Abstract
The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene amplification of selected oncogenes. The changes observed in different HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation. An understanding of the molecular pathogenesis of HCC may provide new markers for tumor staging, for assessment of the relative risk of tumor formation, and open new opportunities for therapeutic intervention.
Highlights
One of the most frequent tumor types worldwide is hepatocellular carcinoma (HCC)
Viral proteins inactivate tumor suppressors early in carcinogenesis that are mutated much later during tumor progression. Viral oncoproteins, such as HBV encoded X antigen (HBxAg), may constitutively activate signal transduction pathways, such as those involving c-jun and ras, and activate oncogenes, such as c-myc, that are otherwise activated by b-catenin mutations
Given that high levels of p16INK4a and p21WAF1/CIP1/SDI1 are associated with polyploidization (Gupta, 2000), which protects against carcinogenesis, it is not surprising that they are inactivated early in tumorigenesis
Summary
Mark A Feitelson*,1,2, Bill Sun, N Lale Satiroglu Tufan, Jie Liu, Jingbo Pan and Zhaorui Lian. The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene ampli®cation of selected oncogenes. The changes observed in dierent HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation.
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