Omori Yasuhiro, Nakayama Fumihito, Li Dong, Kanemitsu Kiyonori, Semba Shuho, Ito Akihiko, Yokozaki Hiroshi
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Cancer Sci. 2009 Mar;100(3):413-8. doi: 10.1111/j.1349-7006.2008.01063.x. Epub 2008 Dec 16.
Maintenance of telomeric ends by the telomerase ribonucleoprotein complex or the telomerase-independent alternative lengthening of telomeres is necessary for the immortalization of human cells. The significance of alternative lengthening of telomeres has been suggested in DNA mismatch repair system-deficient cells; however, much remains unknown in human malignancies. In this study, we investigated the telomere maintenance mechanism in gastric carcinoma. In formalin-fixed and paraffin-embedded sections of the high frequency of microsatellite instability (MSI-H) and non-MSI-H gastric carcinomas, there was no difference in telomere length monitored by telomere intensity ratio using telomere-fluorescent in situ hybridization. Immunoreactivity of hTERT, the catalytic subunit of telomerase, was detected in 48% of MSI-H gastric carcinomas. The frequency was significantly lower than that in non-MSI-H gastric carcinomas (86%, P = 0.02). Conversely, the number of the alternative lengthening of telomeres-associated promyelocytic leukemia bodies (APBs) detected by combined promyelocytic leukemia immunofluorescence and telomere-fluorescent in situ hybridization was statistically higher (57%) in the MSI-H gastric carcinomas compared to that in non-MSI-H gastric carcinomas (19%, P = 0.026). The cases with hTERT(+)APBs(-) were more frequent in non-MSI-H gastric carcinomas (76%) than in MSI-H gastric carcinomas (24%), and the cases with hTERT(-)APBs(+) were more frequent in MSI-H gastric carcinomas (33%) than in non-MSI-H gastric carcinomas (10%). These results suggest that alternative lengthening of telomeres-mediated telomere maintenance plays an important role for microsatellite instability-mediated stomach carcinogenesis, as well as the telomerase ribonucleoprotein complex, although the incidence of MSI-H is low. Defects of the mismatch repair system may lead to homeologous recombination of telomeric ends for the telomerase-independent telomere maintenance in gastric carcinomas.
端粒酶核糖核蛋白复合体维持端粒末端或通过不依赖端粒酶的端粒替代延长途径对于人类细胞永生化是必要的。在DNA错配修复系统缺陷的细胞中，已表明端粒替代延长具有重要意义；然而，在人类恶性肿瘤中仍有许多未知之处。在本研究中，我们调查了胃癌中端粒维持机制。在高频微卫星不稳定（MSI-H）和非MSI-H胃癌的福尔马林固定石蜡包埋切片中，使用端粒荧光原位杂交通过端粒强度比监测的端粒长度没有差异。在48%的MSI-H胃癌中检测到端粒酶催化亚基hTERT的免疫反应性。该频率显著低于非MSI-H胃癌（86%，P = 0.02）。相反，与非MSI-H胃癌（19%，P = 0.026）相比，通过早幼粒细胞白血病免疫荧光和端粒荧光原位杂交联合检测到的端粒替代延长相关的早幼粒细胞白血病小体（APB）数量在MSI-H胃癌中在统计学上更高（57%）。hTERT(+)APB(-)的病例在非MSI-H胃癌（76%）中比在MSI-H胃癌（24%）中更常见，而hTERT(-)APB(+)的病例在MSI-H胃癌（33%）中比在非MSI-H胃癌（10%）中更常见。这些结果表明，尽管MSI-H的发生率较低，但端粒替代延长介导的端粒维持对于微卫星不稳定介导的胃癌发生以及端粒酶核糖核蛋白复合体都起着重要作用。错配修复系统的缺陷可能导致端粒末端的同源重组，从而在胃癌中实现不依赖端粒酶的端粒维持。
