Human hepatocyte carcinogenesis (review)

Abstract

Hepatocellular carcinoma is the third most frequent cause of cancer-related death worldwide; and its incidence rate is increasing. Clinical and molecular medical analyses have revealed substantial information on hepatocarcinogenesis. Hepatocarcinogenesis is a stepwise process during which multiple genes are altered. Genetic changes and their biological consequences in human HCC can be divided into at least 4 groups: i) tumor suppressor genes (p53, retinoblastoma, phosphatase tensin homolog and runt-related transcription factor 3), ii) oncogenes (myc, K-ras, BRAF), iii) reactivation of developmental pathways (Wnt, hedgehog), and iv) growth factors and their receptors (transforming growth factor-α, insulin-like growth factor-2 receptor). An experimental model of human hepatocarcinogenesis such as in vitro neoplastic transformation of human hepatocytes has not been successfully achieved yet, but several immortalized human hepatocyte cell lines have been established. These immortalized human hepatocytes will become useful tools for the elucidation of hepatocarcinogenesis, especially for the initial step of multistep hepatocarcinogenesis.

Figure 1

Gene alterations occurring in HCC. Gene alterations in human HCC are summarized; four major groups of genes are altered in HCC. Gene alterations of growth factors and tumor suppressor genes frequently occur in HCC.

Figure 2

Sequential gene alterations in the human liver leading to HCC. Chronologic sequence of the development of human HCC and gene alterations; HCC develops in the setting of chronic inflammation due to viral hepatitis or alcoholic liver injury. Hepatocarcinogenesis may begin in dysplastic nodules consisting of pre-neoplastic hepatocytes. Accumulation of gene alterations in dysplastic hepatocytes leads to HCC. Further gene alterations are responsible for the malignant transformation of HCC.