Different gene expression of MDM2, GAGE-1, –2 and FHIT in hepatocellular carcinoma and focal nodular hyperplasia

Abstract

SummaryOverexpression and/or mutations of oncogenes, tumour suppressor genes and tumour rejection genes have been observed in several human malignancies. Their analyses might be of diagnostic importance. Therefore, malignant hepatocytes derived from hepatocellular carcinoma (HCC) tissue as well as non-malignant hepatocytes derived from focal nodular hyperplasia (FNH) were studied. Samples containing normal human hepatocytes (HC) served as controls. Cellular material was obtained by fine-needle aspiration biopsy guided by ultrasound. Cells were analysed for expression and mutation of the oncogene MDM2, the genes GAGE-1, -2 coding for tumourassociated antigens and the candidate tumour suppressor gene FHIT. Different patterns of non-mutant FHIT transcripts including precise deletion of exons were found in 7/10 HCC, 2/10 FNH and 2/10 HC. However, expression of non-mutant GAGE-1, -2 RNA was demonstrated exclusively in 6/10 HCC samples. Further genetic features specific of HCC were point mutations in a zinc-finger motif of MDM2 (3/10 HCC samples). Neither GAGE-1, -2 expression nor MDM2 mutations were observed in the FNH samples, or in normal hepatocytes. Our findings suggest that occurrence of variable FHIT transcripts is not restricted to hepatic malignant tumours. In contrast, MDM2 mutations and GAGE-1, -2 expression were associated with HCC specimens. Therefore, the RT-PCR assays for GAGE-1, -2 and MDM2 might be useful adjuncts in cytodiagnosis of liver neoplasms.

Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators

“…Another explanation for the MDM2 protein overexpression is the loss of control by the P14ARF gene which was deleted in two out of three cases revealing MDM2 accumulation. The overexpression was not caused by MDM2 mutations formerly found in hepatocellular carcinoma (Schlott et al, 1997(Schlott et al, , 1999 since none of the three samples accumulating MDM2 demonstrated corresponding changes. However, a novel MDM2 gene mutation was found in a non-expressing, alcohol-induced cirrhosis.…”

Fragile histidine triad gene alterations are not essential for hepatocellular carcinoma development in South Korea

“…The FHIT gene located at one of the most common fragile sites is altered in a variety of tumor cell lines, as well as, in premalignant and malignant lesions of primary tumors, in line with its role as a tumor suppressor gene whose loss or inactivation may contribute to cancer development or malignant progression [13,[15][16][17][18][19][20] . Moreover, several studies have been reported results for chromosome 3p rearrangements, decreased or absent FHIT mRNA expression, intragenic deletions and absence of protein expression, in HCC cell lines and primary HCC [13,[15][16][17][18][19][21][22] . Aberrant FHIT transcripts have been identified in 39%-70% of HCC cases [13,[15][16][17][18] .…”

“…Moreover, several studies have been reported results for chromosome 3p rearrangements, decreased or absent FHIT mRNA expression, intragenic deletions and absence of protein expression, in HCC cell lines and primary HCC [13,[15][16][17][18][19][21][22] . Aberrant FHIT transcripts have been identified in 39%-70% of HCC cases [13,[15][16][17][18] . These transcripts are generated by exon skipping, use of alternative 5' and 3' splice sites, and recognition of cryptic splice sites, resulting in insertions of intronic sequences.…”

“…These transcripts are generated by exon skipping, use of alternative 5' and 3' splice sites, and recognition of cryptic splice sites, resulting in insertions of intronic sequences. Consequently, the patterns of aberrant FHIT transcripts vary, but the majority of transcript splicing occurs within two large introns 4 and 5 [15][16][17][18] . As the fusion functions coincide exactly with splice sites, aberrant transcripts may represent alternatively spliced products [9] .…”

“…These synergistic effects may occur because of stabilization of p53 related to Fhit-mediated downregulation of MDM2 [12] . Altered transcripts and allelic loss of the FHIT gene are frequently identified in premalignant and malignant lesions of various tumors [13][14][15][16][17][18] . Moreover, loss or reduction of Fhit expression has been found in most tumors including HCC [10][11][12][13][14][19][20][21][22] .…”