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Published in: Diagnostic Pathology 1/2016

Open Access 01-12-2016 | Research

DEF6 expression in ovarian carcinoma correlates with poor patient survival

Authors: Phui-Ly Liew, Chih-Yeu Fang, Yu-Chieh Lee, Yi-Chih Lee, Chi-Long Chen, Jan-Show Chu

Published in: Diagnostic Pathology | Issue 1/2016

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Abstract

Background

Increased expression of DEF6 is correlated with the malignant behavior of various cancers. Both DEF6 and p16 contribute to the regulation of cell cycle progression, and p53 plays important role in the cell cycle checkpoints. This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma.

Methods

Immunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis.

Results

We studied 180 cases of ovarian carcinomas (75 high-grade serous, 41 clear cell, 36 mucinous and 28 endometrioid), including 109 FIGO stage I-II cases and 71 FIGO stage III-IV cases. Ovarian carcinomas positive for both DEF6 and p16 expression were associated with the worst OS (P = 0.027) and DFS (P = 0.023), whereas those negative for both DEF6 and p16 had the best OS and DFS. Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028). Kaplan-Meier analysis showed that significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022). Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival. In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis. DEF6 expression was the only independent prognostic factor correlated with shorted OS (HR 2.115; P = 0.025) and DFS (HR 2.248; P = 0.016) upon multivariate analysis.

