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BMC Cancer
Published in: BMC Cancer 1/2020

01-12-2020 | Metastasis | Research article

NR2F2 plays a major role in insulin-induced epithelial-mesenchymal transition in breast cancer cells

Authors: Baili Xia, Lijun Hou, Huan Kang, Wenhui Chang, Yi Liu, Yanli Zhang, Yi Ding

Published in: BMC Cancer | Issue 1/2020

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Abstract

Background

The failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role. Hyperinsulinemia, the hallmark of Type 2 diabetes mellitus (T2DM), has been regarded as a key risk factor for the progression of breast cancer. Nuclear receptor subfamily 2, group F, member 2 (NR2F2) has been implicated in the development of breast cancer, however its contribution to insulin-induced EMT in breast cancer remains unclear.

Methods

Overexpression and knockdown of NR2F2 were used in two breast cancer cell lines, MCF-7 and MDA-MB-231 to investigate potential mechanisms by which NR2F2 leads to insulin-mediated EMT. To elucidate the effects of insulin and signaling events following NR2F2 overexpression and knockdown, Cells’ invasion and migration capacity and changes of NR2F2, E-cadherin, N-cadherin and vimentin were investigated by real-time RT-PCR and western blot.

Results

Insulin stimulation of these cells increased NR2F2 expression levels and promoted cell invasion and migration accompanied by alterations in EMT-related molecular markers. Overexpression of NR2F2 and NR2F2 knockdown demonstrated that NR2F2 expression was positively correlated with cell invasion, migration and the expression of N-cadherin and vimentin. In contrast, NR2F2 had an inverse correlation with E-cadherin expression. In MDA-MB-231, both insulin-induced cell invasion and migration and EMT-related marker alteration were abolished by NR2F2 knockdown.

