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

doi:10.1038/s41467-021-23075-2

. 2021 May 13;12(1):2788.

doi: 10.1038/s41467-021-23075-2.

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

Heng-Huan Lee^#¹, Ying-Nai Wang^#¹, Wen-Hao Yang^#^{1

2}, Weiya Xia¹, Yongkun Wei¹, Li-Chuan Chan¹, Yu-Han Wang^{1

2}, Zhou Jiang¹, Shouping Xu³, Jun Yao¹, Yufan Qiu^{1

4}, Yi-Hsin Hsu¹, Wei-Lun Hwang^{5

6}, Meisi Yan^{1

7}, Jong-Ho Cha^{1

8}, Jennifer L Hsu¹, Jia Shen¹, Yuanqing Ye⁹, Xifeng Wu⁹, Ming-Feng Hou^{10

11}, Lin-Ming Tseng^{12

13}, Shao-Chun Wang², Mei-Ren Pan¹¹, Chin-Hua Yang¹², Yuan-Liang Wang², Hirohito Yamaguchi^{1

2}, Da Pang³, Gabriel N Hortobagyi¹⁴, Dihua Yu¹, Mien-Chie Hung^{15

16

17}

Affiliations

¹ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
³ Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Deptartment III of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁵ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
⁶ Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
⁷ Department of Pathology, Harbin Medical University, Harbin, China.
⁸ Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
⁹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹¹ Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹² Comprehensive Breast Health Center and Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
¹³ Institute of Clinical Medicine and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁴ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhung@cmu.edu.tw.
¹⁶ Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
¹⁷ Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@cmu.edu.tw.

^# Contributed equally.

PMID: 33986289
PMCID: PMC8119676
DOI: 10.1038/s41467-021-23075-2

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

Heng-Huan Lee et al. Nat Commun. 2021.

. 2021 May 13;12(1):2788.

doi: 10.1038/s41467-021-23075-2.

Authors

Affiliations

¹ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
³ Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Deptartment III of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁵ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
⁶ Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
⁷ Department of Pathology, Harbin Medical University, Harbin, China.
⁸ Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
⁹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹¹ Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹² Comprehensive Breast Health Center and Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
¹³ Institute of Clinical Medicine and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁴ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhung@cmu.edu.tw.
¹⁶ Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
¹⁷ Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@cmu.edu.tw.

^# Contributed equally.

PMID: 33986289
PMCID: PMC8119676
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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. High hRNase 1 expression predicts poor clinical outcome in breast cancer patients.**
a, Prognostic correlation of survival analyses of breast cancer patients with high and low hRNase 1 levels. OS, overall survival; RFS, relapse-free survival; DMFS, distant-metastasis-free survival. HR, hazard ratio. b, c Prognostic correlation of the RFS with different grades (b) and lymph node statuses (c) of patients with breast cancer in the indicated groups with different hRNase 1 levels. LN, lymph node. d Top, plots of IHC scores of hRNase 1 level in breast tumor tissues (T; n = 31) vs normal tissues (N; n = 12) (Pantomics Inc., #BRC961). Bottom, representative images of IHC staining of hRNase 1 expression in normal and breast tumor tissues. Bar, 25 µm. ^*p = 0.0188. e Box plots of IHC scores of hRNase 1 level in breast tumor tissues subdivided into four molecular subtypes. Case numbers are shown in the parentheses. f ELISA of hRNase 1 levels in serum samples of breast tumor patients (T; n = 50) compared with noncancerous individuals (N; n = 24). ^*p = 0.0382. g, ELISA of hRNase 1 levels in breast tumor serum samples subdivided into three molecular subtypes. Case numbers are shown in the parentheses. h Box plots of ELISA of hRNase 1 expression in the conditioned medium (CM) of eight breast cancer cells and two normal cells. KPL4 cell line as an outlier. i Western blotting (WB) of hRNase 1 expression level secreted in breast cancer cells; the experiment was repeated a second time with similar results. ^*p = 0.0415. Survival data were analyzed using Kaplan-Meier Plotter (Probe: 201785_at) and p values were calculated by Log-rank test (a–c). Error bars represent mean ± SD (f, g). ^*p < 0.05, ns, not significant, two-tailed unpaired t test (d, f, h), ANOVA analysis (e, g). Box plots indicate minima (lower end of whisker), maxima (upper end of whisker), median (center), 25th percentile (bottom of box), and 75th percentile (top of box) (d, e, h) as well as outlier (single point) (h). Source data are provided as a Source Data file.