Conclusions

DEF6 expression may serve as an independent prognostic factor, and interacted positively with p16 toward high tumor stage and shorter survival.
Appendix
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Literature
1.
go back to reference Kurman RJ, Carcangiu ML, Herrington CS, Young RH. World Health Organization Classification of Tumours of Female Reproductive Organs 4th ed. Lyon: IARC Press; 2014. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. World Health Organization Classification of Tumours of Female Reproductive Organs 4th ed. Lyon: IARC Press; 2014.
4.
go back to reference Gupta S, Lee A, Hu C, Fanzo J, Goldberg I, Cattoretti G, et al. Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system. Hum Immunol. 2003;64:389–401.CrossRefPubMed Gupta S, Lee A, Hu C, Fanzo J, Goldberg I, Cattoretti G, et al. Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system. Hum Immunol. 2003;64:389–401.CrossRefPubMed
5.
go back to reference Biswas PS, Gupta S, Stirzaker RA, Kumar V, Jessberger R, Lu TT, et al. Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med. 2012;209:581–96.CrossRefPubMedPubMedCentral Biswas PS, Gupta S, Stirzaker RA, Kumar V, Jessberger R, Lu TT, et al. Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med. 2012;209:581–96.CrossRefPubMedPubMedCentral
6.
go back to reference Canonigo-Balancio AJ, Fos C, Prod’homme T, Bécart S, Altman A. SLAT/Def6 plays a critical role in the development of Th17 cell-mediated experimental autoimmune encephalomyelitis. J Immunol. 2009;183:7259–67.CrossRefPubMedPubMedCentral Canonigo-Balancio AJ, Fos C, Prod’homme T, Bécart S, Altman A. SLAT/Def6 plays a critical role in the development of Th17 cell-mediated experimental autoimmune encephalomyelitis. J Immunol. 2009;183:7259–67.CrossRefPubMedPubMedCentral
7.
go back to reference Mehta H, Glogauer M, Bécart S, Altman A, Coggeshall KM. Adaptor protein SLAT modulates Fcgamma receptor-mediated phagocytosis in murine macrophages. J Biol Chem. 2009;284:11882–91.CrossRefPubMedPubMedCentral Mehta H, Glogauer M, Bécart S, Altman A, Coggeshall KM. Adaptor protein SLAT modulates Fcgamma receptor-mediated phagocytosis in murine macrophages. J Biol Chem. 2009;284:11882–91.CrossRefPubMedPubMedCentral
8.
go back to reference Pernis AB. Rho GTPase-mediated pathways in mature CD4+ T cells. J Leukoc Biol. 2009;85:539–43.PubMed Pernis AB. Rho GTPase-mediated pathways in mature CD4+ T cells. J Leukoc Biol. 2009;85:539–43.PubMed
9.
go back to reference Fanzo JC, Yang W, Jang SY, Gupta S, Chen Q, Siddiq A, et al. Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest. 2006;116:703–14.CrossRefPubMedPubMedCentral Fanzo JC, Yang W, Jang SY, Gupta S, Chen Q, Siddiq A, et al. Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest. 2006;116:703–14.CrossRefPubMedPubMedCentral
10.
go back to reference Mavrakis KJ, McKinlay KJ, Jones P, Sablitzky F. DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA. Exp Cell Res. 2004;294:335–44.CrossRefPubMed Mavrakis KJ, McKinlay KJ, Jones P, Sablitzky F. DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA. Exp Cell Res. 2004;294:335–44.CrossRefPubMed
11.
go back to reference Xu X, Shuen WH, Chen C, Goudevenou K, Jones P, Sablitzky F. Swap70b is required for convergent and extension cell movement during zebrafish gastrulation linking Wnt11 signalling and RhoA effector function. Dev Biol. 2014;386:191–203.CrossRefPubMed Xu X, Shuen WH, Chen C, Goudevenou K, Jones P, Sablitzky F. Swap70b is required for convergent and extension cell movement during zebrafish gastrulation linking Wnt11 signalling and RhoA effector function. Dev Biol. 2014;386:191–203.CrossRefPubMed
12.
go back to reference Hey F, Czyzewicz N, Jones P, Sablitzky F. DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P-bodies. J Biol Chem. 2012;287:31073–84.CrossRefPubMedPubMedCentral Hey F, Czyzewicz N, Jones P, Sablitzky F. DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P-bodies. J Biol Chem. 2012;287:31073–84.CrossRefPubMedPubMedCentral
13.
go back to reference Goudevenou K, Martin P, Yeh YJ, Jones P, Sablitzky F. Def6 is required for convergent extension movements during zebrafish gastrulation downstream of Wnt5b signaling. PLoS ONE. 2011;6:e26548.CrossRefPubMedPubMedCentral Goudevenou K, Martin P, Yeh YJ, Jones P, Sablitzky F. Def6 is required for convergent extension movements during zebrafish gastrulation downstream of Wnt5b signaling. PLoS ONE. 2011;6:e26548.CrossRefPubMedPubMedCentral
14.
go back to reference Feau S, Schoenberger SP, Altman A, Bécart S. SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner. J Immunol. 2013;190:174–83.CrossRefPubMed Feau S, Schoenberger SP, Altman A, Bécart S. SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner. J Immunol. 2013;190:174–83.CrossRefPubMed
15.
go back to reference Chen Q, Gupta S, Pernis AB. Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases. Autoimmun Rev. 2009;8:199–203.CrossRef Chen Q, Gupta S, Pernis AB. Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases. Autoimmun Rev. 2009;8:199–203.CrossRef
16.
go back to reference Samson T, Will C, Knoblauch A, Sharek L, von der Mark K, Burridge K, et al. Def-6, a guanine nucleotide exchange factor for Rac1, interacts with the skeletal muscle integrin chain alpha7A and influences myoblast differentiation. J Biol Chem. 2007;282:15730–42.CrossRefPubMed Samson T, Will C, Knoblauch A, Sharek L, von der Mark K, Burridge K, et al. Def-6, a guanine nucleotide exchange factor for Rac1, interacts with the skeletal muscle integrin chain alpha7A and influences myoblast differentiation. J Biol Chem. 2007;282:15730–42.CrossRefPubMed
