{"doi":"10.1038/s41467-021-23075-2","title":"Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation","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.","journal":"Nature Communications","year":2021,"id":167877,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":247181,"name":"Ying‐Nai Wang","orcid":"0000-0002-5275-6729","position":1,"is_corresponding":false},{"id":696219,"name":"Wenhao Yang","orcid":"0000-0002-6292-9048","position":2,"is_corresponding":false},{"id":107243,"name":"Weiya Xia","orcid":null,"position":3,"is_corresponding":false},{"id":270648,"name":"Yongkun Wei","orcid":"0000-0001-8998-5333","position":4,"is_corresponding":false},{"id":251994,"name":"Li-Chuan Chan","orcid":"0000-0002-2665-637X","position":5,"is_corresponding":false},{"id":251988,"name":"Yu-Han Wang","orcid":"0000-0002-6015-5587","position":6,"is_corresponding":false},{"id":323232,"name":"Zhou Jiang","orcid":"0000-0003-4247-2949","position":7,"is_corresponding":false},{"id":696220,"name":"Shouping Xu","orcid":"0000-0001-6154-3381","position":8,"is_corresponding":false},{"id":251992,"name":"Jun Yao","orcid":"0000-0003-1418-3576","position":9,"is_corresponding":false},{"id":251990,"name":"Yufan Qiu","orcid":"0000-0002-6791-9957","position":10,"is_corresponding":false},{"id":696221,"name":"Yi‐Hsin Elsa Hsu","orcid":"0000-0001-8962-6111","position":11,"is_corresponding":false},{"id":696222,"name":"Wei‐Lun Hwang","orcid":"0000-0002-8694-877X","position":12,"is_corresponding":false},{"id":485597,"name":"Meisi Yan","orcid":null,"position":13,"is_corresponding":false},{"id":251993,"name":"Jong‐Ho Cha","orcid":"0000-0003-2181-7768","position":14,"is_corresponding":false},{"id":107254,"name":"Jennifer L. 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