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
General aspects of hepatocellular carcinoma
Molecular alterations in human HCC
Experimental hepatocarcinogenesis
Experimental animal model of hepatocarcinogenesis
Conclusion
Hepatocellular carcinoma (HCC) is the sixth most common cancer and third most frequent cause of cancer-related death worldwide (
Chronic viral infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) appears to be the most significant causes of HCC (
Patients diagnosed with HCC have a poor prognosis because of the aggressive nature of the disease (
Elucidation of the mechanism of hepatocarcinogenesis should contribute to the development of molecular target therapy. Although there is a growing understanding of the molecular mechanisms that induce hepatocarcinogenesis, real mechanisms of hepatocarcinogenesis have not been completely elucidated. However, cumulative knowledge regarding the molecular mechanisms of carcinogenesis revealed that the development and progression of HCC are caused by the accumulation of genetic changes, thus resulting in altered expression of cancer-related genes.
The p53 gene is the most extensively studied gene in the solid tumors. Mutation of this gene has been identified in a variety of human cancers (
The retinoblastoma (Rb) gene is another widely studied tumor suppressor gene in HCC and other solid tumors. It is a negative regulator of the cell cycle through its ability to bind the transcription factor E2F and to suppress the transcription of S-phase-related genes (
The p16 gene, also known as cyclin-dependent kinase inhibitor 2A gene, is the regulator of the Rb pathway. Inactivation of either Rb or p16 was frequently found in HCC (81%) (
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosome 10q. It negatively regulates the phosphoinositide 3-kinase/Akt signaling pathway, which is involved in the regulation of cell survival (
Runt-related transcription factor 3 (RUNX3), located in chromosome 1p36, was first reported as a tumor suppressor gene for gastric cancer (
Most of gene alterations in tumor suppressor genes are due to LOH or promoter hypermethylation (
The role of the oncogenes in HCC seems to be less important as compared to that of the tumor suppressor genes, in contrast to other types of cancer. Myc, located on chromosome 8q, is a potent proto-oncogene in HCC and other cancers. It codes for a protein involved in nucleic acid metabolism and in mediating the cellular response to growth factors. The correlation of myc expression and tumor size was reported (
Mutation of the 3 major ras proto-oncogenes (H-, K-, and N-ras) was found in only in few cases of HCCs (
The Wnt/β-catenin pathway plays an essential role in liver development. Activation of the catenin pathway frequently occurred in HCC (
Hedgehog signaling is another developmental pathway that is involved in hepatocarcinogenesis (
The expression of several growth factors has been reported in HCC. Expression of the transforming growth factor-α (TGF-α) was increased in most cases of HCCs (81%) (
The insulin-like growth factor-2 (IGF-2) signaling pathway is also involved in hepatocarcinogenesis. LOH or mutation of the IGF-2 receptor was frequently found (25–55%) in HCC (
Telomere is a region of repetitive DNA at the end of each chromosome, which contributes to the stability and integrity of the chromosome (
Many cancer-related genes are altered in HCC. However, since the frequency of alteration for each individual gene is relatively low, the accumulation of alterations of cancer-related genes may be necessary for hepatocarcinogenesis. Hepatocarcinogenesis is tightly associated with chronic hepatitis or liver cirrhosis in which there are persistent inflammation and cell division of hepatocytes. Continuous inflammation induces oxidative DNA damage, and then DNA repair occurs occasionally accompanied with DNA misrepair, resulting in increased mutation frequency. Constant activation of cell division and the increased chances of DNA replication errors are important factors for the development of HCC (
Normal human cultured cells are quite resistant to neoplastic transformation (
Oncogenic genes have been introduced in order to establish immortalized human hepatocytes. Various types of human cells can be immortalized with oncogenic genes from DNA viruses, such as simian virus 40 (SV40), adenovirus, and papillomavirus (
In studies of other types of cells, myc and ras were able to immortalize human fibroblasts and epithelial cells, respectively (
HCV core protein is known to induce oxidative stress, steatosis, and HCC in the patient with HCV (
Although exposure to some chemical agents is closely related to human HCC, no successful malignant transformation of human hepatocytes by chemical agents or ionizing radiation
Several human hepatocyte cell lines were established by transfection of SV40 T-antigen. THLE-2 and THLE-3 cells were established from an adult human liver autopsy sample (
Immortalized human hepatocytes were also established from surgically resected human adult liver by Schippers
We established another immortalized human hepatocyte OUMS-29 from human embryonic liver using SV40 T-antigen (
The study of
The introduction of TERT might be a useful method for human hepatocyte carcinogenesis. TERT introduction into human primary hepatocytes increases the population doubling level, thus providing easy
Since telomerase activation is a common feature in HCC, telomerase activity may play a key role in hepatocarcinogenesis, especially in immortalization, because the immortalization of the cell is the initial step in the neoplastic transformation process. However, the cause and effect relationship between telomerase activation and hepatocarcinogenesis has not been elucidated yet.
Animal models of carcinogenesis play a critical role in understanding the mechanism of carcinogenesis. Many experimental hepatocarcinogenesis models have been developed (reviewed in ref.
The H-ras or B-raf mutation was frequently found in rodent liver tumors (
As in the case of other types of human cancers, hepatocarcino-genesis seems to be a multistep process in which multiple cancer-related genes are altered. These genetic changes are related to tumor suppressor genes, oncogenes, reactivation of developmental pathways, and growth factors and their receptors. Although numerous genes are altered in HCC, the frequency of each individual gene alteration is relatively low. Telomerase activation is the common feature of HCC and is closely related to immortalization. Thus, telomerase activation may be the common effect of cancer-related genes (
Neoplastic transformation of human hepatocytes has not yet been achieved in an
hepatocellular carcinoma;
hepatitis B virus;
hepatitis C virus;
retinoblastoma;
loss of heterozygoty;
phosphatase and tensin homolog;
runt-related transcription factor 3;
adenomatous polyposis coli;
patched;
smoothened;
transforming growth factor-α;
insulin-like growth factor-2;
transforming growth factor-β;
telomerase reverse transcriptase;
simian virus 40
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.
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.