A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

doi:10.1371/journal.ppat.1005171

. 2015 Sep 24;11(9):e1005171.

doi: 10.1371/journal.ppat.1005171. eCollection 2015 Sep.

A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

Minmin Hu¹, Cong Wang², Wan Li³, Weiping Lu⁴, Zhiqiang Bai³, Di Qin³, Qin Yan³, Jianzhong Zhu⁵, Brian J Krueger⁶, Rolf Renne⁶, Shou-Jiang Gao⁷, Chun Lu¹

Affiliations

¹ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China; Key Laboratory Of Pathogen Biology Of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China; Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
² Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.
³ Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
⁴ Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu, P. R. China.
⁵ Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
⁶ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America.
⁷ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

PMID: 26402907
PMCID: PMC4581863
DOI: 10.1371/journal.ppat.1005171

A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

Minmin Hu et al. PLoS Pathog. 2015.

. 2015 Sep 24;11(9):e1005171.

doi: 10.1371/journal.ppat.1005171. eCollection 2015 Sep.

Authors

Minmin Hu¹, Cong Wang², Wan Li³, Weiping Lu⁴, Zhiqiang Bai³, Di Qin³, Qin Yan³, Jianzhong Zhu⁵, Brian J Krueger⁶, Rolf Renne⁶, Shou-Jiang Gao⁷, Chun Lu¹

Affiliations

¹ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China; Key Laboratory Of Pathogen Biology Of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China; Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
² Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.
³ Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
⁴ Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu, P. R. China.
⁵ Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
⁶ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America.
⁷ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

PMID: 26402907
PMCID: PMC4581863
DOI: 10.1371/journal.ppat.1005171

Abstract

Kaposi's sarcoma (KS) is a highly disseminated angiogenic tumor of endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced tumor dissemination and metastasis remain unknown. Here, we found that ectopic expression of miR-K12-3 (miR-K3) promoted endothelial cell migration and invasion. Bioinformatics and luciferase reporter analyses showed that miR-K3 directly targeted G protein-coupled receptor (GPCR) kinase 2 (GRK2, official gene symbol ADRBK1). Importantly, overexpression of GRK2 reversed miR-K3 induction of cell migration and invasion. Furthermore, the chemokine receptor CXCR2, which was negatively regulated by GRK2, was upregulated in miR-K3-transduced endothelial cells. Knock down of CXCR2 abolished miR-K3-induced cell migration and invasion. Moreover, miR-K3 downregulation of GRK2 relieved its direct inhibitory effect on AKT. Both CXCR2 induction and the release of AKT from GRK2 were required for miR-K3 maximum activation of AKT and induction of cell migration and invasion. Finally, deletion of miR-K3 from the KSHV genome abrogated its effect on the GRK2/CXCR2/AKT pathway and KSHV-induced migration and invasion. Our data provide the first-line evidence that, by repressing GRK2, miR-K3 facilitates cell migration and invasion via activation of CXCR2/AKT signaling, which likely contribute to the dissemination of KSHV-induced tumors.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

**Fig 1. Ectopic expression of miR-K3 promotes endothelial cell migration and invasion.**
**(A)**. KSHV miR-K3 expression in HUVEC infected with KSHV BAC16 virus induced from iSLK-BAC16 cells or transduced by the different MOI of lentiviral miR-K3 were determined by qPCR. The miR-K3 level in KSHV group was set as ‘‘1” for comparison. **(B)**. HUVEC were transduced with 2 MOI of lentivirus empty vector (**mpCDH**; left) and lentivirus-miR-K3 (**miR-K3**; right), and representative images were taken under light microscope (**Phase**; top) and fluorescent microscope (**RFP**; bottom) (Original magnification, ×100). **(C)**. Cells treated as in (B) were analyzed for RFP expression by flow cytometry to determine transduction efficiency. y axis units are numbers of cells. **(D)**. Luciferase activity was detected in 2 MOI of lentivirus empty vector (**mpCDH**) or lentivirus-miR-K3 (**miR-K3**) transduced HUVEC transfected by the pGL3-Control (**Control**) or the pGL3-miR-K3 sensor reporter (**miR-K3-Sensor**). *** P < 0.001 for Student’s t-test. n.s., not significant. **(E)**. Transwell migration (left panel) and Matrigel invasion (right panel) assays for HUVEC transduced with lentivirus empty vector (**mpCDH**) or lentivirus-miR-K3 (**miR-K3**). The representative images were captured at 6 and 12 h post seeding (original magnification, ×100). **(F)**. The quantification results of Transwell migration assay in (E). **(G)**. The quantification results of Matrigel invasion assay in (E). **(H)**. The quantification results of wound healing assay in S1 Fig. **(I)**. The mRNA expression of MMP1, 9, 10 and IL-6, 8 in HUVEC treated as in (B) were determined by qPCR.

