上海交通大学医学院附属瑞金医院于颖彦、朱正纲两位教授领衔的课题组，经过近5年时间的潜心研究，发现位于5号染色体短臂上的同源盒基因IRX1的活性丢失，可以导致胃癌细胞增殖与侵袭能力增加；通过转基因技术将该基因导入胃癌细胞使IRX1基因活性恢复后，无论是在体外培养的胃癌细胞还是小鼠活体内的肿瘤细胞，其恶性增殖与侵袭能力均受到明显抑制。这一研究论文日前发表在国际癌症权威学术刊物《癌基因》（Oncogene）杂志上。
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该研究发现，导致胃癌细胞内IRX1基因失活的主要原因，是位于5号染色体短臂上IRX1的一个等位基因在外界致癌因素等作用下丢失，而幸存下来的另外一个等位基因又因为启动子的高甲基化而失去活性所致。科研人员通过基因补偿或给予去甲基化药物5-氮杂脱氧胞苷处理，可以使胃癌细胞内IRX1基因活性得以恢复。通过比较IRX1基因缺失与恢复IRX1基因活性的胃癌细胞全基因组表达谱，并结合染色质免疫共沉淀等实验发现，由于IRX1基因的失活，使其对其下游癌基因BDKRB2、HIST2H2BE以及FGF7的抑制能力丧失，从而造成胃癌细胞的失控性增殖与侵袭性生长。
科研人员在研究中，不仅首次提出了IRX1基因在胃癌发生发展中的抑癌基因作用，还发现了另外一个重要现象，即不但在胃癌组织中可以检测到IRX1基因启动子的高甲基化，而且在胃癌患者的外周血游离DNA中也可以检测到IRX1基因的高甲基化。有关专家认为，这项原创性研究为今后将IRX1基因甲基化分析作为胃癌诊断中的新型分子标志物，提供了一个重要的线索。
推荐原文出处：
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.
