A Novel Target Gene, SKP2, within the 5p13 Amplicon That Is Frequently Detected in Small Cell Lung Cancers

Abstract

We investigated DNA copy-number aberrations in 22 cell lines derived from small cell lung cancers (SCLCs) using comparative genomic hybridization. A minimal common region at 5p13, within the 5p11-p13 amplicon that was most frequently involved, harbored the CDH6, PC4, and SKP2 genes. These three genes showed amplification and consequent overexpression in the SCLC cell lines. SKP2 positively regulates progression of cell cycle by targeting several regulators, such as the cell-cycle inhibitor p27(KIP1), for ubiquitin-mediated degradation. SKP2 was amplified in 7 (44%) of 16 primary SCLC tumors, and consequently overexpressed in 10 (83%) of the 12 of those tumors we examined. Expression levels of SKP2 protein were cell cycle-dependent in SCLC cells as well as in normal cells, and were correlated with the DNA copy-number of the gene. There was an inverse correlation between the expression of SKP2 and p27(KIP1) proteins. Down-regulation of SKP2 using an anti-sense oligonucleotide remarkably suppressed the growth of SCLC cells. Our results indicate that SKP2 is likely to be a target of the 5p13 amplification and to play an important role in the growth of SCLC cells.

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

“…3). In particular, Skp2 levels have been examined in human tumors and have been shown to correlate with grade of malignancy [51,[53][54][55][56][57]69,70]. Similar findings have been reported for high levels of cyclin E and A (reviewed in [58]).…”

Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1–S transition

“…Overexpression or Regulation of RASSF1A by Skp2 at G 1 -S transition MS Song et al amplification of Skp2 has been reported in a large number of human cancers (Yokoi et al, 2002) and transgenic expression of Skp2 in mice leads to tumor formation, suggesting that Skp2 is oncogenic (Gstaiger et al, 2001;Latres et al, 2001). Skp2 targets p27, cyclin E and FOXO1 for degradation in a phosphorylationdependent manner (Marti et al, 1999;Nakayama et al, 2000;Huang et al, 2005).…”

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

“…In addition to its role as a putative tumor suppressor in normal cellular growth, some other studies also suggest that PC4 may also be involved in the tumorigenesis, probably through the activation or synergizing of other genes required in the pathogenesis of cancer. [20][21][22][23][24] A possible involvement of PC4 in oncogenesis in a chemically induced rat pancreatic B-cell tumor was first observed in 1984. 21 Using a general cDNA screen method, Soma et al were able to identify a clone encoding for 119 amino-acid residues that showed a clearly positive reaction only with a probe derived from rat pancreatic B-cell tumor, but not the probe derived from normal islet B cells.…”

“…Comparative genomic hybridization studies indicated that PC4 was one of the three genes that showed amplification and consequent over expression in the NSCLC cell lines. 22 Gene expression profiling indentified that the expression of PC4 in invasive intraductal papillary mucinous neoplasm of the pancreas was increased 28-fold compared with normal pancreatic epithelium. 23 Statistical analysis of gene expression data from primary colorectal carcinomas, liver metastases and carcinomatoses identified PC4 as one of the top 20 genes upregulated in carcinomatoses.…”

“…However, in contrast to the proposed statement as a tumor suppressor, PC4 has been recently found to show an upregulated level in several kinds of cancer. [20][21][22][23][24] Moreover, our previous work indicated that overexpression of PC4 in a population of normal dermal multipotent fibroblasts results in the tumorigenic transformation of the cells, indicating the role of PC4 in tumor development and progression. 20 This prompted us to further study the significance of PC4 in cancer therapy.…”