Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: Identification of candidate amplified and overexpressed genes

Abstract

Cervical cancer (CC) cells exhibit complex karyotypic alterations, which is consistent with deregulation of numerous critical genes in its formation and progression. To characterize this karyotypic complexity at the molecular level, we used cDNA array comparative genomic hybridization (aCGH) to analyze 29 CC cases and identified a number of over represented and deleted genes. The aCGH analysis revealed at least 17 recurrent amplicons and six common regions of deletions. These regions contain several known tumor-associated genes, such as those involved in transcription, apoptosis, cytoskeletal remodeling, ion-transport, drug metabolism, and immune response. Using the fluorescence in situ hybridization (FISH) approach we demonstrated the presence of high-level amplifications at the 8q24.3, 11q22.2, and 20q13 regions in CC cell lines. To identify amplification-associated genes that correspond to focal amplicons, we examined one or more genes in each of the 17 amplicons by Affymetrix U133A expression arrays and semiquantitative reverse-transcription PCR (RT-PCR) in 31 CC tumors. This analysis exhibited frequent and robust upregulated expression in CC relative to normal cervix for genes EPHB2 (1p36), CDCA8 (1p34.3), AIM2 (1q22-23), RFC4, MUC4, and HRASLS (3q27-29), SKP2 (5p12-13), CENTD3 (5q31.3), PTK2, RECQL4 (8q24), MMP1 and MMP13 (11q22.2), AKT1 (14q32.3), ABCC3 (17q21-22), SMARCA4 (19p13.3) LIG1 (19q13.3), UBE2C (20q13.1), SMC1L1 (Xp11), KIF4A (Xq12), TMSNB (Xq22), and CSAG2 (Xq28). Thus, the gene dosage and expression profiles generated here have enabled the identification of focal amplicons characteristic for the CC genome and facilitated the validation of relevant genes in these amplicons. These data, thus, form an important step toward the identification of biologically relevant genes in CC pathogenesis. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain

“…The gene for MMP1 is overexpressed in HPV-associated cervical cancer and in BPV-1-associated equine sarcoids (Narayan et al, 2007;Yuan et al, 2008), but the papillomavirus proteins involved in the transcriptional activation of the MMP1 gene in these tumours have not yet been identified. MMP9 too has been reported to be activated by papillomavirus (Akgül et al, 2006; Behren et al, 2005).…”

“…Additionally, MMP1 was present in much greater amounts than in HaCaT-pCI-neo cells and also in suprabasal layers (Fig. 3l), indicating that the abundant production of MMP1 by the HaCaT-16E5 cells was not only due to the interaction with type I collagen but also predominantly to the effect of E5.E5-induced invasion might substantially contribute to tumour progression in persistently infected cervical epithelial cells, although this remains to be confirmed.The gene for MMP1 is overexpressed in HPV-associated cervical cancer and in BPV-1-associated equine sarcoids (Narayan et al, 2007;Yuan et al, 2008), but the papillomavirus proteins involved in the transcriptional activation of the MMP1 gene in these tumours have not yet been identified. MMP9 too has been reported to be activated by papillomavirus (Akgül et al, 2006; Behren et al, 2005).…”

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…Furthermore, the highly conserved helicase gene family members WRN and BLM predispose for Werner and Bloom syndromes characterized by high incidence of sarcomas and multiple cancers respectively. RECQL4 has been reported to be amplified and overexpressed in colorectal, and cervical cancer [35,36], but the prognostic significance has not been reported.…”

Transcriptional Activation of Human CDCA8 Gene Regulated by Transcription Factor NF-Y in Embryonic Stem Cells and Cancer Cells

“…Overexpression of the CPC components Aurora B (4,5), INCENP (6), and survivin (7)(8)(9)(10) is associated with tumorigenesis in human cancers. CDCA8 is a putative oncogene that is up-regulated in many types of cancer tissues (11)(12)(13)(14) but has very low or absent expression in normal tissues (12). Its overexpression is required for growth, survival, and the malignant nature of lung cancer cells (12).…”