Molecular and cellular pathology of hepatocellular carcinoma

Abstract

Mutations of the p53 gene are common in hepatocellular carcinoma (HCC) and have been found in 13-33% of HCC in Asia and 23% of HCC in Hong Kong. In addition, p53 overexpression has been found to be associated with poorer cellular differentiation and larger tumour size and may be a late event in hepatocarcinogenesis. The p53 gene is important in controlling cell cycle, apoptosis and DNA repair. The cyclin-dependent kinase inhibitor p21(WAF1/CIP1), which is downstream of p53, is regulated by both p53- dependent and p53-independent pathways. We found that HCC with p53 mutations had lower levels of p21 expression than those without p53 mutations. Moreover, p21 protein expression of the tumours was significantly higher in the tumours than in the corresponding non-tumorous livers. When the tumours were stratified into two groups, those with higher expression were found to have a significantly lower incidence of multiple tumour nodules and lower incidence of turnout microsatellite formation. p21 Expression was, however, not associated with p53 expression. Higher p21 expression is associated with solitary tumour nodules and fewer tumour microsatellites, but may not be enough to suppress tumour progression. Insulin-like growth factor II (IGF- II) gene has complex regulation of transcription resulting in multiple mRNA being produced and different mRNA occur in the adult and foetus. Using northern blot analysis, repression of normal adult promoter and re- expression of foetal promoters of IGF-II are common events in HCC, with repression of the normal adult promoter in 93% of the HCC transcripts and re- expression of the foetal transcripts (6 and 5 kb, respectively) in 40% of tumours. In addition, IGF-II expression was significantly more frequent in older patients. This may suggest that spontaneous expression of IGF-II late in life may promote the growth of turnouts which have already arisen through other mechanisms, but foetal re-expression, itself, may not be enough to contribute to turnout progression.