FKBP10/FKBP65 expression in high-grade ovarian serous carcinoma and its association with patient outcome

Quinn,Michael  C.J.; Wojnarowicz,Paulina  M.; Pickett,Amy; Provencher,Diane  M.; Mes-Masson,Anne-Marie; Davis,Elaine C.; Tonin,Patricia  N.

doi:10.3892/ijo.2013.1797

FKBP10/FKBP65 expression in high-grade ovarian serous carcinoma and its association with patient outcome

Authors:
- Michael C.J. Quinn
- Paulina M. Wojnarowicz
- Amy Pickett
- Diane M. Provencher
- Anne-Marie Mes-Masson
- Elaine C. Davis
- Patricia N. Tonin
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Affiliations: Research Centre of the University of Montreal Hospital Centre/Montreal Cancer Institute, Montreal, QC, Canada, Department of Human Genetics, McGill University, Montreal, QC, Canada, Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
Published online on: January 23, 2013 https://doi.org/10.3892/ijo.2013.1797
Pages: 912-920

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Abstract

The frequent loss of chromosome 17 in epithelial ovarian carcinomas (EOC), particularly high-grade serous carcinomas (HGSC), has been attributed to the disruption of TP53 (at 17p13.1) and other chromosome 17 genes suspected to play a role in tumour suppressor pathways. In a transcriptome analysis of HGSC, we showed underexpression of a number of chromosome 17 genes, which included FKBP10 (at 17q21.1) and collagen I α 1 (COL1A1; at 17q21.33). FKBP10 codes for the immunophilin FKBP65 and is suspected to act as a chaperone for COL1A1. We have investigated FKBP10 (gene) and FKBP65 (protein) expression in HGSC samples and EOC cell lines that differ in their tumourigenic potential. COL1A1 expression was also investigated given the purported function of FKBP65. RT-PCR analysis verified underexpression of FKBP10 and COL1A1 in HGSCs (n=14) and six tumourigenic EOC cell lines, relative to normal ovarian surface epithelial cells and a non‑tumourigenic EOC cell line. Immunohistochemistry analyses of 196 HGSC samples using tissue microarrays revealed variable staining intensities in the epithelial tumour component where only 7.8% and 1.0% of samples stained intensely for FKBP65 and COL1A1, respectively. Variable staining intensities were also observed for the stromal component where 23.6% and 24.1% stained intensely for FKBP65 and COL1A1, respectively. There was no significant correlation of staining intensity of either protein with disease stage. Staining of FKBP65 was clearly visible in normal epithelial cells of the ovarian surface and fallopian tube. There was a significant correlation between absence of FKBP65 staining in the epithelial cell component of the tumour and prolonged overall survival (p<0.001). Our results suggest that underexpression of FKBP65 protein is characteristic of HGSCs and that this expression profile may be linked to molecular pathways associated with an unfavourable outcome in cancer patients.

