Skip to main content
Top
Published in: Journal of Ovarian Research 1/2018

Open Access 01-12-2018 | Research

Adipokine RBP4 drives ovarian cancer cell migration

Authors: Yanyan Wang, Yilin Wang, Zhenyu Zhang

Published in: Journal of Ovarian Research | Issue 1/2018

Login to get access

Abstract

Background

Obesity has been linked to several types of cancers including ovarian cancer. Retinol binding protein 4 (RBP4) is an adipokine that drives the development of hyperinsulinemia and type II diabetes in obesity patients and animals. Previously, we have identified RBP4 as a serum marker for ovarian cancer. Here we further explored the consequence of RBP4 upregulation in ovarian cancer cells and its molecular mechanism.

Results

Our results show that RBP4 is overexpressed in ovarian cancer cells to the same extent as in adipose tissues. The overexpression of RBP4 in ovarian cancer cells promotes cancer cell migration and proliferation. At molecular level, cancer progression factors MMP2 and MMP9 are induced in response to RBP4 overexpression. We further investigated which signaling pathways are utilized by RBP4 to activate ovarian cancer cell migration. We found RhoA/Rock1 pathway is turned on and CyclinD1 is upregulated in RBP4 overexpressed cells. Inhibition of RhoA/Rock1 pathway reduces the RBP4-induced MMP2 and MMP9 expression. The RBP4 action is depend on its associated ligand vitamin A/retinol acid (RA) and possibly involves similar pathways as for conferring insulin resistance. Moreover, we show that knockdown of RBP4 significantly reduce cancer cell migration and proliferation as well as expressions of oncogenic factors.

