title: VGLL3 expression is associated with a tumor suppressor phenotype in epithelial ovarian cancer.
abstract: Previous studies have implicated vestigial like 3 (VGLL3), a chromosome 3p12.3 gene that encodes a putative transcription co-factor, as a candidate tumor suppressor gene (TSG) in high-grade serous ovarian carcinomas (HGSC), the most common type of epithelial ovarian cancer. A complementation analysis based on microcell-mediated chromosome transfer (MMCT) using a centric fragment of chromosome 3 (der3p12-q12.1) into the OV-90 ovarian cancer cell line haploinsufficient for 3p and lacking VGLL3 expression was performed to assess the effect on tumorigenic potential and growth characteristics. Genetic characterization of the derived MMCT hybrids revealed that only the hybrid that contained an intact VGLL3 locus exhibited alterations of tumorigenic potential in a nude mouse xenograft model and various in vitro growth characteristics. Only stable OV-90 transfectant clones expressing low levels of VGLL3 were derived. These clones exhibited an altered cytoplasmic morphology characterized by numerous single membrane bound multivesicular-bodies (MVB) that were not attributed to autophagy. Overexpression of VGLL3 in OV-90 was achieved using a lentivirus-based tetracycline inducible gene expression system, which also resulted in MVB formation in the infected cell population. Though there was no significant differences in various in vitro and in vivo growth characteristics in a comparison of VGLL3-expressing clones with empty vector transfectant controls, loss of VGLL3 expression was observed in tumors derived from mouse xenograft models. VGLL3 gene and protein expression was significantly reduced in HGSC samples (>98%, p < 0.05) relative to either normal ovarian surface epithelial cells or epithelial cells of the fallopian tube, possible tissues of origin of HGSC. Also, there appeared to be to be more cases with higher staining levels in stromal tissue component from HGSC cases that had a prolonged disease-free survival. The results taken together suggest that VGLL3 is involved in tumor suppressor pathways, a feature that is characterized by the absence of VGLL3 expression in HGSC samples.
authors: Department of Human Genetics, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal H3G 1A4, Quebec, Canada.
authors: Karen
authors: K
authors: Gambaro
authors: Michael C J
authors: MC
authors: Quinn
authors: Paulina M
authors: PM
authors: Wojnarowicz
authors: Suzanna L
authors: SL
authors: Arcand
authors: Manon
authors: M
authors: de Ladurantaye
authors: Véronique
authors: V
authors: Barrès
authors: Jean-Sébastien
authors: JS
authors: Ripeau
authors: Ann M
authors: AM
authors: Killary
authors: Elaine C
authors: EC
authors: Davis
authors: Josée
authors: J
authors: Lavoie
authors: Diane M
authors: DM
authors: Provencher
authors: Anne-Marie
authors: AM
authors: Mes-Masson
authors: Mario
authors: M
authors: Chevrette
authors: Patricia N
authors: PN
authors: Tonin
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
chemical_list: D014157:Transcription Factors; C555441:VGLL3 protein, human; C540284:VITO-2 protein, mouse