Frau, Maddalena and Simile, Maria Maddalena and Tomasi, Maria Lauda and Demartis , Maria Ilaria and Daino, Lucia Maria Elisa and Seddaiu, Maria Antonietta and Brozzetti, Stefania and Feo, Claudio F. and Massarelli, Giovannino and Solinas, Maria Giuliana and Feo, Francesco and Lee, Ju-Seog and Pascale, Rosa Maria (2012) An Expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis. Cellular Oncology, Vol. 35 (3), p. 163-173. eISSN 2211-3436. Article.
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Background and aims 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.
Methods Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.
Results 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.
Conclusions 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.
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