Papillomavirus Type 16 Oncogenes Downregulate Expression of Interferon-Responsive Genes and Upregulate Proliferation-Associated and NF-κB-Responsive Genes in Cervical Keratinocytes

Abstract

Infection with high-risk human papillomaviruses (HPV) is a major risk factor for development of cervical cancer. Expression of the HPV E6 and E7 oncoproteins increases in differentiating keratinocytesHuman papillomaviruses (HPVs) are small DNA tumor viruses that replicate in differentiating keratinocytes of the epidermis and anogenital tract (59). The E6 and E7 viral genes are expressed at low levels in proliferating basal cells, but transcription is activated as cells enter the terminal differentiation pathway (11, 16). E6 and E7 delay keratinocyte differentiation, reactivate host DNA synthesis, and stimulate cell cycle progression (60), allowing the virus to utilize host DNA synthetic enzymes to replicate its genome. HPVs induce benign warts and papillomas; however, infection with high-risk types ) is a major risk factor for the development of cervical cancer (reviewed in reference 60). The E6 and E7 genes are particularly important because they are retained and expressed in most cervical carcinomas, and continued expression is required to maintain the malignant phenotype (55).An early step in HPV-associated carcinogenesis is perturbation of cellular gene expression by the E6 and E7 oncoproteins.

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

“…[40][41][42] HPV 16 E5 interacts with HLA I heavy chain preventing transport of the major histocompatibility class I (MHC I in mice; HLA class I in humans) to the cell surface. 43 The E5 expression was accompanied by a decreased expression of HLA-A2 and had a functional impact on recognition of E5 expressing cells by HPV specific CD81 T cells.…”

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

“…Our identification of astrocytoma cases with high immunostaining scores, in the absence of mutations in coding sequences of the p53 gene, suggests that p53 may act through downstream mechanisms that are distinct from purely tumour-suppressive functions in its native form, or as a dominant-negative regulator in mutant or oncogenic forms. Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins were identified and found to be potential oncogenes (Scheffner et al, 1990;Bargonetti et al, 1991;Debbas and White, 1993;Nees et al, 2001;Cobbs et al, 2003;Dai et al, 2003;Calogero et al, 2004). Proteins implicated in cell cycle regulation may serve as downstream effectors of p53 function (Dulic et al, 1994;Agarwal et al, 1995;de Toledo et al, 1998;Skomedal et al, 1999;Ghimenti et al, 2003).…”

“…Indeed, p53 expression is also increased in cells treated with DNA-damaging agents (Okada et al, 2003). Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins have been identified and found to be potential oncogenes (Nees et al, 2001). Alternatively, increased p53 protein expression might be representative of progressive chromosomal damage, such as cells treated in vitro with ultraviolet or gamma irradiation (Zhang et al, 1993;Agami and Bernards, 2000;Denko et al, 2000).…”

Gene expression reveals two distinct groups of anal carcinomas with clinical implications

“…The resulting hierarchical clustering (Figure 3Ad) was highly similar to both the hierarchical clustering of our unsupervised analysis (Figure 3Aa) and to the hierarchical clustering of genes selected by performing two independent statistical analyses between the two tumour groups (Figure 3Ab and Ac). Similarly, to investigate the possible transcriptional influence of high-risk HPV, we performed hierarchical cluster analysis on genes reported differentially Figure 3 (A) Hierarchical clustering of the unsupervised analysis on (Aa) the selection of 8449 probes, (Ab) the 337 individual genes defined by the Ttest, (Ac) the 363 individual genes defined by the SAM analysis together with collections of genes described by others relevant to our study and included within the group of 8449 probes, (Ad) HPV16-induced gene expression (Alazawi et al, 2002), (Ae) HPV16 E6/E7-induced gene expression (Nees et al, 2001), (Af) HPV31-induced gene expression (Chang and Laimins, 2000), (Ag) Gene expression in SSC (Loercher et al, 2004), (Ah) E2F-regulated genes (Ishida et al, 2001), (Ai) HPV16-and HPV18-induced gene expression (Santin et al, 2005) and, finally, (Aj) HPV18 E6/E7-induced gene expression (GarnerHamrick et al, 2004). (B) The total number of genes within each report cited.…”

“…(C) Hierarchical cluster analysis based on (Ca) CDKN2A (p16) transcriptionally regulated genes and (Cb) E2F-regulated genes, as reported by Vernell et al, 2003. expressed in several systems related to high-risk HPV infection. This included gene expression profiling of a mouse SCC model (Loercher et al, 2004), effect on overall gene expression associated with integration of HPV16 in cervix SCC (Alazawi et al, 2002), gene expression profiling of primary HPV16-and HPV18-infected early stage cervical cancer (Santin et al, 2005), effect of HPV18 E6 and E7 on global gene expression in an organotypic keratinocytes culture system (Garner-Hamrick et al, 2004), effect of HPV16 E6 and/or E7 on global gene expression in differentiating cervical keratinocytes (Nees et al, 2001) and, finally, effect of HPV31 on global gene expression in normal human keratinocytes (Chang and Laimins, 2000). Again, the resulting hierarchical cluster (Figure 3Ae-Aj) was practically identical compared to our unsupervised analysis ( Figure 3Aa).…”