**Fig. 2. hRNase 1 increases the tumor-initiating ability of breast cancer cells independently of its ribonucleolytic activity.**
a Representative images of primary spheres in MCF7 control cells (MCF7-NEO) and hRNase 1 expressing MCF7 cells (MCF7-R1). Bar, 100 µm. b Quantification of spheroid-formation assay of primary, secondary, and tertiary spheres derived from the indicated MCF7 stable clones. n = 3 independent experiments. ^*p = 0.0218 for primary spheres, ^*p = 0.0489 for secondary spheres, ^*p = 0.0289 for tertiary spheres. c Flow cytometric analysis of membrane CD44 and CD24 expression in the indicated MCF7 stable clones (parental cells) and primary and tertiary spheres derived from the indicated MCF7 stable clones. d Quantification of flow cytometric analysis from (c). n = 3 independent experiments. ^*p = 0.0148 for parental cells, ^*p = 0.0164 for primary spheres, ^*p = 0.0111 for tertiary spheres. e Spheroid-formation assay of the indicated BT-549 stable clones. Bar, 200 µm. Ctrl vs R1, ^***p = 0.00099, Ctrl vs R1-H12A, ^***p = 0.0002. f Flow cytometric analysis of membrane CD44 and CD24 expression in the indicated BT-549 stable clones. g Limiting dilution assay of the stable transfectants derived from BT-549 as indicated. h Spheroid-formation assay of the indicated KPL4 stable clones. Bar, 200 µm. sh-Ctrl vs sh-R1#1, ^**p = 0.0023, sh-Ctrl vs sh-R1#2, ^***p = 0.0002. i Flow cytometric analysis of membrane CD44 and CD24 expression in the indicated KPL4 stable clones. j Limiting dilution assay of the stable transfectants derived from KPL4 as indicated. k Representative images (top) and quantification (bottom) of spheroid-formation assay of the indicated stable clones in KPL4. Bar, 200 µm. n = 3 independent experiments. ^**p = 0.0020. l WB of KPL4 stable transfectants knocking out hRNase 1 and empty control with hRNase 1 (Sigma-Aldrich, #HPA001140) and β-actin (Sigma-Aldrich, #A2228) antibodies. Red asterisk, glycosylated hRNase 1; black asterisk, non-glycosylated hRNase 1. The experiment was repeated a second time with similar results. m Flow cytometric analysis of ALDH1 activity by ALDEFLUOR assay in cells from (l). The flow cytometry plots showing side scatter (SSC) vs fluorescence intensity. The percentages of ALDEFLUOR-positive cells are shown in the right upper quadrant of each panel. Cells treated with ALDH1 inhibitor diethylaminobenzaldehyde (DEAB) were used as negative control for this assay. In (e, h) representative images (top) and quantification (bottom) of spheroid-formation assay of the indicated stable clones. Data represent three independent experiments in three technical replicates. In (c, f, i) the percentages of CD44⁺CD24^– cells are shown in the right lower quadrant of each panel. In (g, j) the number of tumor-forming mice within each group is shown in the panel. The p values of pairwise comparisons for differences in TIC frequencies using the ELDA web-tool, Chi-squared test. Error bars represent mean ± SEM (b, d) and mean ± SD (e, h, k). *p < 0.05, ^**p < 0.01, ^***p < 0.001, two-tailed unpaired t test (b, d, e, h, k). Source data are provided as a Source Data file.