**Fig 2. GRK2 expression is reduced in miR-K3-expressing HUVEC and KS lesion samples.**
**(A)**. The mRNA level of GRK2 in HUVEC transduced with lentivirus empty vector (**mpCDH**) and lentivirus-miR-K3 (**miR-K3**) were examined by qPCR. **(B)**. The expression of GRK2 proteins in HUVEC transduced with lentivirus empty vector (**mpCDH**) and lentivirus-miR-K3 (**miR-K3**) were detected by Western blotting analysis. Results shown were from a representative experiment of three independent experiments with similar results. The values of density of protein bands after normalization to housekeeping were shown; same for all of the following Western blotting figures. **(C)**. HUVEC were infected with KSHV, and image captured under light microscope (**Phase**) and fluorescent microscope (**GFP**) (Original magnification, ×100). **(D)**. qPCR analysis for GRK2 mRNA in KSHV-infected HUVEC as described in (C) (**KSHV**) or in HUVEC treated with PBS as the negative control (**PBS**). **(E)**. Western blotting analysis of the expression of GRK2 protein in KSHV-infected HUVEC as described in (C) (**KSHV**) or in HUVEC treated with PBS as the negative control (**PBS**). **(F)**. Hematoxylin and eosin (H&E) staining of KS lesion (**right**) and normal (**left**) tissue sections to show histologic features (left panel; original magnification, ×100) and immunohistochemical staining (IHC) of KSHV LANA and GRK2 (middle and left panels; original magnification, ×200). **(G)**. Quantification of results in (F). *** P < 0.001 for Student’s t-test.

**Fig 3. GRK2 is directly targeted by miR-K3.**
**(A)**. Luciferase activity was detected in HEK 293T cells co-transfected by a mimic of miR-K3 (**miR-K3**) or a negative control nucleotide of miRNA (**Neg. Ctrl.**) together with pGL3-Control or pGL3-GRK2 3’UTR luciferase reporter (**pGL3-GRK2 3’UTR**). ** P < 0.01 for Student’s t-test. n.s., not significant. **(B)**. Luciferase assay of 293T cells co-transfected by pGL3-GRK2 3′UTR together with increasing amounts (10, 20, and 50 nM) of miR-K3. **(C)**. Schematic illustration of the putative seed sequences of miR-K3 complementary with GRK2 3’UTR and mutagenesis of binding sites in the 3’UTR of GRK2. **(D)**. The luciferase activity was assayed in 293T cells co-transfected by GRK2 wild type 3’UTR (**WT GRK2**) or the mutant GRK2 3’UTR construct (**mut GRK2**) together with **miR-K3** or mutant miR-K3 mimic (**mut miR-K3**). * P < 0.05 and ** P < 0.01 for Student’s t-test. **(E)**. miR-K3 inhibited the expression of exogenous GRK2 protein by targeting its native 3’UTR. Western blotting was performed in HEK 293T cells co-transfected by pcDNA3.1–3×Flag-GRK2-3’UTR together with pEGFP and increasing amounts (10 and 20 nM) mimic of miR-K3. **(F)**. miR-K3 inhibited the expression of endogenous GRK2 protein in HUVEC transfected with increasing amounts (10 and 20 nM) mimic of miR-K3. **(G)**. Mutant miR-K3 failed to target endogenous GRK2. Western blotting was performed in HUVEC transfected by Neg. Ctrl., miR-K3 mimic (20 nM) or mut miR-K3 lacking the seed sequences. **(H)**. Transfection of miR-K3 mimic (20 nM) has the same inhibition level on GRK2 expression as that of KSHV infection.

**Fig 4. Ectopic expression of GRK2 inhibits miR-K3-induced endothelial cell migration and invasion.**
**(A)**. Transwell migration (top) and Matrigel invasion (bottom) assays for HUVEC transduced with lentivirus-mediated empty vector (**mpCDH**) or miR-K3 (**miR-K3**), which were subsequently co-transduced with lentivirus-mediated empty vector (**pHAGE**) and lentivirus-GRK2 (**GRK2**), respectively. The representative images were captured at 6 and 12 h post seeding (original magnification, ×100). **(B)**. The quantification results of Transwell migration assay in (A). * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(C)**. The quantification results of Matrigel invasion assay in (A). ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(D)**. Western blotting was performed in HUVEC treated as in (A) with the indicated antibodies. The antibody against His-tag was used to detect the exogenous expression of GRK2. **(E)**. Western blotting was performed in normal HUVEC transduced with lentivirus-GRK2 (**GRK2**) and its control (**pHAGE**), or KSHV-infected HUVEC transduced with lentivirus-GRK2 (**GRK2**) and its control (**pHAGE**) with the indicated antibodies. The antibody against His-tag was used to examine the exogenous expression of GRK2. **(F)**. Transwell migration assay for HUVEC treated as in (E) at 6 and 12 h post seeding. * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(G)**. Matrigel invasion assay for HUVEC treated as in (E) at 6 and 12 h post seeding. * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test.

