J Cancer 2022; 13(1):212-224. doi:10.7150/jca.66773 This issue

Research Paper

PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer

Dan Li1#, Jiaping Tang1#, Ruifang Gao1,2#, Jinxin Lan1, Wenzhi Shen3, Yanhua Liu4, Yanan Chen4, Hongwei Sun5, Jie Yan4, Yongwei Nie1, Na Luo1,4✉

1. Department of Anatomy and Histology, School of Medicine, Nankai University, Tianjin 300071, China.
2. Tianjin Institute of Medical & Pharmaceutical Sciences, Tianjin 300131, China.
3. Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
4. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, Nankai University, Tianjin 300071, China.
5. Experimental Center of Operations, Chinese People's Armed Police Force Command College, Tianjin 300250, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Li D, Tang J, Gao R, Lan J, Shen W, Liu Y, Chen Y, Sun H, Yan J, Nie Y, Luo N. PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer. J Cancer 2022; 13(1):212-224. doi:10.7150/jca.66773. Available from https://www.jcancer.org/v13p0212.htm

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Graphic abstract

Breast cancer has become the most newly-diagnosed cancer and the 5th leading cause of cancer death worldwide. The 5-year survival rate of breast cancer is about 90%. However, the 5-year survival rate drops to <30% when metastasis to distant sites occurs. The blood vessel formation (i.e., angiogenesis) plays a crucial role during the metastatic process. In this study, we investigated the role of PFKFB4 in angiogenesis of breast cancer. Employing in vitro HUVEC tube formation or in vivo orthotopic mouse model, and gene editing or specific small inhibitors strategy, and utilizing qPCR, western blot, ELISA, or immunofluorescent/immunohistochemistry staining methods, we found the following: 1) PFKFB4 upregulates IL-6 expression via NF-κB signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-κB activation in breast cancer cells; 3) IL-6 elicits angiogenesis via STAT5A/P-STAT5 in HUVEC; 4) 5-MPN (a specific PFKFB4 inhibitor) suppresses angiogenesis in vitro and in vivo. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.

Keywords: PFKFB4, angiogenesis, IL-6/STAT5A/P-STAT5, breast cancer