An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis.
An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis.
复制标题
DOI：
10.1007/s13402-011-0067-z
复制
发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Pascale RM
中科院分区：
文献类型：
--
作者：
Frau M;Simile MM;Tomasi ML;Demartis MI;Daino L;Seddaiu MA;Brozzetti S;Feo CF;Massarelli G;Solinas G;Feo F;Lee JS;Pascale RM
肝癌的发生受多基因控制。我们分析了在F344和BN大鼠中化学诱导的异型增生肝结节（DN）和肝细胞癌（HCC）的基因表达模式，分别对肝癌发生敏感和抵抗。表达谱通过微阵列进行，并通过定量RT-PCR和Western blot进行验证。聚类分析揭示了两种不同的基因表达模式，第一种包括两种菌株的正常肝脏和BN结节，第二种包括两种菌株的F344结节和HCC。我们确定了一个预测DN和HCC进展的特征，其特征是在DN中肿瘤抑制因子Csmd 1、Dmbt 1、Dusp 1和Gnmt的表达最高，在耐药大鼠的HCC中Bhmt、Dmbt 1、Dusp 1、Gadd 45 g、Gnmt、Napsa、Pp 2ca和Ptpn 13的表达最高。综合基因表达数据显示，在更具侵袭性的大鼠和人HCC中，增殖相关的CTGF、c-MYC和PCNA表达最高，BHMT、DMBT 1、DUSP 1、GADD 45 g和GNMT表达最低。BHMT、DUSP 1和GADD 45 g表达预测患者的生存。我们的研究结果首次揭示了抑癌基因作为肝癌发生的遗传抗性效应子的主要作用。比较功能基因组分析允许发现进化上保守的基因表达特征，其区分大鼠和人类中具有不同进展倾向的HCC。
Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis. Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot. Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients’ survival. Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.