclusions： The expression of 15- PGDH is absent or decreased in gastric cancer, and decreased in paracancerous tissue and precancerous status. The above results suggest that deletion or decrease of 15-PGDH expression may play an important role in the gastric cancer development, progression, infiltration and metastasis.