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Published in: Tumor Biology 12/2016

01-12-2016 | Original Article

Rab14 is overexpressed in ovarian cancers and promotes ovarian cancer proliferation through Wnt pathway

Authors: Rui Hou, Luo Jiang, Zhuo Yang, Shizhuo Wang, Qifang Liu

Published in: Tumor Biology | Issue 12/2016

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Abstract

The Rab GTPase family protein Rab14 has been implicated in cancer development. However, its clinical significance in ovarian cancers and its biological effects have not been examined. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab14 in ovarian cancer progression. We examined expression pattern of Rab14 in 122 cases of ovarian cancer specimens using immunohistochemistry and found Rab14 overexpression correlated with FIGO stage (p = 0.0041). We depleted Rab14 in SKOV3 cells using siRNA and overexpressed Rab14 in SW626 cells. Knockdown of Rab14 inhibited cell growth and invasion while its overexpression facilitated cell growth and invasion. In addition, Rab14 overexpression increased paclitaxel resistance in SW626 cells while its depletion reduced drug resistance. Then, we investigated the role of Rab14 in the regulation of WNT/β-catenin signaling, demonstrating Rab14 overexpression regulated GSK3β phosphorylation and nuclear β-catenin accumulation. Rab14 depletion inhibited while its overexpression enhanced TCF transcriptional activity with corresponding change of Wnt target genes including MMP7 and c-myc. Wnt inhibitor abolished the effect of Rab14 on cell proliferation and Wnt target genes. In conclusion, the present study demonstrated that Rab14 promotes aggressiveness of ovarian cancer cell through, at least partly, Wnt signaling pathway.
Literature
1.
2.
3.
go back to reference Wang YF, Lang HY, Yuan J, et al. Overexpression of keratin 17 is associated with poor prognosis in epithelial ovarian cancer. Tumour Biol. 2013;34(3):1685–9.CrossRefPubMed Wang YF, Lang HY, Yuan J, et al. Overexpression of keratin 17 is associated with poor prognosis in epithelial ovarian cancer. Tumour Biol. 2013;34(3):1685–9.CrossRefPubMed
4.
go back to reference Darcy KM, Birrer MJ. Translational research in the Gynecologic Oncology Group: evaluation of ovarian cancer markers, profiles, and novel therapies. Gynecol Oncol. 2010;117(3):429–39.CrossRefPubMedPubMedCentral Darcy KM, Birrer MJ. Translational research in the Gynecologic Oncology Group: evaluation of ovarian cancer markers, profiles, and novel therapies. Gynecol Oncol. 2010;117(3):429–39.CrossRefPubMedPubMedCentral
5.
go back to reference Despierre E, Lambrechts D, Neven P, et al. The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment. Gynecol Oncol. 2010;117(2):358–65.CrossRefPubMed Despierre E, Lambrechts D, Neven P, et al. The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment. Gynecol Oncol. 2010;117(2):358–65.CrossRefPubMed
6.
go back to reference Fang Y, Li Z, Wang X, et al. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biol. 2012;33(6):2299–306.CrossRefPubMed Fang Y, Li Z, Wang X, et al. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biol. 2012;33(6):2299–306.CrossRefPubMed
7.
go back to reference Zhao Y, Chen S, Gou WF, et al. Aberrant Beclin 1 expression is closely linked to carcinogenesis, differentiation, progression, and prognosis of ovarian epithelial carcinoma. Tumour Biol. 2014;35(3):1955–64.CrossRefPubMed Zhao Y, Chen S, Gou WF, et al. Aberrant Beclin 1 expression is closely linked to carcinogenesis, differentiation, progression, and prognosis of ovarian epithelial carcinoma. Tumour Biol. 2014;35(3):1955–64.CrossRefPubMed
8.
go back to reference Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81(1):153–208.PubMed Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81(1):153–208.PubMed
9.
go back to reference Ming Z, Guo C, Jiang M, et al. Bioinformatics analysis of Rab GDP dissociation inhibitor beta and its expression in non-small cell lung cancer. Diagn Pathol. 2014;9:201.CrossRefPubMedPubMedCentral Ming Z, Guo C, Jiang M, et al. Bioinformatics analysis of Rab GDP dissociation inhibitor beta and its expression in non-small cell lung cancer. Diagn Pathol. 2014;9:201.CrossRefPubMedPubMedCentral
