Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

López-Ocejo, Omar; Viloria-Petit, Alicia; Bequet-Romero, Mónica; Mukhopadhyay, Debabrata; Rak, Janusz; Kerbel, Robert S.

doi:10.1038/sj.onc.1203817

Cited by 187 publications

(130 citation statements)

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“…Studies have shown that HPV 16 E6 oncoprotein can increase VEGF level in cervical cancer cells by activating its promoter. 46 It is also known that expression of HPV 16 E6/E7 in human primary keratinocytes increased the VEGF level in these cells. 38 These reports suggest that there is a relationship between oncogene E6/E7 and angiogenesis factor VEGF with the former modulating the expression of the latter.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Payne

Sun

et al. 2010

Cancer Gene Ther

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RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Payne

Sun

et al. 2010

Cancer Gene Ther

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“…1). The tumor suppressor p53 is one of the most wellcharacterized target genes of HPV-16 E6 (8,30,31) besides the PDZ domain containing proteins (25), human telomerase reverse transcriptase (hTERT) (32), vascular endothelial growth factor (VEGF) (33,34), and hypoxia-inducible factor 1· (HIF-1· ) (34). p53 was recently reported to repress the DNMT1 level in human colon carcinoma HCT116 cells (19).…”

Section: Discussionmentioning

confidence: 99%

HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53

Yeung¹,

Tsang

et al. 2010

Oncol Rep

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Abstract. The HPV-16 early proteins E6 and E7 are considered to function as oncoproteins in cervical cancer. DNA methyltransferase 1 (DNMT1) is one of the enzymes involved in epigenetic silencing of tumor suppressor genes. In the present study, the functional role and regulation of DNMT1 in HPV-16 E6 associated cervical cancer development were examined. Knockdown of E6 in HPV-16 positive human cervical carcinoma SiHa and CaSki cells led to the increase in p53, repression of DNMT1 protein and promoter activity. Moreover, p53 knockdown increased the DNMT1 protein as well as promoter activity, indicating that p53 may mediate E6 upregulation of DNMT1. In addition, E6 knockdown induced growth retardation in SiHa cells, and the effect was partially reverted by DNMT1 overexpression. The results suggest that HPV-16 E6 may act through p53/ DNMT1 to regulate the development of cervical cancer.

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“…C33A cells were cotransfected with STAT3D or control vector, and 1.2 kb of the VEGF promoter construct. The cells were harvested 6 h after transfection and luciferase activities were measured Interleukin-6 activates cervical tumor angiogenesis L-H Wei et al etiologically linked to cervical cancer, may directly activate the VEGF promoter in a p53-independent manner (Lopez-Ocejo et al, 2000). Interestingly, hypoxic stress, a common environmental feature of solid tumors, has been demonstrated to induce IL-6 expression in vascular cells and cardiomyocytes (YamauchiTakihara et al, 1995;Yan et al, 1995), implying that IL-6 may be an important mediator in hypoxia-induced angiogenesis during rapid tumor growth.…”

Section: Discussionmentioning

confidence: 99%