Ptk2 And Eif3s3 Genes May Be Amplification Targets At 8Q23–Q24 and Are Associated With Large Hepatocellular Carcinomas

Abstract

We investigated 39 primary hepatocellular carcinomas (HCCs) for aberrations in DNA copy number, using comparative genomic hybridization (CGH). Gain of DNA at 8q was common in these tumors; high-level gains, indicative of gene amplification, occurred most frequently at 8q23-q24. Gains of 8q correlated with large (>5 cm) tumor size. To identify targets of the amplification events involving 8q, we determined expression levels of 14 candidate genes within that region in a total of 41 HCCs by means of real-time quantitative reverse-transcription polymerase chain reactions (RT-PCR). Significant correlation was found between elevated levels of expression and increases in copy number for PTK2 (located at 8q24.3) and EIF3S3 (at 8q23.3), but for none of the other candidates, which included MYC (8q24.1). Southern blot analyses confirmed that PTK2 and EIF3S3 were amplified, respectively, in 5 (19%) and 7 (26%) of the 27 tumors examined in accordance with expression patterns, an indication that expression of PTK2 and EIF3S3 was probably up-regulated by the amplification mechanism. When we analyzed potential relationships between elevated expression of PTK2 and EIF3S3 and clinicopathologic parameters, high expression of the 2 transcripts was significantly associated with large (>5 cm) tumor size and with hepatitis B virus (HBV) infection. In conclusion, PTK2 and EIF3S3, which, respectively, encode focal adhesion kinase and the p40 subunit of the eukaryotic initiation factor 3, were probable targets within the amplification at 8q23-q24 and may be involved in progression of HCC. Accumulated evidence suggests that multiple genetic alterations occurring sequentially in a cell lineage, at nucleotide as well as chromosome levels, underlie the carcinogenetic process in solid tumors. Amplification of chromosomal DNA is one of the mechanisms capable of activating genes whose over expression contributes to development and progression of cancer in a variety of tissues. We have detected novel regions of amplification in various types of cancer by means of comparative genomic hybridization (CGH) experiments and have identified from such amplicons a number of candidate oncogenes. [1][2][3][4][5][6] Recently we identified TFDP1, CUL4A, and CDC16 as targets of amplification at 13q34 in HCCs. 7 CGH allows a global overview of changes in DNA copy number throughout the genome of a tumor. In the work reported here, we examined 39 primary HCC tumors by CGH to explore genomic alterations that might affect initiation and/or progression of liver tumors. Among losses and gains involving several chromosomal regions, 8q was one of the most frequently amplified seg-

Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH

“…24 The PTK2 gene has also been identified as a target for the amplification event at 8q23-24, and elevated expression of PTK2 is associated with a large tumor size in HCC. 25 Our data revealed that four genes were correlated with poor differentiation of HCV-HCC. As the percentage of poorly differentiated tumor cells is higher in large HCC tumors, 26 the increase in copy number of the other two genes on 8q, MOS and EXT1, may be closely associated with disease progression.…”

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

“…4,13 Other results showed that the oncogenes PTK2 and EIF3S3, mapped to 8q24.3 and 8q23.3, were both upregulated by amplification of this chromosomal region. 25 Our data indicate that telomere shortening plays a causal role in the development of CIN in human HCC. The lack of a further shortening of telomeres above the stage of 5 copies of chromosome 8 indicates that telomeres might have reached a critical short length necessary for cell survival.…”

Increased expression of glycosyl‐phosphatidylinositol anchor attachment protein 1 (GPAA1) is associated with gene amplification in hepatocellular carcinoma

“…4 In particular, chromosome 8q24 amplification has been shown to associate with a number of cancers, including prostate cancer, pancreatic cancer and HCC. [5][6][7][8] In HCC, gain of 8q has been reported to be associated with aggressive tumor behavior and lead to the overexpression of oncogenes. 8,[35][36][37] The loss on 8p was proved to be related to progression and metastasis of HCC.…”

“…[5][6][7][8] In HCC, gain of 8q has been reported to be associated with aggressive tumor behavior and lead to the overexpression of oncogenes. 8,[35][36][37] The loss on 8p was proved to be related to progression and metastasis of HCC. 38 In this study, we have employed QuMA for the determination of relative GPAA1 genomic copy number.…”

“…[2][3][4][5][6][7] A number of novel candidate oncogenes have been identified through analyzing the amplified regions in HCC. [8][9][10][11][12][13] There were 27 genes (from a total of 30 cDNA clones) on chromosome 8q region that demonstrated significantly higher expression levels in HCC from our microarray dataset, where 19 encode for known genes and 8 were ESTs/hypothetical proteins. 1 Among the known genes (ATAD2, BIG1, COPS5, CYC1, DD5, DDEF1, E2F5, EIF2C2, ENPP2, EXOSC4, GPAA1, NCOA2, POLR2K, PTK2, RDH10, RECQL4, TIGD5, TPD52, ZNF252), PTK2 has been reported to demonstrate increased expression and gene copy number.…”