Conclusions

Our results indicated that RBP4 can drive ovarian cancer cell migration and proliferation via RhoA/Rock1 and ERK pathway. It suggests that RBP4 act as a oncogene in ovarian cancer cells. Thus, RBP4 could be a molecular bridge between obesity and cancers and a potential target for treating obese cancer patients.
Literature
1.
go back to reference O'Flanagan CH, Bowers LW, Hursting SD. A weighty problem: metabolic perturbations and the obesity-cancer link. Horm Mol Biol Clin Invest. 2015;23:47–57. O'Flanagan CH, Bowers LW, Hursting SD. A weighty problem: metabolic perturbations and the obesity-cancer link. Horm Mol Biol Clin Invest. 2015;23:47–57.
2.
go back to reference Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and cancer: local and systemic mechanisms. Annu Rev Med. 2015;66:297–309.CrossRefPubMed Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and cancer: local and systemic mechanisms. Annu Rev Med. 2015;66:297–309.CrossRefPubMed
3.
go back to reference Blaner WS. Retinol-binding protein: the serum transport protein for vitamin a. Endocr Rev. 1989;10:308–16.CrossRefPubMed Blaner WS. Retinol-binding protein: the serum transport protein for vitamin a. Endocr Rev. 1989;10:308–16.CrossRefPubMed
4.
go back to reference Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–62.CrossRefPubMed Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–62.CrossRefPubMed
5.
go back to reference Raghu P, Sivakumar B. Interactions amongst plasma retinol-binding protein, transthyretin and their ligands: implications in vitamin a homeostasis and transthyretin amyloidosis. Biochim Biophys Acta. 2004;1703:1–9.CrossRefPubMed Raghu P, Sivakumar B. Interactions amongst plasma retinol-binding protein, transthyretin and their ligands: implications in vitamin a homeostasis and transthyretin amyloidosis. Biochim Biophys Acta. 2004;1703:1–9.CrossRefPubMed
7.
go back to reference Berry DC, Croniger CM, Ghyselinck NB, Noy N. Transthyretin blocks retinol uptake and cell signaling by the holo-retinol-binding protein receptor STRA6. Mol Cell Biol. 2012;32:3851–9.CrossRefPubMedPubMedCentral Berry DC, Croniger CM, Ghyselinck NB, Noy N. Transthyretin blocks retinol uptake and cell signaling by the holo-retinol-binding protein receptor STRA6. Mol Cell Biol. 2012;32:3851–9.CrossRefPubMedPubMedCentral
8.
go back to reference Terra R, Wang X, Hu Y, Charpentier T, Lamarre A, Zhong M, et al. To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses. PLoS One. 2013;8:e82808.CrossRefPubMedPubMedCentral Terra R, Wang X, Hu Y, Charpentier T, Lamarre A, Zhong M, et al. To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses. PLoS One. 2013;8:e82808.CrossRefPubMedPubMedCentral
9.
go back to reference Berry DC, Jacobs H, Marwarha G, Gely-Pernot A, O'Byrne SM, DeSantis D, et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin a homeostasis in tissues other than the eye. J Biol Chem. 2013;288:24528–39.CrossRefPubMedPubMedCentral Berry DC, Jacobs H, Marwarha G, Gely-Pernot A, O'Byrne SM, DeSantis D, et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin a homeostasis in tissues other than the eye. J Biol Chem. 2013;288:24528–39.CrossRefPubMedPubMedCentral
10.
go back to reference Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin a. Science. 2007;315:820–5.CrossRefPubMed Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin a. Science. 2007;315:820–5.CrossRefPubMed
11.
go back to reference Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–63.CrossRefPubMed Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–63.CrossRefPubMed
12.
go back to reference Cho YM, Youn BS, Lee H, Lee N, Min SS, Kwak SH, et al. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care. 2006;29:2457–61.CrossRefPubMed Cho YM, Youn BS, Lee H, Lee N, Min SS, Kwak SH, et al. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care. 2006;29:2457–61.CrossRefPubMed
13.
go back to reference Lee DC, Lee JW, Im JA. Association of serum retinol binding protein 4 and insulin resistance in apparently healthy adolescents. Metab Clin Exp. 2007;56:327–31.CrossRefPubMed Lee DC, Lee JW, Im JA. Association of serum retinol binding protein 4 and insulin resistance in apparently healthy adolescents. Metab Clin Exp. 2007;56:327–31.CrossRefPubMed
14.
go back to reference Gavi S, Stuart LM, Kelly P, Melendez MM, Mynarcik DC, Gelato MC, et al. Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes. J Clin Endocrinol Metab. 2007;92:1886–90.CrossRefPubMed Gavi S, Stuart LM, Kelly P, Melendez MM, Mynarcik DC, Gelato MC, et al. Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes. J Clin Endocrinol Metab. 2007;92:1886–90.CrossRefPubMed
15.
go back to reference Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin Endocrinol Metab. 2007;92:2712–9.CrossRefPubMed Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin Endocrinol Metab. 2007;92:2712–9.CrossRefPubMed
