MPA influences tumor cell proliferation, migration, and invasion induced by RANKL through PRB involving the MAPK pathway in endometrial cancer

Wang,Jing; Sun,Xiao; Zhang,Huijuan; Wang,Yudong; Li,Yuhong

doi:10.3892/or.2014.3651

MPA influences tumor cell proliferation, migration, and invasion induced by RANKL through PRB involving the MAPK pathway in endometrial cancer

Authors:
- Jing Wang
- Xiao Sun
- Huijuan Zhang
- Yudong Wang
- Yuhong Li
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Affiliations: Department of Gynecology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China, Laboratory for Gynecologic Oncology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China, Department of Pathology and Biobank, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China
Published online on: December 5, 2014 https://doi.org/10.3892/or.2014.3651
Pages: 799-809

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Abstract

The targeting of receptor activator of nuclear factor-κB ligand (RANKL) is being increasingly investigated as a potential therapeutic strategy in several types of cancers. However, the exact function and mechanism of RANKL in human endometrial cancer (EC), particularly in progesterone-resistant and aggressive EC, remain unclear. We evaluated whether targeting of RANKL might be an efficient therapeutic strategy in EC. In the present study, we performed the first investigation of the relationship between RANK/RANKL expression in EC tissues and clinicopathological features. In the present study, we showed that RANK/RANKL was aberrantly overexpressed in human EC tissues. The higher RANK expression in human EC was associated with myometrial invasion, lymph node metastasis and lymphovascular space involvement. Additionally, we discovered that RANK/RANKL promoted EC cell proliferation, migration and invasion, which was correlated with the activated mitogen-activated protein kinase (MAPK) pathway. Moreover, medroxyprogesterone acetate (MPA)-mediated progesterone receptor B (PRB) was found to significantly inhibit the EC cell behavior induced by RANKL in vitro. Furthermore, MPA efficiently inhibited the tumorigenicity in an in vivo xenograft model. Collectively, RANKL is a common tumor promoter, which activates MAPK signaling in EC cells. MPA-mediated PRB plays important roles in inhibiting the growth, migratory and invasive capacities of EC cells induced by RANKL. Targeting of RANKL may be useful in the treatment of EC.

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1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Di Cristofano A and Ellenson LH: Endometrial carcinima. Annu Rev Pathol. 2:57–85. 2007. View Article : Google Scholar
3	Salvesen HB, Haldorsen IS and Trovik J: Markers for individualised therapy in endometrial carcinoma. Lancet Oncol. 13:e353–e361. 2012. View Article : Google Scholar : PubMed/NCBI
4	Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, et al: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 397:315–323. 1999. View Article : Google Scholar : PubMed/NCBI
5	Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, et al: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 103:41–50. 2000. View Article : Google Scholar : PubMed/NCBI
6	Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, Schneider P and Brisken C: Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci USA. 107:2989–2994. 2010. View Article : Google Scholar : PubMed/NCBI
7	Armstrong AP, Tometsko ME, Glaccum M, Sutherland CL, Cosman D and Dougall WC: A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem. 277:44347–44356. 2002. View Article : Google Scholar : PubMed/NCBI
8	Darnay BG, Haridas V, Ni J, Moore PA and Aggarwal BB: Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappaB and c-Jun N-terminal kinase. J Biol Chem. 273:20551–20555. 1998. View Article : Google Scholar : PubMed/NCBI
9	Mori K, Le Goff B, Berreur M, Riet A, Moreau A, Blanchard F, Chevalier C, Guisle-Marsollier I, Léger J, Guicheux J, et al: Human osteosarcoma cells express functional receptor activator of nuclear factor-kappa B. J Pathol. 211:555–562. 2007. View Article : Google Scholar : PubMed/NCBI
10	Zhang L, Teng Y, Zhang Y, Liu J, Xu L, Qu J, Hou K, Yang X, Liu Y and Qu X: C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway. Oncol Lett. 3:395–400. 2012.PubMed/NCBI
11	Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D and Dougall WC: RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 468:103–107. 2010. View Article : Google Scholar : PubMed/NCBI
12	Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, et al: Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 468:98–102. 2010. View Article : Google Scholar : PubMed/NCBI
13	Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, Climent F, Soler MT, Muñoz P, Viñals F, et al: RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 72:2879–2888. 2012. View Article : Google Scholar : PubMed/NCBI
14	Schramek D, Sigl V and Penninger JM: RANKL and RANK in sex hormone-induced breast cancer and breast cancer metastasis. Trends Endocrinol Metab. 22:188–194. 2011. View Article : Google Scholar : PubMed/NCBI
15	Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, Ortega C, Porta C, Galluzzo S, Armento G, et al: Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One. 6:e192342011. View Article : Google Scholar : PubMed/NCBI
16	Dai D, Wolf DM, Litman ES, White MJ and Leslie KK: Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res. 62:881–886. 2002.PubMed/NCBI
17	Leslie KK, Kumar NS, Richer J, Owen G, Takimoto G, Horwitz KB and Lange C: Differential expression of the A and B isoforms of progesterone receptor in human endometrial cancer cells. Only progesterone receptor B is induced by estrogen and associated with strong transcriptional activation. Ann NY Acad Sci. 828:17–26. 1997. View Article : Google Scholar : PubMed/NCBI
18	Ai ZH, Wang J, Wang YD, Lu LH, Tong JQ and Teng YC: Overexpressed epidermal growth factor receptor (EGFR)-induced progestin insensitivity in human endometrial carcinoma cells by the EGFR/mitogen-activated protein kinase signaling pathway. Cancer. 116:3603–3613. 2010. View Article : Google Scholar : PubMed/NCBI
19	Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, et al: Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 440:692–696. 2006. View Article : Google Scholar : PubMed/NCBI
20	Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET and Dougall WC: RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 68:92–104. 2008. View Article : Google Scholar
21	Mori K, Le Goff B, Charrier C, Battaglia S, Heymann D and Rédini F: DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. Bone. 40:981–990. 2007. View Article : Google Scholar : PubMed/NCBI
22	Wittrant Y, Théoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D and Rédini F: RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta. 1704:49–57. 2004.PubMed/NCBI
23	Nebreda AR and Porras A: p38 MAP kinases: beyond the stress response. Trends Biochem Sci. 25:257–260. 2000. View Article : Google Scholar : PubMed/NCBI
24	Schieven GL: The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem. 5:921–928. 2005. View Article : Google Scholar : PubMed/NCBI
25	Manning AM and Davis RJ: Targeting JNK for therapeutic benefit: from junk togold? Nat Rev Drug Discov. 2:554–565. 2003. View Article : Google Scholar : PubMed/NCBI
26	Yamamoto Y and Gaynor RB: Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 107:135–142. 2001. View Article : Google Scholar : PubMed/NCBI
27	Barkett M and Gilmore TD: Control of apoptosis by Rel/NFkappaB transcription factors. Oncogene. 18:6910–6924. 1999. View Article : Google Scholar : PubMed/NCBI
28	Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N, Nakashima A, Sakurai H, Saito S, Tsukada K and Saiki I: Blocking on the CXCR4/mTOR signaling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer. 44:1022–1029. 2008. View Article : Google Scholar : PubMed/NCBI