Progressive Loss of Sensitivity to Growth Control by Retinoic Acid and Transforming Growth Factor-Beta at Late Stages of Human Papillomavirus Type 16-Initiated Transformation of Human Keratinocytes

Creek, Kim E.; Geslani, Gemma; Batova, Ayse; Pirisi, Lucia

doi:10.1007/978-1-4899-0949-7_11

Cited by 40 publications

(45 citation statements)

References 37 publications

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“…60, 61), and enhanced radiation sensitivity of cultivated cells. Several in vitro studies described functional interference by HPV16 with retinoid signaling in keratinocyte differentiation and transformation (62)(63)(64)(65)(66)(67). Whether this interference contributes to HPV-related pathogenesis is unclear, yet it may offer novel treatment options.…”

Section: Discussionmentioning

confidence: 99%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

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High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

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Section: Discussionmentioning

confidence: 99%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

View full text Add to dashboard Cite

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“…TGF-b treatment leads to decreased expression of the HPV E6 and E7 oncoproteins. As a consequence, freshly derived HPV containing epithelial cell lines remain sensitive to TGFb (Creek et al, 1995). In a keratinocyte based in vitro progression model, TGF-b resistance occurs in parallel with the acquisition of resistance to dierentiation cues such as retinoic acid, and is characterized by the loss of transcriptional sensitivity of HPV oncogene expression toward TGF-b .…”

Section: Abrogation Of Cytostatic Activities Of Cytokines By Hpv E7mentioning

confidence: 99%

Biological activities and molecular targets of the human papillomavirus E7 oncoprotein

et al. 2001

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The human papillomavirus (HPV) E7 protein is one of only two viral proteins that remain expressed in HPVassociated human cancers. HPV E7 proteins share structural and functional similarities with oncoproteins encoded by other small DNA tumor viruses such as adenovirus E1A and SV40 large tumor antigen. The HPV E7 protein plays an important role in the viral life cycle by subverting the tight link between cellular dierentiation and proliferation in normal epithelium, thus allowing the virus to replicate in dierentiating epithelial cells that would have normally withdrawn from the cell division cycle. The transforming activities of E7 largely re¯ect this important function. Oncogene (2001) 20, 7888 ± 7898.

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“…TGF␤-dependent repression of E6 and E7 transcription appears to be mediated by a TGF␤-response element (TRE) located within the principal viral promoter and enhancer region (long control region, LCR) (Canhoto et al, 1997). Primary cervical keratinocytes that are immortalized by HPV in vitro and are passaged in culture for prolonged periods of time, eventually lose their sensitivity to the inhibitory effects of TGF␤1 (Creek et al, 1995;De Geest et al, 1994). In these TGF␤-resistant cells, transcription of the E6 and E7 genes is no longer repressed by TGF␤ (Creek et al, 1995).…”

mentioning

confidence: 99%

“…A particularly interesting biological characteristic associated with malignant progression of cervical epithelial cells is their progressive loss of responsiveness to TGF␤ (Braun et al, 1990;Creek et al, 1995;De Geest et al, 1994;Kang et al, 1998;. TGF␤ belongs to a multifunctional family of growth factors that tightly regulate basic cellular functions such as proliferation, differentiation and extracellular matrix turnover.…”

mentioning

confidence: 99%

Structural alterations of transforming growth factor-? receptor genes in human cervical carcinoma

et al. 1999

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The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor‐β (TGFβ)‐mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFβ resistance, we screened the 7 exons of the type II (TβR‐II) TGFβ receptor and the 9 exons of the type I (TβR‐I) TGFβ receptor genes for mutations in 16 paraffin‐embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G→T transversion in exon 3 of TβR‐II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor. In one tumor, a silent A→C transversion mutation that may affect mRNA splicing was present in exon 6 of TβR‐I. In addition, 7 of 16 cases were heterozygous for a G→A polymorphism in intron 7 of TβR‐I. Finally, we identified a 9 base pair in‐frame germline deletion in exon 1 of TβR‐I resulting in loss of 3 of 9 sequential alanine residues at the N‐terminus in 6 of 16 cases. Analysis of specimens from case‐control studies indicated that carriers of this del(GGC)3 TβR‐I variant allele may be at a increased risk for the development of cervical carcinoma (p=0.22). Furthermore, the response of cells expressing the variant receptor to TGFβ was diminished. Our results support the notion that diverse alterations in the TGFβ signaling pathway may play a role in the development of cervical cancer. Int. J. Cancer 82:43–51, 1999. © 1999 Wiley‐Liss, Inc.

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Progressive Loss of Sensitivity to Growth Control by Retinoic Acid and Transforming Growth Factor-Beta at Late Stages of Human Papillomavirus Type 16-Initiated Transformation of Human Keratinocytes

Cited by 40 publications

References 37 publications

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Biological activities and molecular targets of the human papillomavirus E7 oncoprotein

Structural alterations of transforming growth factor-? receptor genes in human cervical carcinoma

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