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1	Dion F, Mes-Masson AM, Seymour RJ, Provencher D and Tonin PN: Allelotyping defines minimal imbalance at chromosomal region 17q25 in non-serous epithelial ovarian cancers. Oncogene. 19:1466–1472. 2000. View Article : Google Scholar : PubMed/NCBI
2	Foulkes WD, Black DM, Stamp GW, Solomon E and Trowsdale J: Very frequent loss of heterozygosity throughout chromosome 17 in sporadic ovarian carcinoma. Int J Cancer. 54:220–225. 1993. View Article : Google Scholar : PubMed/NCBI
3	Presneau N, Dewar K, Forgetta V, Provencher D, Mes-Masson AM and Tonin PN: Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1–q25.2. Mol Carcinog. 43:141–154. 2005.PubMed/NCBI
4	Wojnarowicz PM, Provencher DM, Mes-Masson AM and Tonin PN: Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer. Int J Oncol. 40:18656–1880. 2012.PubMed/NCBI
5	TCGA: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar
6	Gorringe KL, George J, Anglesio MS, et al: Copy number analysis identifies novel interactions between genomic loci in ovarian cancer. PloS One. 5:e114082010. View Article : Google Scholar : PubMed/NCBI
7	Pieretti M, Cavalieri C, Conway PS, Gallion HH, Powell DE and Turker MS: Genetic alterations distinguish different types of ovarian tumors. Int J Cancer. 64:434–440. 1995. View Article : Google Scholar : PubMed/NCBI
8	Sangha N, Wu R, Kuick R, et al: Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia. 10:1362–1372. 2008.PubMed/NCBI
9	Feng Q, Deftereos G, Hawes SE, et al: DNA hypermethylation, Her-2/neu overexpression and p53 mutations in ovarian carcinoma. Gynecol Oncol. 111:320–329. 2008. View Article : Google Scholar : PubMed/NCBI
10	Rathi A, Virmani AK, Schorge JO, et al: Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res. 8:3324–3331. 2002.PubMed/NCBI
11	Pergolizzi R, Appierto V, Crosti M, et al: Role of retinoic acid receptor overexpression in sensitivity to fenretinide and tumorigenicity of human ovarian carcinoma cells. Int J Cancer. 81:829–834. 1999. View Article : Google Scholar : PubMed/NCBI
12	Bruening W, Prowse AH, Schultz DC, Holgado-Madruga M, Wong A and Godwin AK: Expression of OVCA1, a candidate tumor suppressor, is reduced in tumors and inhibits growth of ovarian cancer cells. Cancer Res. 59:4973–4983. 1999.PubMed/NCBI
13	Presneau N, Mes-Masson AM, Ge B, Provencher D, Hudson TJ and Tonin PN: Patterns of expression of chromosome 17 genes in primary cultures of normal ovarian surface epithelia and epithelial ovarian cancer cell lines. Oncogene. 22:1568–1579. 2003. View Article : Google Scholar : PubMed/NCBI
14	Wojnarowicz PM, Breznan A, Arcand SL, et al: Construction of a chromosome 17 transcriptome in serous ovarian cancer identifies differentially expressed genes. Int J Gynecol Cancer. 18:963–975. 2008. View Article : Google Scholar : PubMed/NCBI
15	Cody NA, Ouellet V, Manderson EN, et al: Transfer of chromosome 3 fragments suppresses tumorigenicity of an ovarian cancer cell line monoallelic for chromosome 3p. Oncogene. 26:618–632. 2007. View Article : Google Scholar : PubMed/NCBI
16	Quinn MC, Filali-Mouhim A, Provencher DM, Mes-Masson AM and Tonin PN: Reprogramming of the transcriptome in a novel chromosome 3 transfer tumor suppressor ovarian cancer cell line model affected molecular networks that are characteristic of ovarian cancer. Mol Carcinog. 48:648–661. 2009. View Article : Google Scholar
17	Coss MC, Winterstein D, Sowder RC II and Simek SL: Molecular cloning, DNA sequence analysis, and biochemical characterization of a novel 65-kDa FK506-binding protein (FKBP65). J Biol Chem. 270:29336–29341. 1995. View Article : Google Scholar : PubMed/NCBI
18	Zeng B, MacDonald JR, Bann JG, et al: Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-trans isomerases, is only partially inhibited by FK506. Biochem J. 330:109–114. 1998.PubMed/NCBI
19	Patterson CE, Abrams WR, Wolter NE, Rosenbloom J and Davis EC: Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin. Cell Stress Chaperones. 10:285–295. 2005. View Article : Google Scholar
20	Patterson CE, Schaub T, Coleman EJ and Davis EC: Developmental regulation of FKBP65. An ER-localized extra-cellular matrix binding-protein. Mol Biol Cell. 11:3925–3935. 2000. View Article : Google Scholar : PubMed/NCBI