17.
go back to reference Oka T, Ihara S, Fukui Y. Cooperation of DEF6 with activated Rac in regulating cell morphology. J Biol Chem. 2007;282:2011–8.CrossRefPubMed Oka T, Ihara S, Fukui Y. Cooperation of DEF6 with activated Rac in regulating cell morphology. J Biol Chem. 2007;282:2011–8.CrossRefPubMed
18.
go back to reference Subramanian S, West RB, Marinelli RJ, Nielsen TO, Rubin BP, Goldblum JR, et al. The gene expression profile of extraskeletal myxoid chondrosarcoma. J Pathol. 2005;206:433–44.CrossRefPubMed Subramanian S, West RB, Marinelli RJ, Nielsen TO, Rubin BP, Goldblum JR, et al. The gene expression profile of extraskeletal myxoid chondrosarcoma. J Pathol. 2005;206:433–44.CrossRefPubMed
19.
go back to reference Zhang Z, Wang Q, Li P, Zhou Y, Li S, Yi W, et al. Overexpression of the Interferon regulatory factor 4-binding protein in human colorectal cancer and its clinical significance. Cancer Epidemiol. 2009;33:130–6.CrossRefPubMed Zhang Z, Wang Q, Li P, Zhou Y, Li S, Yi W, et al. Overexpression of the Interferon regulatory factor 4-binding protein in human colorectal cancer and its clinical significance. Cancer Epidemiol. 2009;33:130–6.CrossRefPubMed
20.
go back to reference Li P, Zhang Z, Wang Q, Li S, Zhang Y, Bian X, et al. The ectopic expression of IFN regulatory factor 4-binding protein is correlated with the malignant behavior of human breast cancer cells. Int Immunopharmacol. 2009;9:1002–9.CrossRefPubMed Li P, Zhang Z, Wang Q, Li S, Zhang Y, Bian X, et al. The ectopic expression of IFN regulatory factor 4-binding protein is correlated with the malignant behavior of human breast cancer cells. Int Immunopharmacol. 2009;9:1002–9.CrossRefPubMed
21.
go back to reference Jian CX, Yang MZ, Li P, Xiong J, Zhang ZJ, Li CJ, et al. Ectopically expressed IBP promotes cell proliferation in oral squamous cell carcinoma. Cancer Invest. 2012;30:748–56.CrossRefPubMed Jian CX, Yang MZ, Li P, Xiong J, Zhang ZJ, Li CJ, et al. Ectopically expressed IBP promotes cell proliferation in oral squamous cell carcinoma. Cancer Invest. 2012;30:748–56.CrossRefPubMed
22.
go back to reference Otsubo T, Hida Y, Ohga N, Sato H, Kai T, Matsuki Y, et al. Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells. Cancer Sci. 2014;105:560–7.CrossRefPubMedPubMedCentral Otsubo T, Hida Y, Ohga N, Sato H, Kai T, Matsuki Y, et al. Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells. Cancer Sci. 2014;105:560–7.CrossRefPubMedPubMedCentral
23.
go back to reference Yang M, Yuan F, Li P, Chen Z, Chen A, Li S, et al. Interferon regulatory factor 4 binding protein is a novel p53 target gene and suppresses cisplatin-induced apoptosis of breast cancer cells. Mol Cancer. 2012;13:11–54. Yang M, Yuan F, Li P, Chen Z, Chen A, Li S, et al. Interferon regulatory factor 4 binding protein is a novel p53 target gene and suppresses cisplatin-induced apoptosis of breast cancer cells. Mol Cancer. 2012;13:11–54.
24.
go back to reference Novak M, Lester J, Karst AM, Parkash V, Hirsch MS, Crum CP, et al. Stathmin 1 and p16INK4A are sensitive adjunct biomarkers for serous tubal intraepithelial carcinoma. Gynecol Oncol. 2015;139:104–11.CrossRefPubMed Novak M, Lester J, Karst AM, Parkash V, Hirsch MS, Crum CP, et al. Stathmin 1 and p16INK4A are sensitive adjunct biomarkers for serous tubal intraepithelial carcinoma. Gynecol Oncol. 2015;139:104–11.CrossRefPubMed
25.
go back to reference O’Neill CJ, McBride HA, Connolly LE, Deavers MT, Malpica A, McCluggage WG. High-grade ovarian serous carcinoma exhibits significantly higher p16 expression than low-grade serous carcinoma and serous borderline tumour. Histopathology. 2007;50:773–9.CrossRefPubMed O’Neill CJ, McBride HA, Connolly LE, Deavers MT, Malpica A, McCluggage WG. High-grade ovarian serous carcinoma exhibits significantly higher p16 expression than low-grade serous carcinoma and serous borderline tumour. Histopathology. 2007;50:773–9.CrossRefPubMed
26.
go back to reference Liew PL, Hsu CS, Liu WM, Lee YC, Lee YC, Chen CL. Prognostic and predictive values of Nrf2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma. Int J Clin Exp Pathol. 2015;8:5642–9.PubMedPubMedCentral Liew PL, Hsu CS, Liu WM, Lee YC, Lee YC, Chen CL. Prognostic and predictive values of Nrf2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma. Int J Clin Exp Pathol. 2015;8:5642–9.PubMedPubMedCentral
27.
go back to reference Becart S, Charvet C, Ann J, Balancio C, De Trez C, Tanaka Y, et al. SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling. J Clin Invest. 2007;117:2164–75.CrossRefPubMedPubMedCentral Becart S, Charvet C, Ann J, Balancio C, De Trez C, Tanaka Y, et al. SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling. J Clin Invest. 2007;117:2164–75.CrossRefPubMedPubMedCentral
28.
29.
go back to reference Beirne JP, McArt DG, James JA, Salto-Tellez M, Maxwell P, McCluggage WG. p16 As a prognostic indicator in ovarian/tubal high grade serous carcinoma. Histopathology. 2016;68:615–8.CrossRefPubMed Beirne JP, McArt DG, James JA, Salto-Tellez M, Maxwell P, McCluggage WG. p16 As a prognostic indicator in ovarian/tubal high grade serous carcinoma. Histopathology. 2016;68:615–8.CrossRefPubMed
Metadata
Title
DEF6 expression in ovarian carcinoma correlates with poor patient survival
Authors
Phui-Ly Liew
Chih-Yeu Fang
Yu-Chieh Lee
Yi-Chih Lee
Chi-Long Chen
Jan-Show Chu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2016
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-016-0518-y

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