Park Hyun-Joo, Kim Su-Ryun, Kim Su Seong, Wee Hee-Jun, Bae Moon-Kyoung, Ryu Mi Heon, Bae Soo-Kyung
Department of Dental Pharmacology, School of Dentistry, Pusan National University, Yangsan, South Korea.
Department of Biochemistry, College of Pharmacy, Seoul National University, Seoul, South Korea.
Oncotarget. 2014 Jul 15;5(13):5087-99. doi: 10.18632/oncotarget.2086.
Overexpression of Notch1 has been associated with breast cancer. We recently showed that visfatin stimulates breast cancer cell proliferation and invasion. The present study was undertaken to determine whether Notch1 signaling is affected by visfatin and to characterize the functional role of the visfatin-Notch1 axis in breast cancer. Visfatin and Notch1 were expressed at higher levels in breast tumors than in matched control tissues. Visfatin induced Notch1 expression in MDA-MB-231 breast cancer cell line and in nontransformed MCF10A mammary epithelial cells, whereas visfatin depletion reduced Notch1 mRNA and protein levels. Depletion of Notch1 in MDA-MB-231 cells attenuated cell growth in vitro and in vivo; visfatin depletion produced similar effects, but was less potent. Additionally, Notch1 depletion inhibited cell proliferation induced by visfatin. Analysis of the signaling pathways underlying visfatin-mediated Notch1 upregulation revealed that visfatin activated NF-κB p65. Blockade of NF-κB signaling suppressed the effects of visfatin on Notch1 upregulation and breast cancer cell proliferation. Breast tumors expressing high levels of NF-κB p65 exhibited increased expression of Notch1. Our results demonstrate that the visfatin-Notch1 axis contributes to breast tumor growth through the activation of the NF-κB pathway. Study of the visfatin-Notch1 axis may offer new therapeutic directions for breast cancer.
Notch1的过表达与乳腺癌相关。我们最近发现内脂素可刺激乳腺癌细胞增殖和侵袭。本研究旨在确定Notch1信号通路是否受内脂素影响，并阐明内脂素-Notch1轴在乳腺癌中的功能作用。与配对的对照组织相比，内脂素和Notch1在乳腺肿瘤中的表达水平更高。内脂素可诱导MDA-MB-231乳腺癌细胞系和未转化的MCF10A乳腺上皮细胞中Notch1的表达，而内脂素的缺失则降低了Notch1的mRNA和蛋白水平。在MDA-MB-231细胞中敲低Notch1可在体外和体内减弱细胞生长；内脂素的缺失也产生了类似的效果，但作用较弱。此外，Notch1的缺失抑制了内脂素诱导的细胞增殖。对介导内脂素上调Notch1的信号通路分析显示，内脂素激活了NF-κB p65。阻断NF-κB信号通路可抑制内脂素对Notch1上调和乳腺癌细胞增殖的作用。表达高水平NF-κB p65的乳腺肿瘤中Notch1的表达增加。我们的结果表明，内脂素-Notch1轴通过激活NF-κB通路促进乳腺肿瘤生长。对内脂素-Notch1轴的研究可能为乳腺癌提供新的治疗方向。
