RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion

Shang,Wen-Qing; Li,Hui; Liu,Li-Bing; Chang,Kai-Kai; Yu,Jia‑Jun; Xie,Feng; Li,Ming-Qing; Yu,Jin-Jin

doi:10.3892/or.2015.4303

RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion

Authors:
- Wen-Qing Shang
- Hui Li
- Li-Bing Liu
- Kai-Kai Chang
- Jia‑Jun Yu
- Feng Xie
- Ming-Qing Li
- Jin-Jin Yu
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Affiliations: Department of Obstetrics and Gynecology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China, Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, P.R. China, Medical Center of Diagnosis and Treatment for Cervical Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, P.R. China
Published online on: September 22, 2015 https://doi.org/10.3892/or.2015.4303
Pages: 3007-3016

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Abstract

Receptor activator for nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor (TNF) family. The interaction between RANKL and its receptor RANK plays an important role in the development and function of diverse tissues. However, the expression and role of RANKL in cervical cancer are still unknown. In the present study, we found that RANKL and RANK were highly co-expressed in cervical cancer. HeLa and SiHa cells secreted soluble RANKL (sRANKL), expressed member RANKL (mRANKL) and RANK. Recombinant human RANKL protein had no effect on the viability of HeLa and SiHa cells. Yet, blocking RANKL with an anti-human RANKL neutralizing antibody (α-RANKL) or recombinant human osteoprotegrin (OPG) protein resulted in the downregulation of Ki-67 and B-cell lymphoma 2 (Bcl-2) expression and an increase in Fas and Fas ligand (FasL) expression, as well as a high level of viability and a low level of apoptosis in the HeLa and SiHa cells. In addition, α-RANKL led to a decrease in IL-8 secretion. Recombinant human IL-8 protein reversed the effect of α-RANKL on the expression of proliferation- and apoptosis‑related molecules, and proliferation and apoptosis in the HeLa and SiHa cells. The present study suggests that a high level of mRANKL/RANK expression in cervical cancer lesions plays an important role in the rapid growth of cervical cancer cells possibly through strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion, which may be a possible target for cervical cancer therapy.

