Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation

Heng Huan Lee, Ying Nai Wang, Wen Hao Yang, Weiya Xia, Yongkun Wei, Li Chuan Chan, Yu Han Wang, Zhou Jiang, Shouping Xu, Jun Yao, Yufan Qiu, Yi Hsin Hsu, Wei Lun Hwang, Meisi Yan, Jong Ho Cha, Jennifer L. Hsu, Jia Shen, Yuanqing Ye, Xifeng Wu, Ming Feng HouLin Ming Tseng, Shao Chun Wang, Mei Ren Pan, Chin Hua Yang, Yuan Liang Wang, Hirohito Yamaguchi, Da Pang, Gabriel N. Hortobagyi, Dihua Yu, Mien Chie Hung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish
Article number2788
JournalNature Communications
Issue number1
StatePublished - Dec 2021


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