Background
The INK4a/ARF locus encodes p16INK4a and p14ARF, both of which are crucial for two tumor suppressor pathways, retinoblastoma (RB)/p16INK4a and p53/ARF. Inactivation of RB/p16INK4a was frequently reported, but alterations of the p14 ARF gene in hepatocellular carcinoma (HCC) in the Japanese population have been insufficiently analyzed.
Methods
To determine the role of p53/ARF alteration in hepatocarcinogenesis, we examined 44 HCCs for mRNA expression, deletion, mutation, and promoter hypermethylation of the p14 ARF gene; alterations of p53 were also analyzed in the same series of HCCs.
Results
Homozygous deletion, spanning from exon 1 β to exon 2, was found in 1 HCC mutations within exon 2 were found in 2 HCCs, but no promoter hypermethylation was detected. All 3 HCCs with p14 ARF alteration were well differentiated. Twelve of the 44 HCCs (27.2%) showed immunohistochemical evidence of p53 alteration; however, only 1 of the tumors with p53 alteration was well differentiated. TaqMan polymarase chain reaction (PCR) indicated that the expression of p14ARF in HCCs was higher than in that in all but three of the corresponding non-tumorous tissues (P < 0.0001), and increased expression of p14ARF seemed to be associated with poorly differentiated phenotype. Absence of p14ARF expression was seen in only one HCC, with homozygous deletion of the p14 ARF gene.
Conclusions
Compared with p53 alteration, p14 ARF alteration does not occur frequently, but may play a role in a subset of Japanese HCCs in the early stage of hepatocarcinogenesis. On the other hand, overexpression of p14ARF was frequently observed in HCC, especially in poorly differentiated tumors, probably reflecting oncogenic stimuli in these tumors.
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Ito, T., Nishida, N., Fukuda, Y. et al. Alteration of the p14 ARF gene and p53 status in human hepatocellular carcinomas. J Gastroenterol 39, 355–361 (2004). https://doi.org/10.1007/s00535-003-1302-9
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DOI: https://doi.org/10.1007/s00535-003-1302-9