Conclusions

These results suggest that NR2F2 plays a critical role in insulin-mediated breast cancer cell invasion, migration through its effect on EMT.
Literature
1.
Burki TK. Incidence of breast cancer in women with type 2 diabetes. Lancet Oncol. 2016;17(12):e523.PubMed
2.
Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6(2):103–11.PubMed
3.
Kang C, LeRoith D, Gallagher EJ. Diabetes, obesity and breast cancer. Endocrinol. 2018;159(11):3801–12.
4.
Kostev K, Kalder M. Long-term use of basal insulin and the risk of breast cancer. Breast Cancer Res Treat. 2018;168(3):763–4.PubMed
5.
Suissa S, Azoulay L, Dell'Aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54(9):2254–62.PubMed
6.
Kabat GC, Kim M, Caan BJ, Chlebowski RT, Gunter MJ, Ho GY, Rodriguez BL, Shikany JM, Strickler HD, Vitolins MZ, et al. Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer. 2009;125(11):2704–10.PubMed
7.
Kabat GC, Kim MY, Lane DS, Zaslavsky O, Ho GYF, Luo J, Nicholson WK, Chlebowski RT, Barrington WE, Vitolins MZ, et al. Serum glucose and insulin and risk of cancers of the breast, endometrium, and ovary in postmenopausal women. Eur J Cancer Prev. 2018;27(3):261–8.PubMed
8.
Goodwin PJ, Ennis M, Bahl M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N. High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res Treat. 2009;114(3):517–25.PubMed
9.
Onitilo AA, Stankowski RV, Berg RL, Engel JM, Glurich I, Williams GM, Doi SA. Type 2 diabetes mellitus, glycemic control, and cancer risk. Eur J Cancer Prev. 2014;23(2):134–40.PubMed
10.
Flores-Lopez LA, Martinez-Hernandez MG, Viedma-Rodriguez R, Diaz-Flores M, Baiza-Gutman LA. High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol. 2016;39(4):365–78.
11.
Gest C, Joimel U, Huang L, Pritchard LL, Petit A, Dulong C, Buquet C, Hu CQ, Mirshahi P, Laurent M, et al. Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines. BMC Cancer. 2013;13:63.PubMedPubMedCentral
12.
Chappell J, Leitner JW, Solomon S, Golovchenko I, Goalstone ML, Draznin B. Effect of insulin on cell cycle progression in MCF-7 breast cancer cells. Direct and potentiating influence. J Biol Chem. 2001;276(41):38023–8.PubMed
13.
Ladias JA, Karathanasis SK. Regulation of the apolipoprotein AI gene by ARP-1, a novel member of the steroid receptor superfamily. Science. 1991;251(4993):561–5.PubMed
14.
Liu Y, Yang N, Teng CT. COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene. Mol Cell Biol. 1993;13(3):1836–46.PubMedPubMedCentral
15.
Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, O'Malley BW. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989;340(6229):163–6.PubMed
16.
Litchfield LM, Klinge CM. Multiple roles of COUP-TFII in cancer initiation and progression. J Mol Endocrinol. 2012;49(3):R135–48.PubMedPubMedCentral
17.
Li L, Xie X, Qin J, Jeha GS, Saha PK, Yan J, Haueter CM, Chan L, Tsai SY, Tsai MJ. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab. 2009;9(1):77–87.PubMedPubMedCentral
18.
Bardoux P, Zhang P, Flamez D, Perilhou A, Lavin TA, Tanti JF, Hellemans K, Gomas E, Godard C, Andreelli F, et al. Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout. Diabetes. 2005;54(5):1357–63.PubMed
19.
Nagasaki S, Suzuki T, Miki Y, Akahira J, Shibata H, Ishida T, Ohuchi N, Sasano H. Chicken ovalbumin upstream promoter transcription factor II in human breast carcinoma: possible regulator of lymphangiogenesis via vascular endothelial growth factor-C expression. Cancer Sci. 2009;100(4):639–45.PubMed
20.
Qin J, Chen X, Xie X, Tsai MJ, Tsai SY. COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci U S A. 2010;107(8):3687–92.PubMedPubMedCentral
21.
Litchfield LM, Riggs KA, Hockenberry AM, Oliver LD, Barnhart KG, Cai J, Pierce WM Jr, Ivanova MM, Bates PJ, Appana SN, et al. Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor beta transcription in breast cancer cells. PLoS One. 2012;7(5):e38278.PubMedPubMedCentral
22.
Zhang C, Han Y, Huang H, Qu L, Shou C. High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-beta-dependent epithelial-mesenchymal transition in breast cancer. Breast Cancer Res Treat. 2014;147(2):265–81.PubMed
23.
Ding Y, Gao ZG, Jacobson KA, Suffredini AF. Dexamethasone enhances ATP-induced inflammatory responses in endothelial cells. J Pharmacol Exp Ther. 2010;335(3):693–702.PubMedPubMedCentral
24.
