PMID- 31801855
OWN - NLM
STAT- MEDLINE
DCOM- 20200821
LR  - 20210903
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 94
IP  - 5
DP  - 2020 Feb 14
TI  - Kaposi's Sarcoma-Associated Herpesvirus Viral Interleukin-6 Signaling Upregulates 
      Integrin beta3 Levels and Is Dependent on STAT3.
LID - 10.1128/JVI.01384-19 [doi]
LID - e01384-19
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of two 
      B-cell lymphoproliferative diseases and Kaposi's sarcoma, an 
      endothelial-cell-driven cancer. KSHV viral interleukin-6 (vIL-6) is a viral 
      homolog of human IL-6 (hIL-6) that is expressed in KSHV-associated malignancies. 
      Previous studies have shown that the expression of the integrin beta3 (ITGB3) 
      subunit is induced upon KSHV infection. Here we report that KSHV vIL-6 is able to 
      induce the expression of ITGB3 and increase surface expression of the alphaVbeta3 
      integrin heterodimer. We demonstrated using small interfering RNA (siRNA) 
      depletion and inhibitor studies that KSHV vIL-6 can increase ITGB3 by inducing 
      STAT3 signaling. Furthermore, we found that secreted vIL-6 is capable of inducing 
      ITGB3 in endothelial cells in a paracrine manner. Importantly, the ability to 
      induce ITGB3 in endothelial cells seems to be specific to vIL-6, as 
      overexpression of hIL-6 alone did not affect levels of this integrin. Our lab and 
      others have previously shown that vIL-6 can induce angiogenesis, and we 
      investigated whether ITGB3 was involved in this process. We found that siRNA 
      depletion of ITGB3 in vIL-6-expressing endothelial cells resulted in a decrease 
      in adhesion to extracellular matrix proteins. Moreover, depletion of ITGB3 
      hindered the ability of vIL-6 to promote angiogenesis. In conclusion, we found 
      that vIL-6 can singularly induce ITGB3 and that this induction is dependent on 
      vIL-6 activation of the STAT3 signaling pathway.IMPORTANCE Kaposi's 
      sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human 
      malignancies: multicentric Castleman's disease, primary effusion lymphoma, and 
      Kaposi's sarcoma. Kaposi's sarcoma is a highly angiogenic tumor that arises from 
      endothelial cells. It has been previously reported that KSHV infection of 
      endothelial cells leads to an increase of integrin alphaVbeta3, a molecule observed to 
      be involved in the angiogenic process of several malignancies. Our data 
      demonstrate that the KSHV protein viral interleukin-6 (vIL-6) can induce integrin 
      beta3 in an intracellular and paracrine manner. Furthermore, we showed that this 
      induction is necessary for vIL-6-mediated cell adhesion and angiogenesis, 
      suggesting a potential role of integrin beta3 in KSHV pathogenesis and development 
      of Kaposi's sarcoma.
CI  - Copyright (c) 2020 American Society for Microbiology.
FAU - Rivera-Soto, Ricardo
AU  - Rivera-Soto R
AD  - Curriculum in Genetics and Molecular Biology, University of North Carolina at 
      Chapel Hill, Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, North Carolina, USA.
FAU - Dissinger, Nathan J
AU  - Dissinger NJ
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, North Carolina, USA.
FAU - Damania, Blossom
AU  - Damania B
AD  - Curriculum in Genetics and Molecular Biology, University of North Carolina at 
      Chapel Hill, Chapel Hill, North Carolina, USA damania@med.unc.edu.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, North Carolina, USA.
AD  - Department of Microbiology and Immunology, University of North Carolina at Chapel 
      Hill, Chapel Hill, North Carolina, USA.
LA  - eng
GR  - P01 CA019014/CA/NCI NIH HHS/United States
GR  - R01 CA163217/CA/NCI NIH HHS/United States
GR  - R01 DE028211/DE/NIDCR NIH HHS/United States
GR  - T32 GM007092/GM/NIGMS NIH HHS/United States
GR  - R01 CA096500/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200214
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Integrin beta3)
RN  - 0 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Viral Proteins)
RN  - Multi-centric Castleman's Disease
SB  - IM
MH  - Castleman Disease/virology
MH  - Endothelial Cells/metabolism/virology
MH  - Herpesviridae Infections/*metabolism
MH  - Herpesvirus 8, Human/*physiology
MH  - Humans
MH  - Integrin beta3/genetics/*metabolism
MH  - Interleukin-6/*metabolism
MH  - Lymphoma, Primary Effusion/virology
MH  - STAT3 Transcription Factor/*metabolism
MH  - Sarcoma, Kaposi/*metabolism/virology
MH  - *Signal Transduction
MH  - Up-Regulation
MH  - Viral Proteins/*metabolism
PMC - PMC7022358
OTO - NOTNLM
OT  - Kaposi's sarcoma-associated herpesvirus
OT  - integrin beta3
OT  - viral IL-6
EDAT- 2019/12/06 06:00
MHDA- 2020/08/22 06:00
PMCR- 2020/08/14
CRDT- 2019/12/06 06:00
PHST- 2019/08/28 00:00 [received]
PHST- 2019/11/26 00:00 [accepted]
PHST- 2019/12/06 06:00 [pubmed]
PHST- 2020/08/22 06:00 [medline]
PHST- 2019/12/06 06:00 [entrez]
PHST- 2020/08/14 00:00 [pmc-release]
AID - JVI.01384-19 [pii]
AID - 01384-19 [pii]
AID - 10.1128/JVI.01384-19 [doi]
PST - epublish
SO  - J Virol. 2020 Feb 14;94(5):e01384-19. doi: 10.1128/JVI.01384-19. Print 2020 Feb 
      14.