**Fig. 3. hRNase 1 activates EphA4 signaling and associates with EphA4.**
a Top, human phospho-RTK antibody array analysis of HeLa cells treated with or without recombinant hRNase 1 protein purified from HEK293 cells (1 μg/ml) for 5 min after serum starvation for 3 h. Three pairs of positive signals in duplicate coordinates (minus hRNase 1 comparing to plus hRNase 1) are shown in EphA4 (D23/D24), HGFR (C3/C4), and Tie-2 (D1/D2). Bottom, quantification of detected signals by ImageJ. b WB of BT-549 cells treated with recombinant hRNase 1 protein purified from HEK293 cells (1 μg/ml) at various time points, blotted with phospho-EphA4-Y779 (pY779-EphA4), EphA4, and β-actin antibodies. c Top, WB of BT-549 cells treated with hRNase 1 at various concentrations for 30 min with pY779-EphA4 and EphA4 antibodies. Bottom, quantification expressed as fold increases of hRNase 1 induction in EphA4 phosphorylation by normalizing against the EphA4 total protein expression, as compared with untreated control. d WB of MCF7 cells treated with or without hRNase 1 at various time points with the indicated antibodies. e Immunoprecipitation (IP) of MCF7 cells treated with or without hRNase 1 for 30 min with antibodies targeting EphA4 or normal IgG followed by WB with the indicated antibodies. Left, input lysates. f Duolink in situ PLA of BT-549 and KPL4 cells, treated with CM collected from the indicated 293T stable transfectants for 30 min. Bar, 10 µm. Bar diagram, the percentage of cells showing positive interaction calculated from three independent fields of each pool. Negative control, EphA4 antibody only or CM source as 293T-pCDH-hRNase 5. g In vitro GST pull-down assay of GST-tagged hRNase 1/GST-binding magnetic beads incubated with lysate from 293T transfected with Myc-tagged EphA4. Left, input lysates. The 26 kDa GST band is a product of GST-hRNase 1 degradation. h, Top, in vitro binding assay of N-EphA4-Fc incubated with or without hRNase 1 protein purified from *E. coli*. Protein G beads were used for pull-down. Bottom, input lysates. i–k, Left, input lysates of recombinant hRNase 1 without or with PNGase F treatment (i). In vitro binding assay of recombinant hRNase 1 treated without (j) or with (k) PNGase F and incubated with N-EphA4-Fc or human IgG. In (e, i–k) red asterisk, glycosylated hRNase 1; black asterisk, non-glycosylated hRNase 1. Data are presented as mean ± SD of two (a, c) or three (f) independent experiments. Each experiment was repeated an additional time with similar results (b, d, e, g–k). Source data are provided as a Source Data file.

**Fig. 4. hRNase 1 binds to EphA4 ligand-binding domain and binding requires its C-terminus.**
a Schematic diagram of various constructs of Myc-tagged EphA4. The numbers represent amino-acid residues. EphA4-ECD, amino acids 1–547 of EphA4; EphA4-ICD, amino acids 570–986 of EphA4; *, EphA4-K653A, mutation of EphA4 phosphorylation site. b In vitro GST pull-down assay of GST-tagged hRNase 1/glutathione magnetic beads incubated with lysate from 293T transfected with the indicated expression plasmids, including WT, ECD and ICD of EphA4, and pCDH empty vector, followed by three times of PBS washing. Left, input lysates. c, d WB of 293T stable transfectants generated by constructs of (a) or empty vector (V) treated with or without CM collected from 293T stable transfectant containing hRNase 1 for 30 min. e Schematic diagram of various constructs of GST-tagged hRNase 1. f Coomassie blue staining of GST-hRNase 1 plasmids as indicated. The 26 kDa GST band is a product of GST-hRNase 1 degradation. g Duolink in situ PLA of KPL4 cells expressing EphA4 and hRNase 1 knockout (KPL4-A4-KO-R1) treated with GST vector or GST-hRNase 1 proteins from (f) for 30 min. Insets, 6.25× magnification. Bar, 5 µm. Bar diagram indicates the percentage of cells showing positive hRNase 1 and EphA4 interaction calculated from a pool of 50 cells; error bars represent mean ± SD, n = 3 independent experiments. Data in (b–d, f) are representative of two independent experiments with similar results. Source data are provided as a Source Data file.

**Fig. 5. hRNase 1 induces EphA4 dimerization/oligomerization and its binding to EphA4 partially overlaps with that of ephrin A5.**
a Dimerization assay of 293T cells ectopically expressing Myc-tagged EphA4 or vector control, cross-linked with bis(sulfosuccinimidyl)suberate (BS³) followed by WB under a non-reducing and non-denaturing condition. Left, input lysates. b, c Left, saturation binding assay of the Kd values determination for hRNase 1 (b) or ephrin-A5 (c) binding toward EphA4 in BT-549 cell lysates. Right, scatchard plot. Negative control, normal mouse IgG. Each experiment was performed twice in triplicate. d, e Binding assay measuring hRNase 1 binding affinity toward EphA4 in BT-549 cells with increasing concentrations of ephrin-A5 (d) and KYL or KYL-P7A peptide (e) as indicated. The optical density was determined at 450 nm, corrected by subtraction of reading at 570 nm. ^*p < 0.05, ^**p < 0.01, ^***p < 0.001, two-tailed unpaired t test. f–h WB of secreted proteins from CM (f) and lysates (g, h) in BT-549-Ctrl and BT-549-R1 stable clones. Positive control, HepG2 cell lysates. Data are representative of two (a) or three (f–h) independent experiments with similar results. Error bars represent mean ± SD, n = 3 independent experiments (b–e). Source data are provided as a Source Data file.

