Cervical cancer stem cells selectively overexpress HPV oncoprotein E6 that controls stemness and self-renewal through upregulation of HES1

Tyagi, Abhishek, Vishnoi, Kanchan, Mahata, Sutapa, Verma, Gaurav, Srivastava, Yogesh, Masaldan, Shashank, Roy, Bal Gangadhar, Bharti, Alok C. and Das, Bhudev C. 2016, Cervical cancer stem cells selectively overexpress HPV oncoprotein E6 that controls stemness and self-renewal through upregulation of HES1, Clinical cancer research, vol. 22, no. 16, pp. 4170-4184, doi: 10.1158/1078-0432.CCR-15-2574.

Attached Files
Name Description MIMEType Size Downloads

Title Cervical cancer stem cells selectively overexpress HPV oncoprotein E6 that controls stemness and self-renewal through upregulation of HES1
Author(s) Tyagi, Abhishek
Vishnoi, Kanchan
Mahata, Sutapa
Verma, Gaurav
Srivastava, Yogesh
Masaldan, ShashankORCID iD for Masaldan, Shashank orcid.org/0000-0003-4960-4983
Roy, Bal Gangadhar
Bharti, Alok C.
Das, Bhudev C.
Journal name Clinical cancer research
Volume number 22
Issue number 16
Start page 4170
End page 4184
Total pages 15
Publisher American Association for Cancer Research
Place of publication Philadelphia, Pa.
Publication date 2016-08-15
ISSN 1078-0432
1557-3265
Summary PURPOSE: Perturbation of keratinocyte differentiation by E6/E7 oncoproteins of high-risk human papillomaviruses that drive oncogenic transformation of cells in squamocolumnar junction of the uterine cervix may confer "stem-cell like" characteristics. However, the crosstalk between E6/E7 and stem cell signaling during cervical carcinogenesis is not well understood. We therefore examined the role of viral oncoproteins in stem cell signaling and maintenance of stemness in cervical cancer.

EXPERIMENTAL DESIGN: Isolation and enrichment of cervical cancer stem-like cells (CaCxSLCs) was done from cervical primary tumors and cancer cell lines by novel sequential gating using a set of functional and phenotypic markers (ABCG2, CD49f, CD71, CD133) in defined conditioned media for assessing sphere formation and expression of self-renewal and stemness markers by FACS, confocal microscopy, and qRT-PCR. Differential expression level and DNA-binding activity of Notch1 and its downstream targets in CaCxSLCs as well as silencing of HPVE6/Hes1 by siRNA was evaluated by gel retardation assay, FACS, immunoblotting, and qRT-PCR followed by in silico and in vivo xenograft analysis.

RESULTS: CaCxSLCs showed spheroid-forming ability, expressed self-renewal and stemness markers Oct4, Sox2, Nanog, Lrig1, and CD133, and selectively overexpressed E6 and HES1 transcripts in both cervical primary tumors and cancer cell lines. The enriched CaCxSLCs were highly tumorigenic and did recapitulate primary tumor histology in nude mice. siRNA silencing of HPVE6 or Hes1 abolished sphere formation, downregulated AP-1-STAT3 signaling, and induced redifferentiation.

CONCLUSIONS: Our findings suggest the possible mechanism by which HPVE6 potentially regulate and maintain stem-like cancer cells through Hes1.
Language eng
DOI 10.1158/1078-0432.CCR-15-2574
Field of Research 111201 Cancer Cell Biology
1112 Oncology And Carcinogenesis
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, American Association for Cancer Research
Persistent URL http://hdl.handle.net/10536/DRO/DU:30090708

Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 24 times in TR Web of Science
Scopus Citation Count Cited 28 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 97 Abstract Views, 1 File Downloads  -  Detailed Statistics
Created: Thu, 19 Jan 2017, 08:16:31 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.