Cervical keratinocytes containing stably replicating extrachromosomal HPV-16 are refractory to transformation by oncogenic H-Ras

Berger, Kristi L.; Barriga, Felicia; Lace, Michael J.; Turek, Lubomír P.; Zamba, Gideon; Domann, Frederick E.; Lee, John H.; Klingelhutz, Aloysius J.

doi:10.1016/j.virol.2006.07.039

Cited by 14 publications

(17 citation statements)

References 63 publications

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“…Very recently, it was reported that expression of HPV16 E6E7 and Hras are not sufficient for tumorigenic transformation of primary HCKs (38). One of the likely reasons for the discrepancy with our findings is that we injected cells as a mixture with Matirigel, which has been widely used to increase tumorigenicity (Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 78%

An In vitro Multistep Carcinogenesis Model for Human Cervical Cancer

et al. 2008

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Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of E6 and E7 genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 E6 and E7 with or without hTERT into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic Hras G12V (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumorinitiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer. [Cancer Res 2008;68(14):5699-705]

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Section: Discussioncontrasting

confidence: 78%

An In vitro Multistep Carcinogenesis Model for Human Cervical Cancer

et al. 2008

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“…HPVep cells express HPV genes E6 and E7 stably. Compared to normal keratinocytes, HPVep cells show partial but incomplete degradation of p53 [Sprague et al, ; Berger et al, ]. HPVep cells display features that are similar to HPV infected human keratinocytes and appear to be a suitable model for study the mechanism by which GA reduces the viability of HPV‐positive cells.…”

Section: Resultsmentioning

confidence: 99%

Gallic acid induces apoptosis in human cervical epithelial cells containing human papillomavirus type 16 episomes

Shi

Lei

Srivastava

et al. 2015

Journal of Medical Virology

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The high-risk human papillomaviruses (HPV) that infect the anogenital tract are strongly associated with the development of cervical carcinoma, which is the second most common cancer in women worldwide. Therapeutic drugs specifically targeting HPV are not available. Polyphenolic compounds have gained considerable attention because of their cytotoxic effects against a variety of cancers and certain viruses. In this study, we examined the effects of several polyphenols on cellular proliferation and death of the human cervical cancer cells and human cervical epithelial cells containing stable HPV type 16 episomes (HPVep). Our results show that three polyphenols inhibited proliferation of HeLa cells dose-dependently. Furthermore, one of the examined polyphenols, gallic acid (GA), also inhibited the proliferation of HPVep cells and exhibited significant specificity towards HPV-positive cells. The anti-proliferative effect of GA on HPVep and HeLa cells was associated with apoptosis and upregulation of p53. These results suggest that GA can be a potential candidate for the development of anti-HPV agents.

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“…PHKs and cervical epithelial cells (CEs) were obtained from the University of Massachusetts Hospital. Cervical epithelial cells containing the HPV-16 genome (CE-HPV) (27) were provided by Aloysius Klingelhutz, University of Iowa. These cells were cultured on mitomycin Ctreated J2-3T3 feeder cells in E medium composed of three parts Dulbecco's modified Eagle medium (DMEM) and one part Ham's F12 medium plus 5% fetal bovine serum (FBS), with all supplements as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

Human Papillomavirus E7 Induces Rereplication in Response to DNA Damage

Fan

Liu

Heilman

et al. 2013

J Virol

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Human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis. Genomic instability caused by HPV allows cells to acquire additional mutations required for malignant transformation. Genomic instability in the form of polyploidy has been demonstrated to play an important role in cervical carcinogenesis. We have recently found that HPV-16 E7 oncogene induces polyploidy in response to DNA damage; however, the mechanism is not known. Here we present evidence demonstrating that HPV-16 E7-expressing cells have an intact G 2 checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G 2 checkpoint and then undergo rereplication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces rereplication in human cancer cells, is upregulated in E7-expressing cells. Moreover, downregulation of Cdt1 impairs the ability of E7 to induce rereplication. These results demonstrate an important role for Cdt1 in HPV E7-induced rereplication and shed light on mechanisms by which HPV induces genomic instability.

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Cervical keratinocytes containing stably replicating extrachromosomal HPV-16 are refractory to transformation by oncogenic H-Ras

Cited by 14 publications

References 63 publications

An In vitro Multistep Carcinogenesis Model for Human Cervical Cancer

An In vitro Multistep Carcinogenesis Model for Human Cervical Cancer

Gallic acid induces apoptosis in human cervical epithelial cells containing human papillomavirus type 16 episomes

Human Papillomavirus E7 Induces Rereplication in Response to DNA Damage

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