Characterization of the 3p12.3‐pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer

Abstract

The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV-90 ovarian cancer cell line identified the 3p12.3-pcen region as a candidate tumor suppressor gene (TSG) locus. In the present study, polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12.3-pcen interval to a 16.1 Mb common region containing 12 known or hypothetical genes: 3ptel-ROBO2-ROBO1-GBE1-CADM2-VGLL3-CHMP2B-POU1F1-HTR1F-CGGBP1-ZNF654-C3orf38-EPHA3-3pcen. Seven of these genes, ROBO1, GBE1, VGLL3, CHMP2B, CGGBP1, ZNF654, and C3orf38, exhibited gene expression in the hybrids, placing them as top TSG candidates for further analysis. The expression of all but one (VGLL3) of these genes was also detected in the parental OV-90 cell line. Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV-90 and donor normal chromosome 3 contig. However, the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for ROBO1, VGLL3, CHMP2B, and CGGBP1 and cDNA sequencing of the hybrids revealed biallelic expression of these genes. Interestingly, underexpression of VGLL3 and ZNF654 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors, and this occurred regardless of allelic content of 3p12.3-pcen. The results taken together suggest that dysregulation of VGLL3 and/or ZNF654 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV-90, a cell line hemizygous for 3p.

Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer

“…2B). As the same batch of cDNAs were used in the semi-quantitative RT-PCR analyses, the expression profiles likely reflect differential expression of RHBDF2 and CYGB in ovarian tumour samples as has been observed in our previous studies with other genes (22,32,34,41,53,54). RHBDF2 and CYGB expression was also detectable in whole ovary, testes and placenta.…”

“…However, in contrast to TOV-81D, TOV-2223G retains some in vitro features of tumourigenic cells, such as the ability to invade matrigel and form colonies in soft agarose (37). By semi-quantitative RT-PCR or gene expression microarray analyses, TOV-81D has also been shown to retain gene expression profiles that resembled NOSE samples (22,32,34,41,53,54). Notably, TOV-81D exhibited the highest level of expression of RHBDF2 whereas low or undetectable levels of expression were observed in all of the other EOC cell lines (Fig.…”

“…These cell lines were derived in the context of research involving the identification of chromosome 3p TSGs (31,54). Affymetrix gene expression analyses showed an altered transcriptome in comparison to the parental OV-90 cell line, wherein some genes were reprogrammed and reflected the expression profile observed in NOSE samples as compared with malignant ovarian cancer samples (31,32).…”

Role of Genetic Polymorphisms in the Development and Prognosis of Sporadic and Familial Prostate Cancer

“…CHMP2B belongs to the chromatin-modifying protein/charged multivesicular body protein family. In addition, the 3p12.3-pcen region has been identified as a locus harboring candidate to a tumor suppressor gene [14]. However, the same SNP rs2660753 on chromosome 3 was not correlated with PC in Chinese patients [15].…”

Hypoxia-Regulated miR-146a Targets Cell Adhesion Molecule 2 to Promote Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma

“…CADM2 gene expression was high in ovarian cancer [25], prostate cancer [26], and lymphoma and melanoma [27,28]. It was recently, reported that CADM2 suppressed the growth of prostate cancer cells [26].…”