**Fig 5. KSHV infection promotes endothelial cell migration and invasion through miR-K3 by targeting GRK2.**
**(A)**. Western blotting was performed in KSHV-infected HUVEC (**KSHV + HUVEC**) transduced with lentivirus empty vector (**mpCDH**) or lentivirus-miR-K3 (**miR-K3**) with the indicated antibodies. **(B)**. MiR-K3 sponge was functional. HEK 293T cells were co-transfected with miR-K3 sensor reporter and miR-K3 mimic, and subsequently transduced with increasing MOI of lentivirus-mediated miR-K3 sponge (**miR-K3 sponge**) or its control (**pCDH**). The cells were collected at 48 h post-transduction for luciferase assays. *** P < 0.001 for Student’s t-test. n.s., not significant. **(C)**. Western blotting was performed in KSHV-infected HUVEC (**KSHV + HUVEC**) transduced with miR-K3 sponge (**miR-K3 sponge**) or its control (**pCDH**) with the indicated antibodies. **(D)**. Transwell migration (**Left panel**) and Matrigel invasion (**Right panel**) assays for cells treated as in (C) at 6 and 12 h post seeding. **(E)**. Western blotting was performed in normal HUVEC transduced with lentivirus-mediated a mixture of short hairpin RNAs targeting GRK2 (**shGRK2**) or the control (**mpCDH**) with the indicated antibodies. **(F)**. Transwell migration (**Left panel**) and Matrigel invasion (**Right panel**) assays for cells treated as in (E) at 6 and 12 h post seeding.

**Fig 6. Activation of CXCR2, which was negatively regulated by GRK2, contributes to miR-K3-induced endothelial cell migration and invasion.**
**(A)**. The mRNA level of CXCR2 in HUVEC transduced with lentivirus empty vector (**mpCDH**) and lentivirus-miR-K3 (**miR-K3**) or HUVEC treated with PBS (**PBS**) and infected with KSHV (**KSHV**) were examined by qPCR. **(B)**. The expressions of CXCR2 protein in HUVEC treated as in (A). **(C)**. Confocal microscopy of HUVEC treated as in (A), then stained for red fluorescence protein (refers to CXCR2; red). 4’, 6’-diamidino-2-phenylindole (DAPI) (blue) stains nuclei. **(D)**. Representative flow cytometry histograms for CXCR2 expression on the surface of HUVEC treated as in (A). Cells were stained with anti-CXCR2 MAb and fluorescein isothiocyanate-labeled IgG was used as an isotype control antibody. **(E)**. Immunohistochemical (IHC) staining of CXCR2 in normal skin (**Normal Skin**; top) and KS lesions (**Skin KS**; bottom). **(F)**. Quantification of the results in (E). *** P < 0.001 for Student’s t-test. **(G)**. Western blotting was performed using HUVEC transduced with lentivirus-mediated miR-K3 (**miR-K3**) or empty vector (**mpCDH**), and co-transduced with GRK2 (**GRK2**) or its control (**pHAGE**), respectively, with the indicated antibodies. The antibody against His-tag was used to detect the exogenous GRK2. **(H)**. Western blotting was performed in HUVEC transduced with miR-K3 (**miR-K3**) or empty vector (**mpCDH**), which were further transduced with a mixture of short hairpin RNAs targeting CXCR2 (**shCXCR2**) or its control (**mpCDH**), respectively. **(I)**. Transwell migration (left) and Matrigel invasion (right) assays were performed in HUVEC treated as in (E). * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test.

