Silencing MARCH1 suppresses proliferation, migration and invasion of ovarian cancer SKOV3 cells via downregulation of NF-κB and Wnt/β-catenin pathways

Meng,Ying; Hu,Jianguo; Chen,Yuhong; Yu,Tinghe; Hu,Lina

doi:10.3892/or.2016.5076

Silencing MARCH1 suppresses proliferation, migration and invasion of ovarian cancer SKOV3 cells via downregulation of NF-κB and Wnt/β-catenin pathways

Authors:
- Ying Meng
- Jianguo Hu
- Yuhong Chen
- Tinghe Yu
- Lina Hu
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Affiliations: Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: September 8, 2016 https://doi.org/10.3892/or.2016.5076
Pages: 2463-2470
Copyright: © Meng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Membrane-associated RING-CH (MARCH) belongs to the family of RING-CH type E3 ubiquitin ligases. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs and targets major players of the immune system. However, the role of MARCH1 in ovarian cancer has not been elucidated. The present study investigated the function of MARCH1 in ovarian cancer and the potential mechanisms involved. MARCH1 expression was examined in human ovarian cancer tissue specimens by immunohistochemistry. The role of MARCH1 in ovarian cancer cells was assessed by cell proliferation, migration and invasion assays with MARCH1 gene silencing. To investigate the mechanism by which MARCH1 functions, correlation between MARCH1 and the cell signaling pathways were analyzed using a luciferase reporter assay, real-time RT-PCR, western blot assay and immunofluorescence. MARCH1 was found to be overexpressed in ovarian cancer tissues when compared to adjacent non-tumor and normal ovarian tissues. Silencing MARCH1 inhibited SKOV3 cell proliferation, invasion and migration, as well as inhibiting the NF-κB and the Wnt/β‑catenin pathways. MARCH1 functions as a tumor promoter by upregulating the NF-κB and the Wnt/β-catenin pathways, indicating that MARCH1 may be a therapeutic target for patients with ovarian cancer.