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1	Stewart BW and Wild CP: World Cancer Report 2014. World Health Organization. Chapter 5.12. IARC Nonserial Publication; 2014
2	Fu Z, Chen D, Cheng H and Wang F: Hypoxia-inducible factor-1α protects cervical carcinoma cells from apoptosis induced by radiation via modulation of vascular endothelial growth factor and p53 under hypoxia. Med Sci Monit. 21:318–325. 2015. View Article : Google Scholar : PubMed/NCBI
3	Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, et al: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 93:165–176. 1998. View Article : Google Scholar : PubMed/NCBI
4	Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D and Galibert L: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 390:175–179. 1997. 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	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
7	Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, McConnell FM, Scott HS, Penninger JM, Jenkinson EJ, et al: RANK signals from CD4⁺3⁻ inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 204:1267–1272. 2007. View Article : Google Scholar : PubMed/NCBI
8	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
9	Hanada R, Hanada T, Sigl V, Schramek D and Penninger JM: RANKL/RANK-beyond bones. J Mol Med (Berl). 89:647–656. 2011. View Article : Google Scholar
10	Cheng ML and Fong L: Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol. 3:3292014. View Article : Google Scholar : PubMed/NCBI
11	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
12	Hsu CJ, Lin TY, Kuo CC, Tsai CH, Lin MZ, Hsu HC, Fong YC and Tang CH: Involvement of integrin up-regulation in RANKL/RANK pathway of chondrosarcomas migration. J Cell Biochem. 111:138–147. 2010. View Article : Google Scholar : PubMed/NCBI
13	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
14	Chen LM, Kuo CH, Lai TY, Lin YM, Su CC, Hsu HH, Tsai FJ, Tsai CH, Huang CY and Tang CH: RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulation. J Cell Biochem. 112:933–941. 2011. View Article : Google Scholar : PubMed/NCBI
15	Murdoch C and Finn A: Chemokine receptors and their role in inflammation and infectious diseases. Blood. 95:3032–3043. 2000.PubMed/NCBI
16	Mantovani A, Savino B, Locati M, Zammataro L, Allavena P and Bonecchi R: The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev. 21:27–39. 2010. View Article : Google Scholar
17	Vicari AP and Caux C: Chemokines in cancer. Cytokine Growth Factor Rev. 13:143–154. 2002. View Article : Google Scholar : PubMed/NCBI
18	Nickel R, Beck LA, Stellato C and Schleimer RP: Chemokines and allergic disease. J Allergy Clin Immunol. 104:723–742. 1999. View Article : Google Scholar : PubMed/NCBI
19	Liu LB, Xie F, Chang KK, Li MQ, Meng YH, Wang XH, Li H, Li DJ and Yu JJ: Hypoxia promotes the proliferation of cervical carcinoma cells through stimulating the secretion of IL-8. Int J Clin Exp Pathol. 7:575–583. 2014.PubMed/NCBI
20	Secchiero P, Corallini F, Barbarotto E, Melloni E, di Iasio MG, Tiribelli M and Zauli G: Role of the RANKL/RANK system in the induction of interleukin-8 (IL-8) in B chronic lymphocytic leukemia (B-CLL) cells. J Cell Physiol. 207:158–164. 2006. View Article : Google Scholar
21	Xie F, Meng YH, Liu LB, Chang KK, Li H, Li MQ and Li DJ: Cervical carcinoma cells stimulate the angiogenesis through TSLP promoting growth and activation of vascular endothelial cells. Am J Reprod Immunol. 70:69–79. 2013. View Article : Google Scholar : PubMed/NCBI
22	Chu GC and Chung LW: RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev. 33:497–509. 2014. View Article : Google Scholar : PubMed/NCBI
23	Meng YH, Li H, Chen X, Liu LB, Shao J, Chang KK, Du MR, Jin LP, Li MQ and Li DJ: RANKL promotes the growth of decidual stromal cells in an autocrine manner via CCL2/CCR2 interaction in human early pregnancy. Placenta. 34:663–671. 2013. View Article : Google Scholar : PubMed/NCBI
24	Deivendran S, Marzook KH and Radhakrishna Pillai M: The role of inflammation in cervical cancer. Adv Exp Med Biol. 816:377–399. 2014. View Article : Google Scholar : PubMed/NCBI
25	Husseinzadeh N and Davenport SM: Role of toll-like receptors in cervical, endometrial and ovarian cancers: A review. Gynecol Oncol. 135:359–363. 2014. View Article : Google Scholar : PubMed/NCBI
26	Castrilli G, Tatone D, Diodoro MG, Rosini S, Piantelli M and Musiani P: Interleukin 1alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells. Br J Cancer. 75:855–859. 1997. View Article : Google Scholar : PubMed/NCBI
27	Tang ZN, Zhang F, Tang P, Qi XW and Jiang J: Hypoxia induces RANK and RANKL expression by activating HIF-1α in breast cancer cells. Biochem Biophys Res Commun. 408:411–416. 2011. View Article : Google Scholar : PubMed/NCBI
28	Wada T, Nakashima T, Hiroshi N and Penninger JM: RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 12:17–25. 2006. View Article : Google Scholar
29	Wang L, Guo H, Yang L, Dong L, Lin C, Zhang J, Lin P and Wang X: Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol Cell Biochem. 379:7–18. 2013. View Article : Google Scholar : PubMed/NCBI
30	Kim SH, Kim SH, Kim YB, Jeon YT, Lee SC and Song YS: Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells. Ann NY Acad Sci. 1171:495–500. 2009. View Article : Google Scholar : PubMed/NCBI
31	Rashmi R, DeSelm C, Helms C, Bowcock A, Rogers BE, Rader JL, Grigsby PW and Schwarz JK: AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One. 9:e929482014. View Article : Google Scholar : PubMed/NCBI
32	Bendre MS, Margulies AG, Walser B, Akel NS, Bhattacharrya S, Skinner RA, Swain F, Ramani V, Mohammad KS, Wessner LL, et al: Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res. 65:11001–11009. 2005. View Article : Google Scholar : PubMed/NCBI
33	Bouganim N and Clemons MJ: Bone-targeted agents in the treatment of bone metastases: RANK outsider or new kid on the block? Future Oncol. 7:381–383. 2011. View Article : Google Scholar : PubMed/NCBI
34	Sordillo EM and Pearse RN: RANK-Fc: A therapeutic antagonist for RANK-L in myeloma. Cancer. 97(Suppl): S802–S812. 2003. View Article : Google Scholar