**Fig. 6. EphA4 positively regulates hRNase 1-mediated breast tumor initiation.**
a Quantification of spheroid-formation assay of the indicated ZR-75-1 stable clones. NEO-sh-Ctrl vs A4-sh-Ctrl, ^*p = 0.0260, A4-sh-Ctrl vs A4-sh-R1#1, ^**p = 0.0015, A4-sh-Ctrl vs A4-sh-R1#2, ^*p = 0.0105. b Flow cytometric analysis of membrane CD44 and CD24 expression in the indicated ZR-75-1 stable clones. c Quantification of flow cytometric analysis from (b). NEO-sh-Ctrl vs A4-sh-Ctrl, ^**p = 0.0044, A4-sh-Ctrl vs A4-sh-R1#1, ^**p = 0.0033, A4-sh-Ctrl vs A4-sh-R1#2, ^**p = 0.0072. d Flow cytometric analysis of ALDH1 activity by ALDEFLUOR assay of the indicated KPL4 stable clones. Right of each panel, the percentage of ALDEFLUOR-positive cells. e Quantification of spheroid-formation assay of the indicated KPL4 stable clones. NEO vs A4, ^**p = 0.0016, A4-KO-Ctrl vs A4-KO-R1, ^**p = 0.0016. f Limiting dilution assay of the indicated KPL4 stable clones. g Quantification of spheroid-formation assay of the indicated MCF7 stable clones. NEO-sh-Ctrl vs R1-sh-Ctrl, ^*p = 0.0109, R1-sh-Ctrl vs R1-sh-A4#1, ^*p = 0.0371, R1-sh-Ctrl vs R1-sh-A4#2, ^*p = 0.01001. h Flow cytometric analysis of membrane CD44 and CD24 expression in the indicated MCF7 stable clones. i Quantification of flow cytometric analysis from (h). NEO-sh-Ctrl vs R1-sh-Ctrl, ^*p = 0.0103, R1-sh-Ctrl vs R1-sh-A4#1, ^**p = 0.0019, R1-sh-Ctrl vs R1-sh-A4#2, ^**p = 0.0014. j Quantification of spheroid-formation assay of the indicated BT-549 stable clones. NEO vs R1, ^***p = 0.0003, R1-KO-Ctrl vs R1-KO-A4, ^****p < 0.0001. k Limiting dilution assay of the indicated BT-549 stable clones. In (b, h) the percentages of CD44⁺CD24^– cells are shown in the right lower quadrant of each panel. In (f, k) the number of tumor-forming mice within each group is shown in the panel. All error bars represent mean ± SD. Data are representative of three independent experiments; ^*p < 0.05, ^**p < 0.01, ^***p < 0.001, ^****p < 0.0001, two-tailed unpaired t test (a, c, e, g, i, j). Source data are provided as a Source Data file.

**Fig. 7. Pathological relevance of hRNase 1 expression, EphA4 activation, and CD133 in breast cancer.**
a Quantification for the correlation between tissue phospho-EphA4-Y779 and plasma hRNase 1 in the paired breast cancer patients. Chi-squared test. b–d Quantification of IHC staining for the correlation between hRNase 1 and phospho-EphA4-Y779 (b), hRNase 1 and CD133 (c), and CD133 and phospho-EphA4-Y779 (d) by human breast TMA analysis (Pantomics Inc., #BRC1021). Fisher’s exact test. e Two representative cases of IHC staining for (b–d). The experiment was performed an additional time with similar results. Bar, 50 μm. f A proposed model of hRNase 1 as a secretory ligand of EphA4 to positively regulate breast tumor initiation. In brief, elevated levels of serum hRNase 1 induces its binding to EphA4 and triggers EphA4 signaling (red stars) in breast tumor cells in an autocrine/paracrine manner, which in turn promotes breast tumor initiation via the IKK/NF-κB and MEK/Erk activating pathways. Such EphA4 activation and CSC-like state triggered by hRNase 1 may be sustained in conjunction with juxtacrine signaling via the classical membrane-bound EphA4 ligands, ephrins. Artwork by H-H.L., Y-N.W., and M-C.H.

