Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway
Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.
Errataetall: |
ErratumIn: PLoS Pathog. 2022 Jan 7;18(1):e1010232. - PMID 34995339 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2020 |
---|---|
Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
---|---|
Enthalten in: |
PLoS pathogens - 16(2020), 8 vom: 10. Aug., Seite e1008730 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Li, Wan [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 07.10.2020 Date Revised 07.01.2022 published: Electronic-eCollection ErratumIn: PLoS Pathog. 2022 Jan 7;18(1):e1010232. - PMID 34995339 Citation Status MEDLINE |
---|
doi: |
10.1371/journal.ppat.1008730 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM313518912 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM313518912 | ||
003 | DE-627 | ||
005 | 20231225150741.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2020 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1371/journal.ppat.1008730 |2 doi | |
028 | 5 | 2 | |a pubmed24n1045.xml |
035 | |a (DE-627)NLM313518912 | ||
035 | |a (NLM)32776977 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Li, Wan |e verfasserin |4 aut | |
245 | 1 | 0 | |a Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway |
264 | 1 | |c 2020 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 07.10.2020 | ||
500 | |a Date Revised 07.01.2022 | ||
500 | |a published: Electronic-eCollection | ||
500 | |a ErratumIn: PLoS Pathog. 2022 Jan 7;18(1):e1010232. - PMID 34995339 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
650 | 7 | |a Interferon Regulatory Factors |2 NLM | |
650 | 7 | |a SPAG9 protein, human |2 NLM | |
650 | 7 | |a VEGFA protein, human |2 NLM | |
650 | 7 | |a Vascular Endothelial Growth Factor A |2 NLM | |
650 | 7 | |a Viral Proteins |2 NLM | |
650 | 7 | |a viral interferon regulatory factors |2 NLM | |
650 | 7 | |a Mitogen-Activated Protein Kinase 9 |2 NLM | |
650 | 7 | |a EC 2.7.1.24 |2 NLM | |
650 | 7 | |a Mitogen-Activated Protein Kinase 8 |2 NLM | |
650 | 7 | |a EC 2.7.11.24 |2 NLM | |
700 | 1 | |a Wang, Fei |e verfasserin |4 aut | |
700 | 1 | |a Shi, Jiale |e verfasserin |4 aut | |
700 | 1 | |a Feng, Qi |e verfasserin |4 aut | |
700 | 1 | |a Chen, Yuheng |e verfasserin |4 aut | |
700 | 1 | |a Qi, Xiaoyu |e verfasserin |4 aut | |
700 | 1 | |a Wang, Cong |e verfasserin |4 aut | |
700 | 1 | |a Lu, Hongmei |e verfasserin |4 aut | |
700 | 1 | |a Lu, Zhongmou |e verfasserin |4 aut | |
700 | 1 | |a Jia, Xuemei |e verfasserin |4 aut | |
700 | 1 | |a Yan, Qin |e verfasserin |4 aut | |
700 | 1 | |a Gao, Shou-Jiang |e verfasserin |4 aut | |
700 | 1 | |a Lu, Chun |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t PLoS pathogens |d 2005 |g 16(2020), 8 vom: 10. Aug., Seite e1008730 |w (DE-627)NLM158124782 |x 1553-7374 |7 nnns |
773 | 1 | 8 | |g volume:16 |g year:2020 |g number:8 |g day:10 |g month:08 |g pages:e1008730 |
856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.ppat.1008730 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 16 |j 2020 |e 8 |b 10 |c 08 |h e1008730 |