Yu Jun, Cheng Yuen Y, Tao Qian, Cheung Kin F, Lam Cleo N Y, Geng Hua, Tian Lin-Wei, Wong Ying P, Tong Joanna H M, Ying Jian-Ming, Jin Hongchuan, To Ka F, Chan Francis K L, Sung Joseph J Y
Institute of Digestive Disease and Department of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Gastroenterology. 2009 Feb;136(2):640-51.e1. doi: 10.1053/j.gastro.2008.10.050. Epub 2008 Oct 29.
BACKGROUND & AIMS: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer.
Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis.
PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients.
PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.
通过甲基化敏感性代表性差异分析，我们鉴定出原钙黏蛋白10（PCDH10），这是一个编码原钙黏蛋白且以肿瘤特异性方式沉默的基因。我们分析了其在胃癌中的表观遗传失活、生物学效应及预后意义。
通过联合亚硫酸氢盐限制分析和亚硫酸氢盐测序评估甲基化状态。在生长、凋亡、增殖和侵袭试验中确定PCDH10重新表达的影响。通过互补DNA微阵列分析鉴定PCDH10靶基因。
PCDH10在94%（17个中的16个）胃癌细胞系中沉默或下调；通过暴露于去甲基化剂可恢复其表达水平。PCDH10在MKN45胃癌细胞中的重新表达减少了体外集落形成和小鼠体内肿瘤生长；还抑制细胞增殖（P <.01），诱导细胞凋亡（P <.001），并抑制细胞侵袭（P <.05），上调促凋亡基因Fas、半胱天冬酶8、Jun和CDKN1A；抗增殖基因FGFR；以及抗侵袭基因HTATIP2。在104例胃癌肿瘤中，82%（85例）检测到PCDH10甲基化，而配对的非肿瘤组织中为37%（38例）（P <.0001）。在后者中，癌前病变中PCDH10甲基化（45例中的27例；60%）高于慢性胃炎样本（59例中的11例；19%）（P <.0001）。中位随访期为16.个月后，多变量分析显示，相邻非肿瘤区域存在PCDH10甲基化的患者总生存期显著降低。Kaplan-Meier生存曲线显示，PCDH10甲基化与I-III期胃癌患者生存期缩短显著相关。
PCDH10是一种胃癌肿瘤抑制因子；其在胃癌发生早期的甲基化是一个独立的预后因素。
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