Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

Vliet-Gregg, Portia A.; Hamilton, Jennifer; Katzenellenbogen, Rachel A.

doi:10.1016/j.virol.2015.02.002

Cited by 18 publications

(51 citation statements)

References 36 publications

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“…The absence of significant effect of E6 or Hes1 silencing on Notch1 is suggestive of the fact that overexpression of Hes1 may not be absolutely dependent on Notch1 and could be regulated by other heterogeneously expressed transcription factors as reported earlier (48). Nevertheless, our study gains strong support from a recent report that showed existence of crosstalk between HPVE6 and Hes1 (49). To understand the possible mechanism(s) involved, we did STRING database analysis based on a series of reports from our laboratory and others on the role of AP-1 and STAT3 in cervical carcinogenesis (29,(50)(51)(52).…”

Section: Cd71supporting

confidence: 87%

Cervical Cancer Stem Cells Selectively Overexpress HPV Oncoprotein E6 that Controls Stemness and Self-Renewal through Upregulation of HES1

Tyagi

Vishnoi

Mahata

et al. 2016

Clinical Cancer Research

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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.

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Section: Cd71supporting

confidence: 87%

Cervical Cancer Stem Cells Selectively Overexpress HPV Oncoprotein E6 that Controls Stemness and Self-Renewal through Upregulation of HES1

Tyagi

Vishnoi

Mahata

et al. 2016

Clinical Cancer Research

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“…Our laboratory has previously studied the partnership between the E6 protein of HR HPV type 16 (16E6) and the host cytoplasmic protein NFX1-123 [ 32 – 34 ]. NFX1-123 is endogenously expressed in human epithelial cells, and it is increased in cervical cancer cell lines [ 35 ]. NFX1-123 has been shown to bind 16E6 [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus type 16 E6 and NFX1-123 mislocalize immune signaling proteins and downregulate immune gene expression in keratinocytes

et al. 2017

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Human papillomavirus (HPV) is the most prevalent sexually transmitted infection, affecting an estimated 11% of the world’s population. The high-risk HPV types (HR HPV) account for approximately 5% of the global burden of cancer and thus cause high morbidity and mortality. Although it is known that persistent infection with HR HPV is the greatest risk factor for developing HPV-associated cancer, and that the HPV early proteins E6 and E7 dysregulate immune detection by its host cells, the mechanisms of immune evasion by HR HPV are not well understood. Previous work in the laboratory identified the endogenous cytoplasmic host protein NFX1-123 as a binding partner of the HR HPV type 16 oncoprotein E6 (16E6). Together NFX1-123 and 16E6 affect cellular growth, differentiation, and immortalization genes and pathways. In a whole genome microarray, human foreskin keratinocytes (HFKs) stably expressing 16E6 and overexpressing NFX1-123 showed a diverse set of innate immune genes downregulated two-fold or more when compared to 16E6 cells with endogenous NFX1-123. We demonstrated that 16E6 and NFX1-123 decreased expression of pro-inflammatory cytokines and interferon-stimulated genes (ISGs) in 16E6 HFKs at the mRNA and protein level. Knock down of NFX1-123 in 16E6 HFKs resulted in a derepression of innate immune genes, pointing to the requirement of NFX1-123 for immune regulation in the context of 16E6. Studies using immunofluorescent microscopy revealed that 16E6 and NFX1-123 disturbed the normal localization of signaling proteins involved in initiating the immune response. This study identifies NFX1-123 as a critical host protein partner through which 16E6 is able to subvert the immune response and in turn permit a long-lived HR HPV infection.

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“…A significant correlation exists between the presence of HPV DNA and cervical cancer development (21). EMT induction may directly contribute to HPV E6 and E7 viral proteins (22), and the HPV-18 E6 oncoprotein has been expressed in keratinocytes, leading to a morphological conversion to a fibroblast-like morphology (23).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Suppression of E-Cadherin by HPV-16 E6 and E7 Oncogenes is Independent of Hypermethylation of E-Cadherin Promoter

Faghihloo

Sadeghizadeh

Shahmahmoodi

et al. 2016

Iran Red Crescent Med J

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Background: Cervical cancer is one of the most common cancers observed in women worldwide, and its development is related to E6 and E7 two viral oncoproteins of high-risk human papillomavirus (HPV) types. Aberrant expression of E-cadherin, which is associated with epithelial-to-mesenchymal transition (EMT), is frequently observed in cervical cancer. Objectives: The mechanisms underlying E-cadherin suppression in cervical cancer are not clear; therefore, this experimental study from Iran was designed to elucidate the relationship of DNA methyltransferase expression and E-cadherin promoter methylation with E-cadherin expression in HPV-16 E6-and E7-expressing cells. Materials and Methods: Real-time PCR and western blot were used to determine the effects of HPV-16 E6 and E7 on E-cadherin, DNMT1, DNMT3a, and DNMT3b expression in HCT-116 cell line. We also analyzed E-cadherin promoter methylation in cells expressing HPV-16 E6 and E7 oncoproteins by bisulfite sequencing. Results: HPV-16 E6 and E7 proteins reduced E-cadherin expression 3.7 and 2.2 times when compared with control cells (P = 0.0221 and P = 0.0461, respectively). This reduction was greater in HPV-16 E6-expressing cells than in HPV-16 E7-expressing cells. Although HPV-16 E6 and E7 increased DNA methyltransferase 1 expression 2.6 and 3.4 times, respectively (P = 0.0133 and P = 0.0113) when compared with control cells, they was no E-cadherin promoter methylation. Conclusions: Unlike other cancer-associated viruses (HBV, HCV, and EBV), reduction in E-cadherin expression in HPV-16 E6-and E7-expressing cells is not due to hypermethylation of the E-cadherin promoter.

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Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

Cited by 18 publications

References 36 publications

Cervical Cancer Stem Cells Selectively Overexpress HPV Oncoprotein E6 that Controls Stemness and Self-Renewal through Upregulation of HES1

Cervical Cancer Stem Cells Selectively Overexpress HPV Oncoprotein E6 that Controls Stemness and Self-Renewal through Upregulation of HES1

Human papillomavirus type 16 E6 and NFX1-123 mislocalize immune signaling proteins and downregulate immune gene expression in keratinocytes

Transcriptional Suppression of E-Cadherin by HPV-16 E6 and E7 Oncogenes is Independent of Hypermethylation of E-Cadherin Promoter

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