上海交通大學醫(yī)學院附屬瑞金醫(yī)院于穎彥,、朱正綱兩位教授領銜的課題組,，經(jīng)過近5年時間的潛心研究，發(fā)現(xiàn)位于5號染色體短臂上的同源盒基因IRX1的活性丟失,，可以導致胃癌細胞增殖與侵襲能力增加,；通過轉基因技術將該基因導入胃癌細胞使IRX1基因活性恢復后，無論是在體外培養(yǎng)的胃癌細胞還是小鼠活體內(nèi)的腫瘤細胞,，其惡性增殖與侵襲能力均受到明顯抑制,。這一研究論文日前發(fā)表在國際癌癥權威學術刊物《癌基因》（Oncogene）雜志上。
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該研究發(fā)現(xiàn),，導致胃癌細胞內(nèi)IRX1基因失活的主要原因,，是位于5號染色體短臂上IRX1的一個等位基因在外界致癌因素等作用下丟失，而幸存下來的另外一個等位基因又因為啟動子的高甲基化而失去活性所致,?？蒲腥藛T通過基因補償或給予去甲基化藥物5-氮雜脫氧胞苷處理，可以使胃癌細胞內(nèi)IRX1基因活性得以恢復,。通過比較IRX1基因缺失與恢復IRX1基因活性的胃癌細胞全基因組表達譜,，并結合染色質(zhì)免疫共沉淀等實驗發(fā)現(xiàn),，由于IRX1基因的失活,，使其對其下游癌基因BDKRB2、HIST2H2BE以及FGF7的抑制能力喪失,，從而造成胃癌細胞的失控性增殖與侵襲性生長,。
科研人員在研究中，不僅首次提出了IRX1基因在胃癌發(fā)生發(fā)展中的抑癌基因作用,，還發(fā)現(xiàn)了另外一個重要現(xiàn)象,，即不但在胃癌組織中可以檢測到IRX1基因啟動子的高甲基化，而且在胃癌患者的外周血游離DNA中也可以檢測到IRX1基因的高甲基化,。有關專家認為,，這項原創(chuàng)性研究為今后將IRX1基因甲基化分析作為胃癌診斷中的新型分子標志物，提供了一個重要的線索,。(生物谷Bioon.net)
生物谷推薦原文出處：
Oncogene doi: 10.1038/onc.2010.143
Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma
X Guo1,3, W Liu1,3, Y Pan1, P Ni2, J Ji1, L Guo1, J Zhang1, J Wu1, J Jiang1, X Chen1, Q Cai1, J Li1, J Zhang1, Q Gu1, B Liu1, Z Zhu1 and Y Yu1
1Department of Surgery of Shanghai Ruijin Hospital and Shanghai Institute of Digestive Surgery, Shanghai, PR China
2Department of Clinical Biochemistry, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China
The IRX1 tumor suppressor gene is located on 5p15.33, a cancer susceptibility locus. Loss of heterozygosity of 5p15.33 in gastric cancer was identified in our previous work. In this study, we analyzed the molecular features and function of IRX1. We found that IRX1 expression was lost or reduced in gastric cancer. However, no mutations were identified in IRX1-encoding regions. IRX1 transcription was suppressed by hypermethylation, and the expression of IRX1 mRNA was partially restored in gastric cancer cells after 5-Aza-dC treatment. Restoring IRX1 expression in SGC-7901 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay. BDKRB2, an angiogenesis-related gene, HIST2H2BE and FGF7, cell proliferation and invasion-related genes, were identified as direct IRX1 target genes. The hypermethylation of IRX1 was not only detected in primary gastric cancer tissues but also in the peripheral blood of gastric cancer patients, suggesting IRX1 could potentially serve as a biomarker for gastric cancer.
