Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma

Abstract

Summary Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson twohit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.Keywords: p73; hepatocellular carcinoma; p53; mutation; mRNA expression; 1p36.3 164British Journal of Cancer (1999) 79(1), 164-167 © 1999 Cancer Research Campaign Received 18 February 1998 Revised 11 May 1998 Accepted 13 May 1998Correspondence to: A Nakagawara, Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan Analysis of p73 in hepatocellular carcinoma 165

Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells

“…The p73 gene, encoding only DN-p73 transcripts in normal liver, may function as a tumour promoter rather than a tumour suppressor in this tissue, by interfering with wild-type p53 function Pozniak et al, 2000). This could explain why p73 is not mutated in HCC (Mihara et al, 1999). However, p53 gene is frequently mutated in HCC (Ozturk, 1999), as also demonstrated here in HCC-derived cell lines (Figure 2c).…”

“…However, p53, but not the other family members, is considered a tumour-suppressor gene. For example, unlike p53, p73 de®ciency in mice does not lead to a cancerprone phenotype , and p73 gene is not mutated in human tumours, including hepatocellular carcinoma (HCC) Mihara et al, 1999). Presently, the reasons for this discrepancy are not known.…”

“…On the other hand, Mihara et al (1999) reported the absence of mutation, as well as absence of overexpression of p73 gene in HCC. These observations were in apparent contradiction and they did not provide evidence about the mechanisms of p73 involvement in liver malignancy.…”

p73 can suppress the proliferation of cells that express mutant p53

“…For example, p73 and p63 are rarely mutated in tumors (Nomoto et al, 1998;Mihara et al, 1999;Yokomizo et al, 1999;Moll et al, 2001). However, both proteins have been found to play a role in development.…”

Mutation analysis of P73 and TP53 in Merkel cell carcinoma

“…Jost et al (1997) showed that overexpression of p73 can activate the transcription of TP53-responsive genes like p21 wafl/cipl and inhibit cell growth in the same way as TP53 by inducing apoptosis. Mutation analyses for the p73 gene have been performed in lung carcinoma, oligodendrogliomas, prostatic carcinoma, neuroblastomas, colorectal carcinoma, oesophageal carcinoma and hepatocellular carcinoma (Kovalev et al, 1998;Mai et al, 1998aMai et al, , 1998bNimura et al, 1998;Nomoto et al, 1998;Sunahara et al, 1998;Ichimiya et al, 1999;Mihara et al, 1999). Except for two mutations in primary neuroblastomas resulting in amino acid substitutions in the C-terminal region of p73 , no other mutations have been reported.…”