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01-06-2012 | Original Paper

An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis

Authors: Maddalena Frau, Maria M. Simile, Maria L. Tomasi, Maria I. Demartis, Lucia Daino, Maria A. Seddaiu, Stefania Brozzetti, Claudio F. Feo, Giovanni Massarelli, Giuliana Solinas, Francesco Feo, Ju-Seog Lee, Rosa M. Pascale

Published in: Cellular Oncology | Issue 3/2012

Abstract

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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Title: An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis
Authors: Maddalena Frau
Maria M. Simile
Maria L. Tomasi
Maria I. Demartis
Lucia Daino
Maria A. Seddaiu
Stefania Brozzetti
Claudio F. Feo
Giovanni Massarelli
Giuliana Solinas
Francesco Feo
Ju-Seog Lee
Rosa M. Pascale
Publication date: 01-06-2012
Publisher: Springer Netherlands
Published in: Cellular Oncology / Issue 3/2012
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-011-0067-z

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