**Fig 7. MiR-K3 enhances the activation of AKT in HUVEC by targeting GRK2.**
**(A)**. Western blotting analysis of phosphorylated and total AKT in HUVEC transduced with **mpCDH** or **miR-K3**, and HUVEC treated with PBS (**PBS**) or infected with KSHV (**KSHV**), respectively. **(B)**. Western blotting analysis of phosphorylated AKT in HUVEC transduced with **mpCDH** or **miR-K3**, which were further transduced with lentivirus-GRK2 (**GRK2**) or its control (**pHAGE**). **(C)**. Western blotting analysis for CXCR2 and phosphorylation levels of AKT in normal HUVEC or KSHV-infected HUVEC transduced with lentivirus-GRK2 (**GRK2**) or its control (**pHAGE**). **(D)**. Western blotting analysis of CXCR2 and the phosphorylation levels of AKT in KSHV-infected HUVEC transduced with lentivirus-mediated miR-K3 (**miR-K3**) and its control (**mpCDH**) or lentivirus-mediated miR-K3 sponge (**miR-K3 sponge**) and its control (**pCDH**), respectively. **(E)**. Western blotting analysis of phosphorylation levels of AKT in normal HUVEC transduced with lentivirus-mediated a mixture of short hairpin RNAs targeting GRK2 (**shGRK2**) or the control (**mpCDH**). **(F)**. Western blotting analysis of phosphorylation levels of AKT in HUVEC transduced with lentivirus-mediated miR-K3 (**miR-K3**) or empty vector (**mpCDH**), and further with lentivirus-mediated a mixture of short hairpin RNAs targeting CXCR2 (**shCXCR2**). **(G)**. Western blotting analysis of phosphorylated AKT in normal HUVEC or KSHV-infected HUVEC transduced with lentivirus-mediated a mixture of short hairpin RNAs targeting CXCR2 (**shCXCR2**) or its control (**mpCDH**). **(H)**. GRK2 physiologically hijacked AKT in GRK2-expressing HUVEC. HUVEC were transduced with lentivirus-GRK2 (**GRK2**) or its control (**pHAGE**) and subjected to co-immunoprecipitation with the antibody against GRK2 (**IP: Anti GRK2**) or AKT (**IP: Anti AKT**) followed by Western blotting using indicated antibodies.

**Fig 8. Activation of AKT is necessary to miR-K3-induced endothelial cell migration and invasion.**
**(A)**. Transwell migration (**Left panel**) and Matrigel invasion (**Right panel**) assays for HUVEC which were transduced with lentivirus-mediated empty vector (**mpCDH**) or miR-K3 (**miR-K3**) expression and further with lentivirus-AKT-DN (**AKT-DN**) or its control (**pCDH**). * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(B)**. Western blotting analysis of phosphorylated AKT in HUVEC treated as in (A). The antibody against HA-tag was used to detect the transduction of AKT-DN. **(C)**. Transwell migration (**Left panel**) and Matrigel invasion (**Right panel**) assays for KSHV-infected HUVEC transduced with lentivirus-mediated a mixture of short hairpin RNAs targeting AKT (**shAKT**) or its control (**pCDH**). * P < 0.05 and *** P < 0.001 for Student’s t-test. **(D)**. Western blotting analysis of phosphorylated AKT levels in HUVEC treated as in (C). **(E)**. The mRNA expression of MMP1, 9, 10 and IL-6, 8 in HUVEC, which were transduced with lentivirus-mediated empty vector (**mpCDH**) or miR-K3 (**miR-K3**) expression and further treated with the AKT inhibitor, MK-2206 (**MK-2206**) or its control (**DMSO**), were determined by qPCR. * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(F)**. The mRNA expression of MMP1, 9, 10 and IL-6, 8 in KSHV-infected HUVEC treated with the AKT inhibitor, MK-2206 (**MK-2206**) or its control (**DMSO**) were determined by qPCR. * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test.

**Fig 9. Deletion of miR-K3 from the KSHV genome attenuates KSHV induction of endothelial cell migration and invasion.**
**(A)**. Transwell migration assay for HUVEC infected with BAC16 KSHV wide type virus (**KSHV_WT**) or BAC16 KSHV miR-K3 deletion mutant virus (**miR-K3_Mut**). * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(B)**. Matrigel invasion assay for HUVEC treated as in (A). * P < 0.05, ** P < 0.01 and *** P < 0.001 for Student’s t-test. **(C)**. The mRNA expression of MMP1, 9, 10 and IL-6, 8 in HUVEC treated as in (A) were determined by RT-qPCR. **(D)**. Western blotting analysis of expression of GRK2, CXCR2, phosphorylated AKT, and KSHV RTA in HUVEC treated as in (A) with the indicated antibodies. **(E)**. Schematic representation of the mechanism by which miR-K3 facilitates endothelial cell migration and invasion.

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References

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869. - PubMed
1. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. - PubMed
1. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280. - PubMed
1. Mesri EA, Cesarman E, Boshoff C (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719. 10.1038/nrc2888 - DOI - PMC - PubMed
1. Ganem D (1997) KSHV and Kaposi's sarcoma: the end of the beginning? Cell 91: 157–160. - PubMed

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[1] Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869. - PubMed

[2] Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869. - PubMed

[3] Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. - PubMed

[4] Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. - PubMed

[5] Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280. - PubMed

[6] Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280. - PubMed

[7] Mesri EA, Cesarman E, Boshoff C (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719. 10.1038/nrc2888 - DOI - PMC - PubMed

[8] Mesri EA, Cesarman E, Boshoff C (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707–719. 10.1038/nrc2888 - DOI - PMC - PubMed

[9] Ganem D (1997) KSHV and Kaposi's sarcoma: the end of the beginning? Cell 91: 157–160. - PubMed

[10] Ganem D (1997) KSHV and Kaposi's sarcoma: the end of the beginning? Cell 91: 157–160. - PubMed

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A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

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A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

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