16.
go back to reference Fedders R, Muenzner M, Schupp M. Retinol binding protein 4 and its membrane receptors: a metabolic perspective. Horm Mol Biol Clin Invest. 2015;22:27–37. Fedders R, Muenzner M, Schupp M. Retinol binding protein 4 and its membrane receptors: a metabolic perspective. Horm Mol Biol Clin Invest. 2015;22:27–37.
17.
go back to reference Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1996;10:940–54.CrossRef Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1996;10:940–54.CrossRef
18.
go back to reference Berry DC, Jin H, Majumdar A, Noy N. Signaling by vitamin a and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci U S A. 2011;108:4340–5.CrossRefPubMedPubMedCentral Berry DC, Jin H, Majumdar A, Noy N. Signaling by vitamin a and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci U S A. 2011;108:4340–5.CrossRefPubMedPubMedCentral
19.
go back to reference Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, et al. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32:2010–9.CrossRefPubMedPubMedCentral Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, et al. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32:2010–9.CrossRefPubMedPubMedCentral
20.
go back to reference Selvaggi SM. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. Archives of pathology & laboratory medicine. 2000;124:477. Selvaggi SM. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. Archives of pathology & laboratory medicine. 2000;124:477.
21.
go back to reference Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, et al. Obesity contributes to ovarian Cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Res. 2015;75:5046–57.CrossRefPubMedPubMedCentral Liu Y, Metzinger MN, Lewellen KA, Cripps SN, Carey KD, Harper EI, et al. Obesity contributes to ovarian Cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Res. 2015;75:5046–57.CrossRefPubMedPubMedCentral
22.
go back to reference Cheng Y, Liu C, Zhang N, Wang S, Zhang Z. Proteomics analysis for finding serum markers of ovarian cancer. Biomed Res Int. 2014;2014:179040.PubMedPubMedCentral Cheng Y, Liu C, Zhang N, Wang S, Zhang Z. Proteomics analysis for finding serum markers of ovarian cancer. Biomed Res Int. 2014;2014:179040.PubMedPubMedCentral
23.
go back to reference Wang DD, Zhao YM, Wang L, Ren G, Wang F, Xia ZG, et al. Preoperative serum retinol-binding protein 4 is associated with the prognosis of patients with hepatocellular carcinoma after curative resection. J Cancer Res Clin Oncol. 2011;137:651–8.CrossRefPubMed Wang DD, Zhao YM, Wang L, Ren G, Wang F, Xia ZG, et al. Preoperative serum retinol-binding protein 4 is associated with the prognosis of patients with hepatocellular carcinoma after curative resection. J Cancer Res Clin Oncol. 2011;137:651–8.CrossRefPubMed
24.
go back to reference Uehara H, Takahashi T, Izumi K. Induction of retinol-binding protein 4 and placenta-specific 8 expression in human prostate cancer cells remaining in bone following osteolytic tumor growth inhibition by osteoprotegerin. Int J Oncol. 2013;43:365–74.CrossRefPubMedPubMedCentral Uehara H, Takahashi T, Izumi K. Induction of retinol-binding protein 4 and placenta-specific 8 expression in human prostate cancer cells remaining in bone following osteolytic tumor growth inhibition by osteoprotegerin. Int J Oncol. 2013;43:365–74.CrossRefPubMedPubMedCentral
25.
go back to reference Jiao C, Cui L, Ma A, Li N, Si H. Elevated serum levels of retinol-binding protein 4 are associated with breast Cancer risk: a case-control study. PLoS One. 2016;11:e0167498.CrossRefPubMedPubMedCentral Jiao C, Cui L, Ma A, Li N, Si H. Elevated serum levels of retinol-binding protein 4 are associated with breast Cancer risk: a case-control study. PLoS One. 2016;11:e0167498.CrossRefPubMedPubMedCentral
26.
go back to reference Abola MV, Thompson CL, Chen Z, Chak A, Berger NA, Kirwan JP, et al. Serum levels of retinol-binding protein 4 and risk of colon adenoma. Endocr Relat Cancer. 2015;22:L1–4.CrossRefPubMedPubMedCentral Abola MV, Thompson CL, Chen Z, Chak A, Berger NA, Kirwan JP, et al. Serum levels of retinol-binding protein 4 and risk of colon adenoma. Endocr Relat Cancer. 2015;22:L1–4.CrossRefPubMedPubMedCentral
27.
go back to reference Noy N, Li L, Abola MV, Berger NA. Is retinol binding protein 4 a link between adiposity and cancer? Horm Mol Biol Clin Invest. 2015;23:39–46. Noy N, Li L, Abola MV, Berger NA. Is retinol binding protein 4 a link between adiposity and cancer? Horm Mol Biol Clin Invest. 2015;23:39–46.
28.
go back to reference Yu W, Qu H, Cao G, Liu C, Deng H, Zhang Z. MtHsp70-CLIC1-pulsed dendritic cells enhance the immune response against ovarian cancer. Biochem Biophys Res Commun. 2017;494:13–9.CrossRefPubMed Yu W, Qu H, Cao G, Liu C, Deng H, Zhang Z. MtHsp70-CLIC1-pulsed dendritic cells enhance the immune response against ovarian cancer. Biochem Biophys Res Commun. 2017;494:13–9.CrossRefPubMed
