Gene Expression Profile Related to the Progression of Preneoplastic Nodules toward Hepatocellular Carcinoma in Rats

Abstract

In this study, we investigated the time course gene expression profile of preneoplastic nodules and hepatocellular carcinomas (HCC) to define the genes implicated in cancer progression in a resistant hepatocyte model. Tissues that included early nodules (1 month, ENT-1), persistent nodules (5 months, ENT-5), dissected HCC (12 months), and normal livers (NL) from adult rats were analyzed by cDNA arrays including 1185 rat genes. Differential genes were derived in each type of sample (n = 3) by statistical analysis. The relationship between samples was described in a Venn diagram for 290 genes. From these, 72 genes were shared between tissues with nodules and HCC. In addition, 35 genes with statistical significance only in HCC and with extreme ratios were identified. Differential expression of 11 genes was confirmed by comparative reverse transcription-polymerase chain reaction, whereas that of 2 genes was confirmed by immunohistochemistry. Members involved in cytochrome P450 and second-phase metabolism were downregulated, whereas genes involved in glutathione metabolism were upregulated, implicating a possible role of glutathione and oxidative regulation. We provide a gene expression profile related to the progression of nodules into HCC, which contributes to the understanding of liver cancer development and offers the prospect for chemoprevention strategies or early treatment of HCC.

DNA methyltransferases 3a and 3b are differentially expressed in the early stages of a rat liver carcinogenesis model

“…Animal models also allow the analysis of stages prior to tumor formation. The early stages of carcinogenesis are characterized by the presence of altered cells foci or preneoplastic lesions (20,21). Although the analysis of these lesions are potentially useful for the identification of early genetic and epigenetic events leading to cancer in human beings, such dysplastic nodules are difficult to detect in biopsies and commonly coexist with other tissue pathologies (20).…”

“…The early stages of carcinogenesis are characterized by the presence of altered cells foci or preneoplastic lesions (20,21). Although the analysis of these lesions are potentially useful for the identification of early genetic and epigenetic events leading to cancer in human beings, such dysplastic nodules are difficult to detect in biopsies and commonly coexist with other tissue pathologies (20). Thus, animal models for carcinogenesis have proven to be important tools for the analysis of nodules and cancer progression (22).…”

Analysis of gene expression profiles as a tool to uncover tumor markers of liver cancer progression in a rat model

“…These types of nodules were susceptible to dissection. In the present model, rats with persistent hepatic nodular lesions will coexist with HCC after 9 to 10 months (19). Hypothetically, persistent nodule cells may exhibit an altered genetic background that allows autonomous cell proliferation to undergo a slow evolution to cancer.…”

Chemically Induced Hepatocellular Carcinoma and Stages of Development with Biochemical and Genetic Modulation: A Special Reference to Insulin-Like-Growth Factor II and Raf Gene Signaling

“…Some of these changes are well-distinguishable and vary along with the stages of development during various cancer processes including hepatocarcinogenesis. They have been described as preneoplastic or neoplastic markers, depending on the developmental stages (Pérez-Carreón et al, 2006). Liver is the largest organ in our body and it takes major role in metabolism.…”