The research to establish the recurrence predicting system for hepatocellular carcinoma patients by use of genome-wide microarray database and to identify therapeutic molecular targets

利用全基因组微阵列数据库建立肝细胞癌患者复发预测系统并确定治疗分子靶点的研究

• 批准号: 16390377
• 负责人: SATOH Seiji
• 金额: $ 9.15万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390377/
• 关键词: Hepatocellular carcinoma; β-atenin; cDNA microarray; TaqMan PCR; LOH; Recurrence; SIAH1; PEG10; 定量的RT-PCR

Results 1We 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 SIAH1 and found a correlation between its suppressed expression and progression. It has been shown that SIAH1 functions in the phosphorylation-independent degradation of β-catenin and induces apoptosis and growth arrest. To examine if the effects of SIAH1 over-expression depend on the altered β-catenin signaling pathway, we transferred SIAH1 gene into hepatoma cells. SIAH1 significantly induced growth arrest and apoptosis, despite of accumulation of aberrant β-catenin. SIAH1 interacts with another target protein but β-catenin. Immunoblotting study demonstrated that SIAH1 also reduces the amount of PEG10 protein, which is known to be frequently over-expressed in HCC and to promote cell proliferation. SIAH1 induces apoptosis and growth arrest in hepatoma cells through different mechanisms.Results 2Through a genome-wide cDNA microarray of hepatocellular carcinomas(HCCs), we identified a number a number of genes associated with tumor progression. Thus, to analyze expression profiles more precisely and 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 patient.

结果1在16号染色体上观察到高频率的洛，LOH与肿瘤的血管侵袭性有关。我们进行了16号染色体的缺失定位，然后鉴定了SIAH 1，并发现其表达抑制与进展之间的相关性。研究表明，SIAH 1在β-连环蛋白的磷酸化非依赖性降解中起作用，并诱导细胞凋亡和生长停滞。为了研究SIAH 1过表达的影响是否依赖于β-catenin信号通路的改变，我们将SIAH 1基因转入肝癌细胞。SIAH 1显著诱导生长停滞和凋亡，尽管异常β-连环蛋白的积累。SIAH 1与β-catenin以外的另一种靶蛋白相互作用。免疫印迹研究表明，SIAH 1还减少了PEG 10蛋白的量，已知PEG 10蛋白在HCC中经常过表达并促进细胞增殖。SIAH 1通过不同的机制诱导肝癌细胞凋亡和生长停滞。结果2通过全基因组肝癌cDNA微阵列，我们发现了许多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，我们通过TaqMan PCR对47例HCC进行了由120个基因组成的第二次筛选。然后我们将47例HCC分为两组。25个HCC用于训练，22个HCC是用于验证的盲集。我们确定了27个与根治性切除术后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组中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确定单个肿瘤的性质，为识别新的治疗靶点提供线索，并最终优化每个患者的治疗。

项目成果

Up-regulation of PSF2, a member of the GINS multiprotein complex, in intrahepatic cholangiocarcinoma.

• DOI: 10.3892/or.14.3.701
• 发表时间: 2005-09
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: K. Obama;Katsuaki Ura;S. Satoh;Yusuke Nakamura;Y. Furukawa

SIAH1 causes growth arrest and apoptosis in hepatoma cells through β-catenin degradation-dependent and independent mechanisms

SIAH1通过β-catenin降解依赖和独立机制导致肝癌细胞生长停滞和凋亡

• 发表时间: 2007
• 期刊: Oncology Reports (in press)
• 作者: Chiharu Tabata;Hajime Kubo;Rie Tabata;Manabu Wada;Keiichiro Sakuma;Masataka Ichikawa;Shiro Fujita;Tadashi Mio;Michiaki Mishima;Yoshibayashi H
• 通讯作者: Yoshibayashi H

Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma

• DOI: 10.1002/hep.20718
• 发表时间: 2005-06-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Obama, K;Ura, K;Furukawa, Y
• 通讯作者: Furukawa, Y