Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers
Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers
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DOI：
10.1158/1078-0432.ccr-05-0729
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发表时间：
2005-09-15
影响因子：
11.5
通讯作者：
Hagiwara, A
中科院分区：
文献类型：
--
作者：
Sakakura, C;Hasegawa, K;Hagiwara, A
目的：我们以前的研究结果表明，RUNX 3功能的缺乏有助于人类胃癌的发生，但RUNX 3在进展和转移中的作用仍不清楚。在动物实验中使用胃癌细胞的稳定RUNX 3转染子评估转移潜力的变化。最后，全球表达的变化进行了分析，使用cDNA microarray.Experimental Design and Results：显着下调RUNX 3通过甲基化的启动子区域被观察到在原发性肿瘤（75%），以及在所有临床腹膜转移的胃癌（100%）相比，与正常胃粘膜。RUNX 3的稳定转染轻微抑制细胞增殖，并观察到适度的转化生长因子-β（TGF-β）诱导的抗增殖和凋亡作用。对胃癌腹腔转移有明显的抑制作用（P < 0.01）。此外，我们还利用基因芯片技术对RUNX 3的亲本细胞和稳定转染细胞中的21，000个相似基因进行了基因表达谱分析，发现RUNX 3下游可能调控的28个候选基因，其中一些基因可能与腹膜转移有关，与信号转导有关（vav 3、TOLL样受体MAPKK、MET S100 A11和组织蛋白酶E）、细胞凋亡（胱天蛋白酶9）、免疫应答（CP 55和TLR 10）和细胞粘附（唾液酸转移酶1和半乳糖凝集素4）。结论：RUNX 3基因沉默可影响胃癌细胞粘附、增殖、凋亡等转移相关基因的表达，促进胃癌腹膜转移。这些基因的鉴定可以提出新的治疗方式和治疗靶点。
Purpose: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear.We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray.Experimental Design and Results: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared With normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-beta (TGF-beta)-induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of similar to 21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray, Microarray analysis identified similar to 28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor MAPKK, MET S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CP55 and TLR10), and cell adhesion (sialyltransterase 1 and galectin 4). Some of the genes are involved in the TGF-beta signaling pathway.Conclusion: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.