Unknown,Transcriptomics,Genomics,Proteomics

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Chromosomes 6 and 18 Induce Neoplastic Suppression in Epithelial Ovarian Cancer Cells

ABSTRACT: Metaphase comparative genomic hybridisation (CGH) studies indicate that chromosomes 4, 5, 6, 13, 14, 15 and 18 are frequently deleted in primary ovarian cancers (OC). Therefore, we used microcell-mediated chromosome transfer (MMCT) to establish the functional effects of transferring normal copies of these chromosomes into two epithelial OC cell lines. The in vitro neoplastic phenotype (measured as anchorage dependent and independent growth and invasion) was compared between recipient OC cell lines and multiple MMCT hybrids. Chromosomes 6 and 18 showed strong evidence of functional, neoplastic suppression for multiple hybrids in both cell lines. We also found evidence in one cancer cell line suggesting that chromosomes 4, 13 and 14 may also cause functional suppression. Array CGH and microsatellite analyses were used to characterise the extent of genomic transfer in chromosome 6 and 18 hybrids. A 35Mb deletion on chromosome 6 in two hybrids from one cell line mapped the candidate region proximal to 6q15 and distal to 6q22.2; and an approximate 10Mb candidate region spanning the centromere on chromosome 18 was identified in another two hybrids from the other cell line. These data confirm reported functional effects of chromosome 6 in OC cell lines; but to our knowledge, this is the first time that functional suppression for chromosome18 has been reported. This suggests that these chromosomes may harbour genes that behave as tumour suppressors. The future identification of these genes may have a significant impact on the understanding and treatment of the disease and the identification of novel therapeutic targets. Four clones from chr 6 and chr 18 hybrids that were transferred by MMCT successfully were mapped by CGH microarray to identified transferred regions that induced neoplastic suppression in epithelial ovarian cancer cell lines (TOV21G and TOV112D).

ORGANISM(S): Homo sapiens

SUBMITTER: Ken Choi

PROVIDER: E-GEOD-11872 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer 12 previously established cell hybrids, all carrying the same genetic background were subjected to microarray expression analysis. These hybrids were generated by the introduction of chromosome 6 in the HPV16 immortalized cell line FK16A, which resulted in a suppression of hTERT expression and telomerase activity. 8 hybrids were endogenous hTERT positive and 8 hybrids were hTERT negative. Additionally primary keratinocytes (hTERT negative), parental cell line FK16A and cervical cancer cell line SiHa (both hTERT positive) were hybridized.

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Chromosomes 6 and 18 Induce Neoplastic Suppression in Epithelial Ovarian Cancer Cells

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