Inflammatory factor TNF-α promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1

// Xiaoli Cai 1 , Can Cao 1 , Jiong Li 2 , Fuquan Chen 2 , Shuqin Zhang 2 , Bowen Liu 1 , Weiying Zhang 1 , Xiaodong Zhang 2 and Lihong Ye 1 1 State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China 2 State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China Correspondence to: Lihong Ye, email: yelihong@nankai.edu.cn Xiaodong Zhang, email: zhangxd@nankai.edu.cn Weiying Zhang, email: zhwybao@nankai.edu.cn Keywords: TNF-α, HBXIP, STAT3, growth, breast cancer Received: November 01, 2016      Accepted: March 15, 2017      Published: April 06, 2017 ABSTRACT In the connection between inflammation and cancer development, tumor necrosis factor-alpha (TNF-α) contributes to the tumorigenesis. However, the underlying mechanism remains poorly understood. In this study, we report that TNF-α enhances the growth of breast cancer through up-regulation of oncoprotein hepatitis B X-interacting protein (HBXIP). Our data showed that the levels of TNF-α were positively related to those of HBXIP in clinical breast cancer tissues. Moreover, TNF-α could up-regulate HBXIP in breast cancer cells. Interestingly, silencing of TNF-α receptor 1 (TNFR1) blocked the effect of TNF-α on HBXIP. Mechanistically, we revealed that TNF-α could increase the activities of HBXIP promoter through activating transcriptional factor signal transducer and activator of transcription 3 (STAT3). In addition, nuclear factor kappa B (NF-κB) and/or p38 signaling increased the levels of p-STAT3 in the cells. Strikingly, HBXIP could also up-regulate TNFR1, forming a positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1. Notably, TNF-α was able to up-regulate TNFR1 through driving the loop. In function, we demonstrated that the knockdown of HBXIP remarkably abolished the growth of breast cancer mediated by TNF-α in vitro and in vivo . Thus, we conclude that TNF-α promotes the growth of breast cancer through the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1.Our finding provides new insights into the mechanism by which TNF-α drives oncoprotein HBXIP in the development of breast cancer.