Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23075-2
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Funding
- MDA Startup Fund
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund
- Breast Cancer Research Foundation [BCRF-20-070]
- Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence in Taiwan [MOHW108-TDU-B-212-122015, MOHW108-TDU-B-212-124024]
- Drug Development Center, China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan
- National Breast Cancer Foundation, Inc.
- T32 Training Grant in Cancer Biology [5T32CA186892]
- National Institutes of Health [CCSG CA016672]
- YingTsai Young Scholar Award [CMU108-YTY-04]
- Ministry of Science and Technology Oversees Project for Post Graduate Research (MOST) [104-2917-I-564-003]
- Ministry of Science and Technology (MOST) [109-2314-B-039-054]
- Ministry of Education (Taiwan) Joint of International Talent Training Program [1040082029B]
- AACR-Pfizer Immuno-oncology Research Fellowship [19-40-49]
- Project Nn10 of Harbin Medical University Cancer Hospital [Nn102017-02]
- National Natural Science Foundation of China [81602323, 81872149]
- Outstanding Youth Project of Heilongjiang Provincial Natural Science Foundation [YQ2019H027]
- INHA UNIVERSITY Research Grant
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The study demonstrates that human ribonuclease 1 (hRNase 1) can independently of its ribonucleolytic activity, promoting breast tumor initiation by activating the EphA4 receptor signal and showing a positive correlation with EphA4 activation and the stem cell marker CD133 in tumor tissue. High levels of hRNase 1 in plasma samples are associated with EphA4 activation in breast cancer patients' tumor tissues, suggesting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer.
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. Human ribonuclease 1 (hRNase 1) regulates innate immunity, hemostasis and RNA clearance. Here, the authors report an alternative function of hRNase 1 as a secretory ligand of Eph receptor EphA4 to enhance breast cancer stemness and promote breast tumour initiation.
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