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

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

doi:10.1038/s41467-021-23075-2

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.

Highlights

Human ribonuclease 1 is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; whether it plays a role in cancer remains elusive
To systematically identify members of the hRNase A superfamily that contribute to cancer progression in addition to hRNase 5, we first examined the prognostic significance of hRNases in breast cancer using the median values for patient stratification analyzed by the Kaplan-Meier Plotter, a tool for meta-analysis-based biomarker assessment
The luminal B subtype in each grade displayed a higher hazard ratio and a smaller p value, suggesting a stronger correlation between high hRNase 1 expression and poor patient survival in the luminal B subtype, there is a lack of statistical significance (Supplementary Fig. 2b)

Summary

Introduction

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; whether it plays a role in cancer remains elusive. 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. Recent studies indicated that hRNase 5 serves as a ligand for the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) and plexin-B2 (PLXNB2) receptor[13,14,15] in solid and hematopoietic cancers Together, those findings reveal an unconventional ligand–receptor relationship and a role of the hRNase A superfamily in tumor progression[16,17,18]. We uncovered a ligand–receptor pair of hRNase 1–EphA4 critical for breast cancer initiation, namely that hRNase 1 acts as a natively secretory ligand of EphA4 to stimulate EphA4 signaling in an autocrine/paracrine manner, leading to upregulation of stem-like cell properties in breast cancer

Methods

Results

Conclusion