Cheng CC, Shi LH, Wang XJ, Wang SX, Wan XQ, Liu SR, Wang YF, Lu Z, Wang LH, Ding Y. Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066. Int J Oncol. 2018;53(1):339–48.PubMed
25.
Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121(4):856–62.PubMed
26.
Xin C, Jing D, Jie T, Wu-Xia L, Meng Q, Ji-Yan L. The expression difference of insulin-like growth factor 1 receptor in breast cancers with or without diabetes. J Cancer Res Ther. 2015;11(2):295–9.PubMed
27.
Pan F, Hong LQ. Insulin promotes proliferation and migration of breast cancer cells through the extracellular regulated kinase pathway. Asian Pac J Cancer Prev. 2014;15(15):6349–52.PubMed
28.
Catsburg C, Gunter MJ, Chen C, Cote ML, Kabat GC, Nassir R, Tinker L, Wactawski-Wende J, Page DL, Rohan TE. Insulin, estrogen, inflammatory markers, and risk of benign proliferative breast disease. Cancer Res. 2014;74(12):3248–58.PubMed
29.
Rodriguez-Monterrosas C, Diaz-Aragon R, Leal-Orta E, Cortes-Reynosa P, Perez Salazar E. Insulin induces an EMT-like process in mammary epithelial cells MCF10A. J Cell Biochem. 2018;119(5):4061–71.PubMed
30.
Qin JH, Wang L, Li QL, Liang Y, Ke ZY, Wang RA. Epithelial-mesenchymal transition as strategic microenvironment mimicry for cancer cell survival and immune escape? Genes Dis. 2017;4(1):16–8.PubMed
31.
Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118(3):277–9.PubMed
32.
Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor Budding: The Name is EMT. Partial EMT. J Clin Med. 2016;5(5):51.
33.
Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15(6):740–6.PubMed
34.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.PubMed
35.
Oh SC, Sohn BH, Cheong JH, Kim SB, Lee JE, Park KC, Lee SH, Park JL, Park YY, Lee HS, et al. Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype. Nat Commun. 2018;9(1):1777.PubMedPubMedCentral
36.
Shawe-Taylor M, Kumar JD, Holden W, Dodd S, Varga A, Giger O, Varro A, Dockray GJ. Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway. Peptides. 2017;91:49–57.PubMed
37.
Tseng CH. Diabetes but not insulin is associated with higher colon cancer mortality. World J Gastroenterol. 2012;18(31):4182–90.PubMedPubMedCentral
38.
Sachdev D. Regulation of breast cancer metastasis by IGF signaling. J Mammary Gland Biol Neoplasia. 2008;13(4):431–41.PubMed
39.
Belfiore A, Frasca F. IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13(4):381–406.PubMed
40.
Suzuki T, Moriya T, Darnel AD, Takeyama J, Sasano H. Immunohistochemical distribution of chicken ovalbumin upstream promoter transcription factor II in human tissues. Mol Cell Endocrinol. 2000;164(1–2):69–75.PubMed
41.
Xie X, Tang K, Yu CT, Tsai SY, Tsai MJ. Regulatory potential of COUP-TFs in development: stem/progenitor cells. Semin Cell Dev Biol. 2013;24(10–12):687–93.PubMed
42.
Xu Z, Yu S, Hsu CH, Eguchi J, Rosen ED. The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II is a critical regulator of adipogenesis. Proc Natl Acad Sci U S A. 2008;105(7):2421–6.PubMedPubMedCentral
43.
Wang H, Nie L, Wu L, Liu Q, Guo X. NR2F2 inhibits Smad7 expression and promotes TGF-beta-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21. Biochem Biophys Res Commun. 2017;485(1):181–8.PubMed
44.
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85–96.PubMed
45.
Perilhou A, Tourrel-Cuzin C, Kharroubi I, Henique C, Fauveau V, Kitamura T, Magnan C, Postic C, Prip-Buus C, Vasseur-Cognet M. The transcription factor COUP-TFII is negatively regulated by insulin and glucose via Foxo1- and ChREBP-controlled pathways. Mol Cell Biol. 2008;28(21):6568–79.PubMedPubMedCentral
46.
Hwung YP, Crowe DT, Wang LH, Tsai SY, Tsai MJ. The COUP transcription factor binds to an upstream promoter element of the rat insulin II gene. Mol Cell Biol. 1988;8(5):2070–7.PubMedPubMedCentral
47.
Le Guevel R, Oger F, Martinez-Jimenez CP, Bizot M, Gheeraert C, Firmin F, Ploton M, Kretova M, Palierne G, Staels B, et al. Inactivation of the nuclear orphan receptor COUP-TFII by small chemicals. ACS Chem Biol. 2017;12(3):654–63.PubMed
Metadata
Title
NR2F2 plays a major role in insulin-induced epithelial-mesenchymal transition in breast cancer cells
Authors
Baili Xia
Lijun Hou
Huan Kang
Wenhui Chang
Yi Liu
Yanli Zhang
Yi Ding
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-020-07107-6

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