The research to establish the orader-made therapy system for hepatocellular carcinoma patients by use of genome-wide microarray database

通过肝细胞癌（hcc）的全基因组cDNA微阵列，我们发现了一些与肿瘤进展相关的基因。因此，为了更精确地分析表达谱并建立手术后肝内复发的预测系统，我们使用TaqMan PCR对47个hcc进行了第二次筛选，其中包括120个基因。然后我们将47个hcc分为两组，25个hcc用于训练，22个hcc用于盲法验证。我们确定了27个与治愈性切除后1年内肝内复发相关的基因。基于15个基因表达谱的预测评分，正确预测了盲法组22例hcc中16例的复发状态。阳性预测值为75%，阴性预测值为71.4%。这些数据的积累将有可能定义单个肿瘤的性质，为确定新的治疗靶点提供线索，并最终优化每个患者的治疗。结果2在之前的研究中，我们观察到16号染色体上LOH的高频率，这与肿瘤的血管侵袭性有关。我们对16号染色体进行缺失定位，确定SIAHI为HCC的推定抑癌基因，并发现其抑制表达与肿瘤大小和分化之间存在相关性，提示SIAHI在HCC的发生发展中发挥重要作用。通过全基因组cDNA微阵列，我们发现父系表达基因10 （PEG10）在绝大多数hcc中高度表达。外源表达PEG10具有致癌活性，转染抑制PEG10的反义s -寡核苷酸可抑制肝癌细胞的生长。进一步的实验发现，与SIAHI相关的PEG10蛋白和PEG10 **的表达减少了SIAH1介导的细胞死亡。这些发现表明，开发抑制PEG10活性的药物可能是治疗hcc的新途径。结果3利用基因芯片分析了20个肠型胃肿瘤的表达谱，发现了一些在癌组织中普遍上调或下调的基因。基于5个基因表达谱的预测评分，正确诊断了另外9例胃癌的淋巴结状态。它可以帮助临床医生预测淋巴结转移，帮助研究人员了解肠型胃癌发展过程中的分子变化，并确定这类癌症的新治疗靶点。VEGF-C/D Al VEGFR-3通路在肿瘤淋巴管生成和淋巴转移中发挥重要作用。我们发现，在小鼠原位胃癌模型中施用抗vegfr -3阻断抗体，可降低原发肿瘤的区域淋巴结转移和淋巴管密度。此外，原发性肿瘤lyve -1阳性淋巴管密度增加与胃癌人标本淋巴结转移密切相关。通过抑制VEGFR-3信号传导抑制淋巴管生成可能为预防胃癌淋巴结转移提供潜在的策略。少

Results 1Through a genome-wide cDNA microarray of hepatocellular carcinomas (HCCs), we identified a number of genes associated with tumor progression. Thus, to analyze expression profiles more precisely and to establish a predictive system of intrahepatic recurrence after surgery, we performed second screening of 47 HCCs by TaqMan PCR consisting of 120 genes. Then we divided 47 HCCs into two groups, 25 HCCs are for training and 22 HCCs are blinded sets for validation. We identified 27 genes that associated with intrahepatic recurrence within 1 year after curative resection. A predictive score, based on expression profiles of 15 of the genes, correctly predicted the recurrent status in 16 of 22 HCCs in the blinded sets. A positive predictive value was 75% and negative predictive value was 71.4%. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each … More patient.Results 2In a previous study, we observed a high frequency of LOH on chromosome 16, which correlated with vascular invasiveness of tumors. We performed deletion mapping of chromosome 16 and then identified SIAHI as a putative tumor suppressor gene for HCC and found a correlation between its suppressed expression and tumor size and differentiation, suggesting an important role of SIAHI in the development of HCC. Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10) was highly expressed in a great majority of HCCs. Exogenous expression of PEG 10 conferred oncogenic activity and transfection of hepatoma cells with antisense S-oligonucleotides **ppressing PEG10 resulted in their growth inhibition. Additional experiments revealed that PEG10 protein associated with SIAHI and **erexpression of PEG 10 decreased the cell death mediated by SIAH1. These findings suggested that development of drug(s) inhibiting PEG10 activity could be a novel approach for the treatment of HCCs.Results 3We analyzed expression profiles of 20 intestinal type gastric tumors by a cDNA microarray and identified a number of genes that are commonly up-regulated or down-regulated in the cancer tissues. A predictive score, based on expression profiles of 5 genes, correctly diagnosed the lymph node status of 9 additional gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in understanding molecular changes during the development of intestinal type gastric cancers and identifying novel therapeutic targets for this type of cancer. VEGF-C/D Al VEGFR-3 pathway is said to play an important role in tumor lymphangiogenesis and lymphatic metastasis. We identified that by administrating anti-VEGFR-3 blocking antibodies in murine orthotopic gastric cancer models, regional lymph node metastasis and lymphatic vessel density in the primary tumors are reduced. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Anti-lymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer. Less