The integration of HPV-18 DNA in cervical carcinoma

Corden, Sally; Sant-Cassia, L J; Easton, Andrew J.; Morris, Alan

doi:10.1136/mp.52.5.275

Cited by 94 publications

(87 citation statements)

References 46 publications

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“…However, in cervical cancer cells HR-HPV DNA is often integrated into the host genome (13,42,46). Although the integrated genomes retain the E6 and E7 open reading frames (ORFs), the viral E2 ORF is often disrupted, resulting in loss of the E2 protein (2,5). In other cases, the viral E1 ORF is disrupted (26).…”

mentioning

confidence: 99%

E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death

Parish

Kowalczyk

Chen

et al. 2006

J Virol

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The E2 proteins from oncogenic (high-risk) human papillomaviruses (HPVs) can induce apoptotic cell death in both HPV-transformed and non-HPV-transformed cells. Here we show that the E2 proteins from HPV type 6 (HPV6) and HPV11, two nononcogenic (low-risk) HPV types, fail to induce apoptosis. Unlike the high-risk HPV16 E2 protein, these low-risk E2 proteins fail to bind p53 and fail to induce p53-dependent transcription activation. Interestingly, neither the ability of p53 to activate transcription nor the ability of p53 to bind DNA, are required for HPV16 E2-induced apoptosis in non-HPV-transformed cells. However, mutations that reduce the binding of the HPV16 E2 protein to p53 inhibit E2-induced apoptosis in non-HPV-transformed cells. In contrast, the interaction between HPV16 E2 and p53 is not required for this E2 protein to induce apoptosis in HPV-transformed cells. Thus, our data suggest that this high-risk HPV E2 protein induces apoptosis via two pathways. One pathway involves the binding of E2 to p53 and can operate in both HPV-transformed and non-HPV-transformed cells. The second pathway requires the binding of E2 to the viral genome and can only operate in HPV-transformed cells.Human papillomaviruses (HPVs) that infect the genital tract can be divided into two groups. High-risk (HR) or oncogenic viral types, such as HR-HPV type 16 (HR-HPV16) and HR-HPV18, are associated with cervical cancer and some other human tumors (7). In contrast, low-risk (LR) or nononcogenic types, such as LR-HPV6 and LR-HPV11, cause genital warts and are not associated with cancer. An appreciation of the differences between the HR-and LR-HPV types is central to an understanding of the origins of cervical cancer and other HPV-induced diseases. The E6 and E7 proteins from HR-HPV have long been recognized to be oncoproteins (33), and significant differences in the properties of E6 and E7 proteins from HR and LR viral types have been identified. For example, the E6 proteins from HR-HPV16 and HR-HPV18 bind to the p53 tumor suppressor protein, resulting in increased degradation of p53 (22,41). Although the E6 proteins from LR-HPV6 and LR-HPV11 can also bind to p53, these interactions do not increase p53 degradation (6,28,41). The E7 proteins from HR-and LR-HPV types also show significant differences. Although the E7 proteins from HR-HPV16 and HR-HPV18 bind to the retinoblastoma tumor suppressor protein p105Rb in vitro, the E7 proteins from LR-HPV6 and LR-HPV11 bind this protein poorly (16,34). Interesting though these differences in the E6 and E7 proteins are, it is important to note that the HR-HPV infections are relatively common and the presence of an HR-HPV type does not therefore always result in oncogenesis (36). Thus, although these differences in the E6 and E7 proteins from different HPV types are undoubtedly important in the establishment and/or progression of cervical cancer, they cannot in themselves completely explain why some HPV types are oncogenic while others are not.In cervical warts the HPV genome exists as an extrach...

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mentioning

confidence: 99%

E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death

Parish

Kowalczyk

Chen

et al. 2006

J Virol

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“…The frequency of integration of HPV16 was significantly associated with severity of disease (Liu et al, 2008;Szostek et al, 2008). Transcriptional repression of the early promoter by E2 is lost during successful integration, as integrants are truncated forms of the HPV genome lacking full length E2 (Corden et al, 1999).…”

Section: E6 and E7 Expression And Integrationmentioning

confidence: 99%

“…In contrast, high grade CIN lesions have high levels of E6 and E7 mRNA in all layers of the epithelium. The majority of HPV-18-associated carcinomas (Cullen et al, 1991;Pirami et al, 1997;Corden et al, 1999) and most HPV-16-associated carcinomas (Cullen et al, 1991;Pirami et al, 1997;Melsheimer et al, 2004) are found to have HPV genomic integrants within the host genome. This critical step in immortalisation of infected cells allows high and unregulated expression of E6 and E7 protein (Schwarz et al, 1985).…”

Section: E6 and E7 Expression And Integrationmentioning

confidence: 99%

“…E6 and E7 mRNA is found throughout high grade CIN lesions, low grade neoplasias and carcinomas (Cullen et al, 1991;Yukawa et al, 1996;Pirami et al, 1997;Corden et al, 1999). E6 and E7 are HPV oncoproteins that function synergistically during the natural lifecycle of HPV, to restrain cells from cell cycle arrest .…”

Section: Metastatic Lung Tumourmentioning

confidence: 99%

“…To maintain an immortalised cell phenotype, E6 and E7 must be continually expressed from the HPV genome, whether it be from an integrant or episomal DNA (Jeon et al, 1995;Corden et al, 1999;Francis et al, 2000;Wentzensen et al, 2004;. This requires the activation of the early promoter.…”

Section: E6 and E7 Are Tumour Specific Antigensmentioning

confidence: 99%

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Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

Haigh¹

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Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

Rey¹,

Izquierdo²,

Caja³

et al. 2009

Arthritis & Rheumatism

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Objective. Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis.Methods. Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice. Cell infiltration and angiogenesis were analyzed in the grafts by immunohistochemical studies. The role of vascular endothelial growth factor (VEGF), CXCL12, and hypoxia-inducible transcription factor 1␣ (HIF-1␣) in these processes was investigated using specific antagonists or small interfering RNA (siRNA)-mediated down-regulation of HIF-1␣ in fibroblasts.Results. Inflammatory (OA and RA) synovial fibroblasts, compared with healthy dermal or synovial tissue fibroblasts, induced a significant enhancement in myeloid cell infiltration and angiogenesis in immunodeficient mice. These activities were associated with increased constitutive and hypoxia-induced expression of VEGF, but not CXCL12, in inflammatory fibroblasts compared with healthy fibroblasts. VEGF and CXCL12 antagonists significantly reduced myeloid cell infiltration and angiogenesis. Furthermore, targeting of HIF-1␣ expression by siRNA or of HIF-1␣ transcriptional activity by the small molecule chetomin in RA fibroblasts significantly reduced both responses.Conclusion. These results demonstrate that chronic synovial inflammation is associated with stable fibroblast changes that, under hypoxic conditions, are sufficient to induce inflammatory cell recruitment and angiogenesis, both of which are processes relevant to the perpetuation of chronic inflammation.Fibroblasts are ubiquitous mesenchymal cells with vital functions during development and adulthood. They synthesize the extracellular matrix components of connective tissues needed for homeostasis and reparative responses. During development, interactions between mesenchymal and other cell lineages are necessary for the formation of many organs, and fibroblasts are sufficient to provide the positional cues required for the induction and development of the different tissues (1,2). In the adult, multiple evidence points to specialized fibroblasts as a major force in the regulation of cell homing, migration, and differentiation of highly dynamic cell populations, such as cells of the immune system or the bone marrow (3,4). With regard to the pathologic

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The integration of HPV-18 DNA in cervical carcinoma

Cited by 94 publications

References 46 publications

E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death

E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

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