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References

1. Sorrentino S. The eight human “canonical” ribonucleases: molecular diversity, catalytic properties, and special biological actions of the enzyme proteins. FEBS Lett. 2010;584:2194–2200. doi: 10.1016/j.febslet.2010.04.018. - DOI - PubMed
1. Lu L, Li J, Moussaoui M, Boix E. Immune modulation by human secreted RNases at the extracellular space. Front. Immunol. 2018;9:1012. doi: 10.3389/fimmu.2018.01012. - DOI - PMC - PubMed
1. Landre JB, et al. Human endothelial cells selectively express large amounts of pancreatic-type ribonuclease (RNase 1) J. Cell Biochem. 2002;86:540–552. doi: 10.1002/jcb.10234. - DOI - PubMed
1. Beintema JJ, Kleineidam RG. The ribonuclease A superfamily: general discussion. Cell Mol. Life Sci. 1998;54:825–832. doi: 10.1007/s000180050211. - DOI - PMC - PubMed
1. Barrabes S, et al. Glycosylation of serum ribonuclease 1 indicates a major endothelial origin and reveals an increase in core fucosylation in pancreatic cancer. Glycobiology. 2007;17:388–400. doi: 10.1093/glycob/cwm002. - DOI - PubMed

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[1] Sorrentino S. The eight human “canonical” ribonucleases: molecular diversity, catalytic properties, and special biological actions of the enzyme proteins. FEBS Lett. 2010;584:2194–2200. doi: 10.1016/j.febslet.2010.04.018. - DOI - PubMed

[2] Sorrentino S. The eight human “canonical” ribonucleases: molecular diversity, catalytic properties, and special biological actions of the enzyme proteins. FEBS Lett. 2010;584:2194–2200. doi: 10.1016/j.febslet.2010.04.018. - DOI - PubMed

[3] Lu L, Li J, Moussaoui M, Boix E. Immune modulation by human secreted RNases at the extracellular space. Front. Immunol. 2018;9:1012. doi: 10.3389/fimmu.2018.01012. - DOI - PMC - PubMed

[4] Lu L, Li J, Moussaoui M, Boix E. Immune modulation by human secreted RNases at the extracellular space. Front. Immunol. 2018;9:1012. doi: 10.3389/fimmu.2018.01012. - DOI - PMC - PubMed

[5] Landre JB, et al. Human endothelial cells selectively express large amounts of pancreatic-type ribonuclease (RNase 1) J. Cell Biochem. 2002;86:540–552. doi: 10.1002/jcb.10234. - DOI - PubMed

[6] Landre JB, et al. Human endothelial cells selectively express large amounts of pancreatic-type ribonuclease (RNase 1) J. Cell Biochem. 2002;86:540–552. doi: 10.1002/jcb.10234. - DOI - PubMed

[7] Beintema JJ, Kleineidam RG. The ribonuclease A superfamily: general discussion. Cell Mol. Life Sci. 1998;54:825–832. doi: 10.1007/s000180050211. - DOI - PMC - PubMed

[8] Beintema JJ, Kleineidam RG. The ribonuclease A superfamily: general discussion. Cell Mol. Life Sci. 1998;54:825–832. doi: 10.1007/s000180050211. - DOI - PMC - PubMed

[9] Barrabes S, et al. Glycosylation of serum ribonuclease 1 indicates a major endothelial origin and reveals an increase in core fucosylation in pancreatic cancer. Glycobiology. 2007;17:388–400. doi: 10.1093/glycob/cwm002. - DOI - PubMed

[10] Barrabes S, et al. Glycosylation of serum ribonuclease 1 indicates a major endothelial origin and reveals an increase in core fucosylation in pancreatic cancer. Glycobiology. 2007;17:388–400. doi: 10.1093/glycob/cwm002. - DOI - PubMed

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

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

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