Lentivirus-mediated RNA interference targeting the ObR gene in human breast cancer MCF-7 cells in a nude mouse xenograft model
- Author:
- No author available
- Journal Title:
- Chinese Medical Journal
- Issue:
- 9
- DOI:
- 10.3760/cma.j.issn.0366-6999.2012.09.008
- Key Word:
- RNA interference;breast neoplasms;xenograft model;leptin receptor;estrogen receptor α;vascular endothelial growth factor
Abstract： Background There is a significant association between obesity and breast cancer,which is possibly due to the expression of leptin.Therefore,it is important to clarify the role of leptin/ObR (leptin receptor) signaling during the progression of human breast cancer.Methods Nude mice with xenografts of MCF-7 human breast cancer cells were administered recombinant human leptin subcutaneous via injection around the tumor site.Mice in the experimental group were intratumorally injected with ObR-RNAi-lentivirus,while negative control group mice were injected with the same dose of negative-lentivirus.Tumor size was blindly measured every other day,and mRNA and protein expression levels of ObR,estrogen receptor α(ERα),and vascular endothelial growth factor (VEGF) for each group were determined.Results Knockdown of ObR-treated xenografted nude mice with a high leptin microenvironment was successfully established.Local injection of ObR-RNAi-lentivirus significantly suppressed the established tumor growth in nude mice.ObR level was significantly lower in the experimental group than in the negative control group,while the amounts of ERα and VEGF expression were significantly lower in the leptin group than in the control group (P ＜0.01 for all).Conclusions Inhibition of leptin/ObR signaling is essential to breast cancer proliferation and possible crosstalk between ObR and ERα,and VEGF,and may lead to novel therapeutic treatments aiming at targeting ObR in breast cancers.
- [1]XIA Xiang-hou,GU Jun-chao,BAI Qing-yang,etc.Overexpression of leptin and leptin receptors in breast cancer positively correlates with clinicopathological features[J].2009,(24).
- [2]HOU Wei-kai,XU Yu-xin,YU Ting,etc.Adipocytokines and breast cancer risk[J].2007,(18).
- [3]王劭宏,马雪梅,谷俊朝,等.瘦素对乳腺癌MCF-7细胞增殖的影响及调控机制的研究[J].2007,(24).
- [4]YU Wei,GU Jun-chao,LIU Jian-zhong,etc.Regulation of estrogen receptors α and β in human breast carcinoma by exogenous leptin in nude mouse xenograft model[J].2010,(3).
- [5]Tartaglia L. A..The Leptin Receptor[J].1997.
- [6]Mauro L,Rizza P,Panno ML,etc.Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line.[J].2003,278(31).
- [7]Gonzalez-Perez, R.R.,Guo, S.,Watters, A.,etc.Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFκB/HIF-1α activation[J].2010,22(9).
- [8]J, Folkman.Angiogenesis in cancer, vascular, rheumatoid and other disease.[J].1995,1(1).
- [9]McManus MT,Sharp PA.Gene silencing in mammals by small interfering RNAs.[J].2002,3(10).
- [10]Yasuo, Miyoshi,Tohru, Funahashi,Sachiyo, Tanaka,etc.High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels.[J].2006,118.
- [11]Y, Zhang,R, Proenca,M, Maffei,etc.Positional cloning of the mouse obese gene and its human homologue.[J].1994,372(6505).
- [12]Key TJ,Appleby PN,Reeves GK,etc.Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.[J].2003,95(16).
- [13]Chin HG,Duru N,Perera CN,etc.Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression.[J].2008,199(2).
- [14]Steckelbroeck S,Wessler S,Lower R,etc.Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells.[J].2010,127(1).
- [15]Bokhari S,Shenton A,Howell A,etc.Adult weight gain and central obesity in women with and without a family history of breast cancer: a case control study.[J].2007,6(3).
- [16]S M, Elbashir,J, Harborth,W, Lendeckel,etc.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.[J].2001,411(6836).
- [17]Lopez-Tarruella S.,Schiff R..The Dynamics of Estrogen Receptor Status in Breast Cancer: Re-shaping the Paradigm[J].2007.
- [18]Carino C,Cherfils S,Sakamoto H,etc.Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2).[J].2006,281(36).
- [19].Weight, height, body mass index and risk of breast cancer in postmenopausal women: a case-control study[J].2008,8(1).
- [20]Brakenhielm E,Wahlestedt C,Cao R,etc.Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF.[J].2001,98(11).
- [21]Marsico S,Mauro L,Rizza P,etc.Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells.[J].2004,279(19).
- [22]Giacinti L,Claudio PP,Lopez M,etc.Epigenetic information and estrogen receptor alpha expression in breast cancer.[J].2006,11(1).
- [23]Stephenson GD,Rose DP,Komninou D.Obesity, adipocytokines, and insulin resistance in breast cancer.[J].2004,5(3).
- [24]Dannenberg AJ,Sinicrope FA.Obesity and breast cancer prognosis: weight of the evidence.[J].2011,29(1).
- [25]Carroll KK.Obesity as a risk factor for certain types of cancer.[J].1998,33(11).
- [26]Gonzalez RR,Lynch MP,Cherfils S,etc.Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells.[J].2008,123(12).