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 Hou, Lin-Ming Tseng, Shao-Chun Wang, Mei-Ren Pan, Chin-Hua Yang, Yuan-Liang Wang, Hirohito Yamaguchi, Da Pang, Gabriel N. Hortobagyi, Dihua Yu and Mien-Chie Hung ()
Additional contact information
Heng-Huan Lee: The University of Texas MD Anderson Cancer Center
Ying-Nai Wang: The University of Texas MD Anderson Cancer Center
Wen-Hao Yang: The University of Texas MD Anderson Cancer Center
Weiya Xia: The University of Texas MD Anderson Cancer Center
Yongkun Wei: The University of Texas MD Anderson Cancer Center
Li-Chuan Chan: The University of Texas MD Anderson Cancer Center
Yu-Han Wang: The University of Texas MD Anderson Cancer Center
Zhou Jiang: The University of Texas MD Anderson Cancer Center
Shouping Xu: Harbin Medical University Cancer Hospital
Jun Yao: The University of Texas MD Anderson Cancer Center
Yufan Qiu: The University of Texas MD Anderson Cancer Center
Yi-Hsin Hsu: The University of Texas MD Anderson Cancer Center
Wei-Lun Hwang: National Yang Ming Chiao Tung University
Meisi Yan: The University of Texas MD Anderson Cancer Center
Jong-Ho Cha: The University of Texas MD Anderson Cancer Center
Jennifer L. Hsu: The University of Texas MD Anderson Cancer Center
Jia Shen: The University of Texas MD Anderson Cancer Center
Yuanqing Ye: The University of Texas MD Anderson Cancer Center
Xifeng Wu: The University of Texas MD Anderson Cancer Center
Ming-Feng Hou: Kaohsiung Medical University Hospital
Lin-Ming Tseng: Taipei Veterans General Hospital
Shao-Chun Wang: China Medical University
Mei-Ren Pan: Kaohsiung Medical University
Chin-Hua Yang: Taipei Veterans General Hospital
Yuan-Liang Wang: China Medical University
Hirohito Yamaguchi: The University of Texas MD Anderson Cancer Center
Da Pang: Harbin Medical University Cancer Hospital
Gabriel N. Hortobagyi: The University of Texas MD Anderson Cancer Center
Dihua Yu: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23075-2

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