21	Ishikawa Y, Vranka J, Wirz J, Nagata K and Bachinger HP: The rough endoplasmic reticulum-resident FK506-binding protein FKBP65 is a molecular chaperone that interacts with collagens. J Biol Chem. 283:31584–31590. 2008. View Article : Google Scholar : PubMed/NCBI
22	Forbes SA, Bindal N, Bamford S, et al: COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acid Res. 39:D945–D950. 2011. View Article : Google Scholar : PubMed/NCBI
23	Alanay Y, Avaygan H, Camacho N, et al: Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 86:551–559. 2010. View Article : Google Scholar : PubMed/NCBI
24	Kelley BP, Malfait F, Bonafe L, et al: Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J Bone Miner Res. 26:666–672. 2011. View Article : Google Scholar : PubMed/NCBI
25	Nishida T, Oda T, Sugiyama T, Izumi S and Yakushiji M: Concurrent ovarian serous carcinoma and osteogenesis imperfecta. Arch Gynecol Obstet. 253:153–156. 1993. View Article : Google Scholar : PubMed/NCBI
26	Ouellet V, Zietarska M, Portelance L, et al: Characterization of three new serous epithelial ovarian cancer cell lines. BMC Cancer. 8:1522008. View Article : Google Scholar : PubMed/NCBI
27	Le Page C, Marineau A, Bonza PK, et al: BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T cells and a better prognosis. PloS One. 7:e385412012.PubMed/NCBI
28	Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 92:205–216. 2000. View Article : Google Scholar
29	Ouellet V, Provencher DM, Maugard CM, et al: Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling. Oncogene. 24:4672–4687. 2005. View Article : Google Scholar
30	Rozen S and Skaletsky H: Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 132:365–386. 2000.PubMed/NCBI
31	Karolchik D, Baertsch R, Diekhans M, et al: The UCSC Genome Browser Database. Nucleic Acid Res. 31:51–54. 2003. View Article : Google Scholar
32	Arcand SL, Maugard CM, Ghadirian P, et al: Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat. 108:399–408. 2008. View Article : Google Scholar : PubMed/NCBI
33	Davis EC, Broekelmann TJ, Ozawa Y and Mecham RP: Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway. J Cell Biol. 140:295–303. 1998. View Article : Google Scholar : PubMed/NCBI
34	Salvador S, Gilks B, Kobel M, Huntsman D, Rosen B and Miller D: The fallopian tube: primary site of most pelvic high-grade serous carcinomas. Int J Gynecol Cancer. 19:58–64. 2009. View Article : Google Scholar : PubMed/NCBI
35	Henriksen R, Sorensen FB, Orntoft TF and Birkenkamp-Demtroder K: Expression of FK506 binding protein 65 (FKBP65) is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium. Tumour Biol. 32:671–676. 2011. View Article : Google Scholar
36	Provencher DM, Lounis H, Champoux L, et al: Characterization of four novel epithelial ovarian cancer cell lines. In Vitro Cell Dev Biol Anim. 36:357–361. 2000. View Article : Google Scholar : PubMed/NCBI
37	Birch AH, Quinn MC, Filali-Mouhim A, Provencher DM, Mes-Masson AM and Tonin PN: Transcriptome analysis of serous ovarian cancers identifies differentially expressed chromosome 3 genes. Mol Carcinog. 47:56–65. 2008. View Article : Google Scholar : PubMed/NCBI
38	Cody NA, Shen Z, Ripeau JS, et al: 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. Mol Carcinog. 48:1077–1092. 2009. View Article : Google Scholar : PubMed/NCBI
39	Manderson EN, Birch AH, Shen Z, Mes-Masson AM, Provencher D and Tonin PN: Molecular genetic analysis of a cell adhesion molecule with homology to L1CAM, contactin 6, and contactin 4 candidate chromosome 3p26pter tumor suppressor genes in ovarian cancer. Int J Gynecol Cancer. 19:513–525. 2009. View Article : Google Scholar
40	Kobel M, Kalloger SE, Boyd N, et al: Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 5:e2322008. View Article : Google Scholar : PubMed/NCBI
41	Schauer IG, Sood AK, Mok S and Liu J: Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia. 13:393–405. 2011.PubMed/NCBI
42	Finak G, Bertos N, Pepin F, et al: Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 14:518–527. 2008. View Article : Google Scholar : PubMed/NCBI