29.
go back to reference Qu H, Chen Y, Cao G, Liu C, Xu J, Deng H, et al. Identification and validation of differentially expressed proteins in epithelial ovarian cancers using quantitative proteomics. Oncotarget. 2016;7:83187–99.PubMedPubMedCentral Qu H, Chen Y, Cao G, Liu C, Xu J, Deng H, et al. Identification and validation of differentially expressed proteins in epithelial ovarian cancers using quantitative proteomics. Oncotarget. 2016;7:83187–99.PubMedPubMedCentral
30.
go back to reference Bai H, Li H, Li W, Gui T, Yang J, Cao D, et al. The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 2015;6:25520–32.PubMedPubMedCentral Bai H, Li H, Li W, Gui T, Yang J, Cao D, et al. The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 2015;6:25520–32.PubMedPubMedCentral
31.
go back to reference Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16–27.CrossRefPubMed Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16–27.CrossRefPubMed
32.
go back to reference Tanaka Y, Terai Y, Tanabe A, Sasaki H, Sekijima T, Fujiwara S, et al. Prognostic effect of epidermal growth factor receptor gene mutations and the aberrant phosphorylation of Akt and ERK in ovarian cancer. Cancer Biol Ther. 2011;11:50–7.CrossRefPubMedPubMedCentral Tanaka Y, Terai Y, Tanabe A, Sasaki H, Sekijima T, Fujiwara S, et al. Prognostic effect of epidermal growth factor receptor gene mutations and the aberrant phosphorylation of Akt and ERK in ovarian cancer. Cancer Biol Ther. 2011;11:50–7.CrossRefPubMedPubMedCentral
33.
go back to reference Lok GT, Chan DW, Liu VW, Hui WW, Leung TH, Yao KM, et al. Aberrant activation of ERK/FOXM1 signaling cascade triggers the cell migration/invasion in ovarian cancer cells. PLoS One. 2011;6:e23790.CrossRefPubMedPubMedCentral Lok GT, Chan DW, Liu VW, Hui WW, Leung TH, Yao KM, et al. Aberrant activation of ERK/FOXM1 signaling cascade triggers the cell migration/invasion in ovarian cancer cells. PLoS One. 2011;6:e23790.CrossRefPubMedPubMedCentral
34.
go back to reference Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, et al. Calcium sensitization of smooth muscle mediated by a rho-associated protein kinase in hypertension. Nature. 1997;389:990–4.CrossRefPubMed Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, et al. Calcium sensitization of smooth muscle mediated by a rho-associated protein kinase in hypertension. Nature. 1997;389:990–4.CrossRefPubMed
35.
go back to reference Morikawa K, Hanada H, Hirota K, Nonaka M, Ikeda C. All-trans retinoic acid displays multiple effects on the growth, lipogenesis and adipokine gene expression of AML-I preadipocyte cell line. Cell Biol Int. 2013;37:36–46.CrossRefPubMed Morikawa K, Hanada H, Hirota K, Nonaka M, Ikeda C. All-trans retinoic acid displays multiple effects on the growth, lipogenesis and adipokine gene expression of AML-I preadipocyte cell line. Cell Biol Int. 2013;37:36–46.CrossRefPubMed
36.
go back to reference Narumiya S, Tanji M, Ishizaki T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 2009;28:65–76.CrossRefPubMed Narumiya S, Tanji M, Ishizaki T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 2009;28:65–76.CrossRefPubMed
37.
go back to reference Chang HR, Huang HP, Kao YL, Chen SL, Wu SW, Hung TW, et al. The suppressive effect of rho kinase inhibitor, Y-27632, on oncogenic Ras/RhoA induced invasion/migration of human bladder cancer TSGH cells. Chem Biol Interact. 2010;183:172–80.CrossRefPubMed Chang HR, Huang HP, Kao YL, Chen SL, Wu SW, Hung TW, et al. The suppressive effect of rho kinase inhibitor, Y-27632, on oncogenic Ras/RhoA induced invasion/migration of human bladder cancer TSGH cells. Chem Biol Interact. 2010;183:172–80.CrossRefPubMed
38.
go back to reference Chan CC, Wong AK, Liu J, Steeves JD, Tetzlaff W. ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans. Glia. 2007;55:369–84.CrossRefPubMed Chan CC, Wong AK, Liu J, Steeves JD, Tetzlaff W. ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans. Glia. 2007;55:369–84.CrossRefPubMed
39.
go back to reference Xue F, Takahara T, Yata Y, Xia Q, Nonome K, Shinno E, et al. Blockade of rho/rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner. Hepatology research: the official journal of the Japan society of. Hepatology. 2008;38:810–7.CrossRef Xue F, Takahara T, Yata Y, Xia Q, Nonome K, Shinno E, et al. Blockade of rho/rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner. Hepatology research: the official journal of the Japan society of. Hepatology. 2008;38:810–7.CrossRef
Metadata
Title
Adipokine RBP4 drives ovarian cancer cell migration
Authors
Yanyan Wang
Yilin Wang
Zhenyu Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2018
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-018-0397-9

Other articles of this Issue 1/2018

Journal of Ovarian Research 1/2018 Go to the issue