Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation
Heng‐Huan Lee, Ying‐Nai Wang, Wenhao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Yu-Han Wang, Zhou Jiang, Shouping Xu, Jun Yao, Yufan Qiu, Yi‐Hsin Elsa Hsu, Wei‐Lun Hwang, Meisi Yan, Jong‐Ho Cha, Jennifer L. Hsu, Jia Shen, Yuanqing Ye, Xifeng Wu, Ming‐Feng Hou, Lin-Ming Tseng, Shao‐Chun Wang, Mei‐Ren Pan, Chin-Hua Yang, Yuan-Liang Wang, Hirohito Yamaguchi, Da Pang, Gabriel N. Hortobágyi, Dihua Yu, Mien‐Chie Hung
Abstract
Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.