Toda Keisuke, Nagasaka Takeshi, Umeda Yuzo, Tanaka Takehiro, Kawai Takashi, Fuji Tomokazu, Taniguchi Fumitaka, Yasui Kazuya, Kubota Nobuhito, Takehara Yuko, Tazawa Hiroshi, Kagawa Shunsuke, Sun Dong-Sheng, Nishida Naoshi, Goel Ajay, Fujiwara Toshiyoshi
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan.
Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan.
Clin Epigenetics. 2015 Jul 23;7(1):73. doi: 10.1186/s13148-015-0096-y. eCollection 2015.
The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.
In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.
Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.
在许多癌症中，netrin-1依赖受体DCC和UNC5C的基因表达常常下调。我们推测DCC和UNC5C的下调在胃癌发生过程中具有重要的生长调节功能。
在本研究中，对98例日本散发性胃癌及相应正常胃黏膜标本进行了一系列关于DCC和UNC5C的遗传和表观遗传分析。分别应用杂合性缺失（LOH）分析和微卫星不稳定性（MSI）分析来确定染色体不稳定性（CIN）和MSI表型。在胃癌中，分别有45%（44/98）和32%（31/98）检测到DCC和UNC5C启动子甲基化超过5%，在正常胃黏膜中分别为9%（9/105）和5%（5/105）。总体而言，83例信息充分的胃癌病例中有70%（58例）、79例信息充分的病例中有51%（40例）分别在DCC和UNC5C基因中存在LOH或异常甲基化。总共77%（66例信息充分的病例中有51例）的胃癌在这两种依赖受体中存在累积缺陷，且与染色体不稳定性显著相关。在97%的CIN阳性胃癌和55%的CIN阴性胃癌中，DCC和UNC5C均失活。
netrin受体缺陷是胃癌的一个常见特征。DCC改变在早期明显，而UNC5C改变随疾病进展而增加，这表明netrin-1受体的累积改变是胃癌进展中的一个晚期事件，并强调了这种生长调节途径在胃癌发生中的重要性。