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1	Kandukuri SR and Rao J: FIGO 2013 staging system for ovarian cancer: What is new in comparison to the 1988 staging system? Curr Opin Obstet Gynecol. 27:48–52. 2015. View Article : Google Scholar
2	Tew WP and Fleming GF: Treatment of ovarian cancer in the older woman. Gynecol Oncol. 136:136–142. 2015. View Article : Google Scholar
3	Musto A, Grassetto G, Marzola MC, Rampin L, Chondrogiannis S, Maffione AM, Colletti PM, Perkins AC, Fagioli G and Rubello D: Management of epithelial ovarian cancer from diagnosis to restaging: An overview of the role of imaging techniques with particular regard to the contribution of 18F-FDG PET/CT. Nucl Med Commun. 35:588–597. 2014. View Article : Google Scholar : PubMed/NCBI
4	Nathan JA and Lehner PJ: The trafficking and regulation of membrane receptors by the RING-CH ubiquitin E3 ligases. Exp Cell Res. 315:1593–1600. 2009. View Article : Google Scholar
5	Ohmura-Hoshino M, Goto E, Matsuki Y, Aoki M, Mito M, Uematsu M, Hotta H and Ishido S: A novel family of membrane-bound E3 ubiquitin ligases. J Biochem. 140:147–154. 2006. View Article : Google Scholar : PubMed/NCBI
6	Jabbour M, Campbell EM, Fares H and Lybarger L: Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression. J Immunol. 183:6500–6512. 2009. View Article : Google Scholar : PubMed/NCBI
7	Bourgeois-Daigneault MC and Thibodeau J: Identification of a novel motif that affects the conformation and activity of the MARCH1 E3 ubiquitin ligase. J Cell Sci. 126:989–998. 2013. View Article : Google Scholar
8	Corcoran K, Jabbour M, Bhagwandin C, Deymier MJ, Theisen DL and Lybarger L: Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1). J Biol Chem. 286:37168–37180. 2011. View Article : Google Scholar : PubMed/NCBI
9	Tze LE, Horikawa K, Domaschenz H, Howard DR, Roots CM, Rigby RJ, Way DA, Ohmura-Hoshino M, Ishido S, Andoniou CE, et al: CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. J Exp Med. 208:149–165. 2011. View Article : Google Scholar : PubMed/NCBI
10	Chattopadhyay G and Shevach EM: Antigen-specific induced T regulatory cells impair dendritic cell function via an IL-10/MARCH1-dependent mechanism. J Immunol. 191:5875–5884. 2013. View Article : Google Scholar : PubMed/NCBI
11	Bourgeois-Daigneault MC and Thibodeau J: Autoregulation of MARCH1 expression by dimerization and autoubiquitination. J Immunol. 188:4959–4970. 2012. View Article : Google Scholar : PubMed/NCBI
12	Matsuki Y, Ohmura-Hoshino M, Goto E, Aoki M, Mito-Yoshida M, Uematsu M, Hasegawa T, Koseki H, Ohara O, Nakayama M, et al: Novel regulation of MHC class II function in B cells. EMBO J. 26:846–854. 2007. View Article : Google Scholar : PubMed/NCBI
13	Chen R, Li M, Zhang Y, Zhou Q and Shu HB: The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation. Proc Natl Acad Sci USA. 109:14128–14133. 2012. View Article : Google Scholar
14	van de Kooij B, Verbrugge I, de Vries E, Gijsen M, Montserrat V, Maas C, Neefjes J and Borst J: Ubiquitination by the membrane-associated RING-CH-8 (MARCH-8) ligase controls steady-state cell surface expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 1. J Biol Chem. 288:6617–6628. 2013. View Article : Google Scholar : PubMed/NCBI
15	Hayden MS and Ghosh S: Signaling to NF-kappaB. Genes Dev. 18:2195–2224. 2004. View Article : Google Scholar : PubMed/NCBI
16	Fujita T, Nolan GP, Ghosh S and Baltimore D: Independent modes of transcriptional activation by the p50 and p65 subunits of NF-kappa B. Genes Dev. 6:775–787. 1992. View Article : Google Scholar : PubMed/NCBI
17	Woronicz JD, Gao X, Cao Z, Rothe M and Goeddel DV: IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 278:866–869. 1997. View Article : Google Scholar : PubMed/NCBI
18	Schreck R, Albermann K and Baeuerle PA: Nuclear factor kappa B: An oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun. 17:221–237. 1992. View Article : Google Scholar : PubMed/NCBI
19	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
20	Neth P, Ries C, Karow M, Egea V, Ilmer M and Jochum M: The Wnt signal transduction pathway in stem cells and cancer cells: Influence on cellular invasion. Stem Cell Rev. 3:18–29. 2007. View Article : Google Scholar : PubMed/NCBI
21	Katoh M and Katoh M: WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 13:4042–4045. 2007. View Article : Google Scholar : PubMed/NCBI
22	Cheng CW, Wu PE, Yu JC, Huang CS, Yue CT, Wu CW and Shen CY: Mechanisms of inactivation of E-cadherin in breast carcinoma: Modification of the two-hit hypothesis of tumor suppressor gene. Oncogene. 20:3814–3823. 2001. View Article : Google Scholar : PubMed/NCBI
23	Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C and van Roy F: E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 14:6107–6115. 1995.PubMed/NCBI
24	Gottardi CJ, Wong E and Gumbiner BM: E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol. 153:1049–1060. 2001. View Article : Google Scholar : PubMed/NCBI
25	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
26	Nelson WJ and Nusse R: Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 303:1483–1487. 2004. View Article : Google Scholar : PubMed/NCBI
27	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
28	Liotta LA and Kohn EC: The microenvironment of the tumour-host interface. Nature. 411:375–379. 2001. View Article : Google Scholar : PubMed/NCBI
29	Tak PP and Firestein GS: NF-kappaB: A key role in inflammatory diseases. J Clin Invest. 107:7–11. 2001. View Article : Google Scholar : PubMed/NCBI
30	Ghosh S, May MJ and Kopp EB: NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 16:225–260. 1998. View Article : Google Scholar : PubMed/NCBI
31	Van Antwerp DJ, Martin SJ, Kafri T, Green DR and Verma IM: Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science. 274:787–789. 1996. View Article : Google Scholar : PubMed/NCBI
32	Micheau O, Lens S, Gaide O, Alevizopoulos K and Tschopp J: NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol. 21:5299–5305. 2001. View Article : Google Scholar : PubMed/NCBI
33	Thomas RP, Farrow BJ, Kim S, May MJ, Hellmich MR and Evers BM: Selective targeting of the nuclear factor-kappaB pathway enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated pancreatic cancer cell death. Surgery. 132:127–134. 2002. View Article : Google Scholar : PubMed/NCBI
34	Guttridge DC, Albanese C, Reuther JY, Pestell RG and Baldwin AS Jr: NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol. 19:5785–5799. 1999. View Article : Google Scholar : PubMed/NCBI
35	Chen F, Castranova V and Shi X: New insights into the role of nuclear factor-kappaB in cell growth regulation. Am J Pathol. 159:387–397. 2001. View Article : Google Scholar : PubMed/NCBI
36	Dolcet X, Llobet D, Pallares J and Matias-Guiu X: NF-kB in development and progression of human cancer. Virchows Arch. 446:475–482. 2005. View Article : Google Scholar : PubMed/NCBI
37	Sirotkin AV, Alexa R, Kišová G, Harrath AH, Alwasel S, Ovcharenko D and Mlynček M: MicroRNAs control transcription factor NF-kB (p65) expression in human ovarian cells. Funct Integr Genomics. 15:271–275. 2015. View Article : Google Scholar
38	Cafferata EG, Guerrico AM, Pivetta OH and Santa-Coloma TA: NF-kappaB activation is involved in regulation of cystic fibrosis transmembrane conductance regulator (CFTR) by interleukin-1beta. J Biol Chem. 276:15441–15444. 2001. View Article : Google Scholar : PubMed/NCBI
39	Lu Z, Ghosh S, Wang Z and Hunter T: Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 4:499–515. 2003. View Article : Google Scholar