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

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.

Dietary vitamin D deficiency in rats from middle to old age leads to elevated tyrosine nitration and proteomics changes in levels of key proteins in brain: Implications for low vitamin D-dependent age-related cognitive decline

“…Steric hindrance by the NO 2 group in the 3-position of tyrosine may prevent phosphorylation at the 4-position thereby causing dysregulation of activation/deactivation processes in the affected proteins [33, 45, 95–98]. Such considerations have implications for cognitive dysfunction following low dietary vitamin D.…”

Stat3 Inhibits PTPN13 Expression in Squamous Cell Lung Carcinoma through Recruitment of HDAC5

“…For instance, PTPN13 gene mutations have been identified in colorectal, head and neck, and hepatocellular carcinoma [3–5]. Besides, reduced PTPN13 expression in breast cancer correlates with decreased survival in patients [6].…”

Alterations of methionine metabolism in hepatocarcinogenesis: the emergent role of glycine N-methyltransferase in liver injury

“…Studies of GNMT in human HCC have shown that GNMT gene alteration , including insertion/deletion polymorphism in the promoter region, is an early event in HCC development and that GNMT could be considered a new tumor susceptibility gene for HCC [ 61 , 77 ]. In respect to these findings, it is interesting the observation that some genes involved in methionine metabolism, such as BHMT and GNMT , are connected to the genetic susceptibility to liver cancer [ 77 ].…”

“…Studies of GNMT in human HCC have shown that GNMT gene alteration , including insertion/deletion polymorphism in the promoter region, is an early event in HCC development and that GNMT could be considered a new tumor susceptibility gene for HCC [ 61 , 77 ]. In respect to these findings, it is interesting the observation that some genes involved in methionine metabolism, such as BHMT and GNMT , are connected to the genetic susceptibility to liver cancer [ 77 ]. Chemically induced hepatocarcinogenesis in genetically susceptible F344 rats is characterized by the development of numerous DN that progress to HCCs, whereas the same treatments induce in the genetically resistant BN rats only a few slow-proliferating DN and HCCs [ 77 ].…”