10.
go back to reference Jin L, Huo Y, Zheng Z, et al. Down-regulation of Ras-related protein Rab 5C-dependent endocytosis and glycolysis in cisplatin-resistant ovarian cancer cell lines. Mol Cell Proteomics. 2014;13(11):3138–51.CrossRefPubMedPubMedCentral Jin L, Huo Y, Zheng Z, et al. Down-regulation of Ras-related protein Rab 5C-dependent endocytosis and glycolysis in cisplatin-resistant ovarian cancer cell lines. Mol Cell Proteomics. 2014;13(11):3138–51.CrossRefPubMedPubMedCentral
11.
14.
go back to reference Chia WJ, Tang BL. Emerging roles for Rab family GTPases in human cancer. Biochim Biophys Acta. 2009;1795(2):110–6.PubMed Chia WJ, Tang BL. Emerging roles for Rab family GTPases in human cancer. Biochim Biophys Acta. 2009;1795(2):110–6.PubMed
15.
go back to reference Cheng KW, Lahad JP, Gray JW, et al. Emerging role of RAB GTPases in cancer and human disease. Cancer Res. 2005;65(7):2516–9.CrossRefPubMed Cheng KW, Lahad JP, Gray JW, et al. Emerging role of RAB GTPases in cancer and human disease. Cancer Res. 2005;65(7):2516–9.CrossRefPubMed
16.
go back to reference Zhao Z, Liu XF, Wu HC, et al. Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathway. Cancer Sci. 2010;101(6):1454–62.CrossRefPubMed Zhao Z, Liu XF, Wu HC, et al. Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathway. Cancer Sci. 2010;101(6):1454–62.CrossRefPubMed
17.
go back to reference Fan Y, Wang L, Han X, et al. Rab25 is responsible for phosphoinositide 3-kinase/AKTmediated cisplatin resistance in human epithelial ovarian cancer cells. Mol Med Rep. 2015;11(3):2173–8.PubMed Fan Y, Wang L, Han X, et al. Rab25 is responsible for phosphoinositide 3-kinase/AKTmediated cisplatin resistance in human epithelial ovarian cancer cells. Mol Med Rep. 2015;11(3):2173–8.PubMed
18.
go back to reference Liu Y, Tao X, Jia L, et al. Knockdown of RAB25 promotes autophagy and inhibits cell growth in ovarian cancer cells. Mol Med Rep. 2012;6(5):1006–12.PubMed Liu Y, Tao X, Jia L, et al. Knockdown of RAB25 promotes autophagy and inhibits cell growth in ovarian cancer cells. Mol Med Rep. 2012;6(5):1006–12.PubMed
19.
go back to reference Fan Y, Xin XY, Chen BL, et al. Knockdown of RAB25 expression by RNAi inhibits growth of human epithelial ovarian cancer cells in vitro and in vivo. Pathology. 2006;38(6):561–7.CrossRefPubMed Fan Y, Xin XY, Chen BL, et al. Knockdown of RAB25 expression by RNAi inhibits growth of human epithelial ovarian cancer cells in vitro and in vivo. Pathology. 2006;38(6):561–7.CrossRefPubMed
20.
go back to reference Wang R, Wang ZX, Yang JS, et al. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14. Oncogene. 2011;30(23):2644–58.CrossRefPubMed Wang R, Wang ZX, Yang JS, et al. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14. Oncogene. 2011;30(23):2644–58.CrossRefPubMed
21.
go back to reference Psyrri A, Bamias A, Yu Z, et al. Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin Cancer Res. 2005;11(23):8384–90.CrossRefPubMed Psyrri A, Bamias A, Yu Z, et al. Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin Cancer Res. 2005;11(23):8384–90.CrossRefPubMed
22.
go back to reference Bedrosian I, Lu KH, Verschraegen C, et al. Cyclin E deregulation alters the biologic properties of ovarian cancer cells. Oncogene. 2004;23(15):2648–57.CrossRefPubMed Bedrosian I, Lu KH, Verschraegen C, et al. Cyclin E deregulation alters the biologic properties of ovarian cancer cells. Oncogene. 2004;23(15):2648–57.CrossRefPubMed
23.
go back to reference Dhar KK, Branigan K, Howells RE, et al. Prognostic significance of cyclin D1 gene (CCND1) polymorphism in epithelial ovarian cancer. Int J Gynecol Cancer. 1999;9(4):342–7.CrossRefPubMed Dhar KK, Branigan K, Howells RE, et al. Prognostic significance of cyclin D1 gene (CCND1) polymorphism in epithelial ovarian cancer. Int J Gynecol Cancer. 1999;9(4):342–7.CrossRefPubMed
24.
go back to reference Marone M, Scambia G, Giannitelli C, et al. Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression. Int J Cancer. 1998;75(1):34–9.CrossRefPubMed Marone M, Scambia G, Giannitelli C, et al. Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression. Int J Cancer. 1998;75(1):34–9.CrossRefPubMed
