Chapter 59

## Abstract

Abstract

1. Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. The multifactorial and multistage pathogenesis of HCC has fascinated a wide spectrum of cancer researchers for decades. While a number of etiologic factors have been identified, the elucidation of their mechanistic roles in hepatocarcinogenesis has recently just begun. Clearly, in sub-Saharan Africa and Eastern Asia, viral and chemical carcinogenic components are involved, with the subsequent inactivation of the p53 tumor suppressor gene playing a central role. A better understanding of the molecular pathogenesis of HCC will provide clues for more effective preventive and therapeutic strategies.

2. HCC is the predominant cause of cancer mortality in Southern China and sub-Saharan Africa. Infection with hepatitis B virus (HBV) and food contamination with aflatoxin B1 (AFB1) are major and possible synergistic risk factors. A number of conditions associated with chronic hepatic inflammation and cirrhosis have also been identified as important etiologic factors worldwide.

3. HBV sequences randomly integrate into host chromosomal DNA, resulting in frequent rearrangements. HBV-induced chromosomal aberrations may in part explain the loss of heterozygosity reported on many chromosomes in HCCs. Allelic loss of the short arm of chromosome 17, which includes the p53 tumor suppressor gene, has commonly been found in human HCCs.

4. In specific geographic regions of Asia, Africa, and North America with high HCC risk, e.g., Qidong and Tongon, China, southern Africa, and Mexico, a G to T transversion at the third position of codon 249 of p53 has provided a molecular link between dietary AFB1 exposure and liver cancer development. Data from laboratory studies indicate that this region of p53 is highly sensitive to AFB1-induced DNA damage and that the resulting mutated protein provides a selective growth advantage in liver cells. Inactivation of p53 gene function may also result from its association with the HBV X protein (HBx). p53 and HBx physically associate, resulting in the inability of p53 to bind specific DNA sequences, transcriptionally transactivate p53-effector genes, associate with critical DNA repair proteins, and induce apoptosis. Abnormalities of the retinoblastoma tumor suppressor gene, typically in advanced lesions and associated with loss of p53, have also been reported in HCCs.

5. While mutation and amplification of protooncogenes, e.g., the ras family, are rarely detected in human HCCs, their overexpression is a common finding. c-myc and c-fos overexpression may result in part from HBV-encoded transcriptional transactivators, which are often expressed and functionally active in HCCs.

6. Insulin-like growth factor II (IGF-II) and insulin receptor substrate 1 (IRS-1) are frequently expressed at high levels in HCCs. The insulin growth factor signal transduction pathways may contribute to hepatocarcinogenesis by providing a strong proliferative stimulus, promoting tumor angiogenesis and/or preventing transforming growth factor-β1(TGF-β1)-induced apoptosis. Overexpression of transforming growth factor-α also is observed in many HCCs, particularly in those tumors associated with HBV infection.

7. A better understanding of the complex pathobiological process of hepatocarcinogenesis has resulted in more effective preventive measures, including the implementation of HBV vaccination programs. The possibility of p53 as a target for HCC therapy is discussed.

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.