25.
go back to reference Baekelandt M, Holm R, Trope CG, et al. Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study. Clin Cancer Res. 1999;5(10):2848–53.PubMed Baekelandt M, Holm R, Trope CG, et al. Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study. Clin Cancer Res. 1999;5(10):2848–53.PubMed
26.
go back to reference Anttila MA, Kosma VM, Hongxiu J, et al. p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. Br J Cancer. 1999;79(11–12):1870–8.CrossRefPubMedPubMedCentral Anttila MA, Kosma VM, Hongxiu J, et al. p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. Br J Cancer. 1999;79(11–12):1870–8.CrossRefPubMedPubMedCentral
27.
go back to reference Al-Alem LF, McCord LA, Southard RC, et al. Activation of the PKC pathway stimulates ovarian cancer cell proliferation, migration, and expression of MMP7 and MMP10. Biol Reprod. 2013;89(3):73.CrossRefPubMedPubMedCentral Al-Alem LF, McCord LA, Southard RC, et al. Activation of the PKC pathway stimulates ovarian cancer cell proliferation, migration, and expression of MMP7 and MMP10. Biol Reprod. 2013;89(3):73.CrossRefPubMedPubMedCentral
28.
go back to reference Schummer M, Drescher C, Forrest R, et al. Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125. Gynecol Oncol. 2012;125(1):65–9.CrossRefPubMed Schummer M, Drescher C, Forrest R, et al. Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125. Gynecol Oncol. 2012;125(1):65–9.CrossRefPubMed
29.
go back to reference Bodnar L, Stanczak A, Cierniak S, et al. Wnt/beta-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer. J Ovarian Res. 2014;7:16.CrossRefPubMedPubMedCentral Bodnar L, Stanczak A, Cierniak S, et al. Wnt/beta-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer. J Ovarian Res. 2014;7:16.CrossRefPubMedPubMedCentral
30.
go back to reference Yoshioka S, King ML, Ran S, et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Mol Cancer Res. 2012;10(3):469–82.CrossRefPubMedPubMedCentral Yoshioka S, King ML, Ran S, et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Mol Cancer Res. 2012;10(3):469–82.CrossRefPubMedPubMedCentral
31.
go back to reference Badiglian Filho L, Oshima CT, De Oliveira Lima F, et al. Canonical and noncanonical Wnt pathway: a comparison among normal ovary, benign ovarian tumor and ovarian cancer. Oncol Rep. 2009;21(2):313–20.PubMed Badiglian Filho L, Oshima CT, De Oliveira Lima F, et al. Canonical and noncanonical Wnt pathway: a comparison among normal ovary, benign ovarian tumor and ovarian cancer. Oncol Rep. 2009;21(2):313–20.PubMed
32.
go back to reference Nagaraj AB, Joseph P, Kovalenko O, et al. Critical role of Wnt/beta-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget. 2015;6(27):23720–34.CrossRefPubMedPubMedCentral Nagaraj AB, Joseph P, Kovalenko O, et al. Critical role of Wnt/beta-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget. 2015;6(27):23720–34.CrossRefPubMedPubMedCentral
33.
go back to reference Benelli R, Monteghirfo S, Vene R, et al. The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3beta pathway and beta-catenin stability. Mol Cancer. 2010;9:142.CrossRefPubMedPubMedCentral Benelli R, Monteghirfo S, Vene R, et al. The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3beta pathway and beta-catenin stability. Mol Cancer. 2010;9:142.CrossRefPubMedPubMedCentral
34.
go back to reference Luo J. Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett. 2009;273(2):194–200.CrossRefPubMed Luo J. Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett. 2009;273(2):194–200.CrossRefPubMed
35.
go back to reference Yook JI, Li XY, Ota I, et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8(12):1398–406.CrossRefPubMed Yook JI, Li XY, Ota I, et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8(12):1398–406.CrossRefPubMed
Metadata
Title
Rab14 is overexpressed in ovarian cancers and promotes ovarian cancer proliferation through Wnt pathway
Authors
Rui Hou
Luo Jiang
Zhuo Yang
Shizhuo Wang
Qifang Liu
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5420-4

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