Cyclooxygenase-2 Transcription Is Regulated by Human Papillomavirus 16 E6 and E7 Oncoproteins: Evidence of a Corepressor/Coactivator Exchange

Abstract

Cyclooxygenase (COX-2) is overexpressed in human papillomavirus (HPV)-induced diseases, including cervical cancer. Although HPV E6 and E7 oncoproteins have been causally linked to cervical carcinogenesis, their effects on COX-2 gene expression are unknown. Increased levels of COX-2 mRNA, protein, and prostaglandin E 2 synthesis were detected in HPV16 E6-and E7-expressing cervical cancer cells (CaSki and SiHa) compared with an uninfected cervical cancer cell line (C33A). HPV16 E6 and E7 oncoproteins induced COX-2 transcription by activating the epidermal growth factor receptor (EGFR)!Ras!mitogen-activated protein kinase pathway. Interestingly, HPV16 oncoproteins stimulated EGFR signaling, in part, by inducing the release of amphiregulin, an EGFR ligand. The inductive effects of HPV16 E6 and E7 were mediated by enhanced binding of activator protein-1 to the cyclic AMP (cAMP)-responsive element (À59/À53) of the COX-2 promoter. The potential contribution of coactivators and corepressors to HPV16 E6-and E7-mediated induction of COX-2 was also investigated. Chromatin immunoprecipitation assays indicated that E6 and E7 oncoproteins induced the recruitment of phosphorylated c-Jun, c-Fos, UbcH5, and cAMP-responsive element binding protein-binding protein/ p300 to the COX-2 promoter. In contrast, E6 and E7 inhibited the binding of the histone deacetylase 3-nuclear receptor corepressor (NCoR) complex to the COX-2 promoter. Moreover, overexpression of NCoR blocked E6-and E7-mediated stimulation of the COX-2 promoter. Taken together, these results indicate that HPV16 E6 and E7 oncoproteins stimulated COX-2 transcription by inducing a corepressor/coactivator exchange. To our knowledge, this study also provides the first evidence that NCoR can function as a repressor of COX-2 gene expression. [Cancer Res 2007;67(8):3976-85]

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

“…To inhibit production of PGE 2 by COX-2, cells were treated with celecoxib, a COX-2-specific inhibitor. Celecoxib effectively blocks production of PGE 2 from COX-2 (2,5,17). Although PGE 2 production was blocked by celecoxib, EGFR expression was still down-regulated in both HCT-116-COX-2 and H460-COX-2 cells (Fig.…”

“…Overexpression of cyclooxygenase-2 (COX-2) has been detected in malignant tumors of a variety of tissues, including colon, prostate, lung, breast, and uterine cervix (1)(2)(3)(4)(5). COX-2 is known to play an important role in carcinogenesis by stimulating growth, survival, invasion, metastasis, and angiogenesis of tumor cells (3,4,(6)(7)(8)(9), but its exact role in cancer development has not been well understood.…”

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

“…49 Salicyclic acid is also used as an inexpensive treatment for cutaneous warts, possibly affecting HPV E6 and E7 protein action on cyclooxygenase-2 transcription. 50 Infection with HPV has been regarded as restricted to keratinocytes, and that both HPV L1 IHC and CISH were detected HPV in the cytoplasm of trophoblast initially raised concerns that this was a non-specific reaction. However, strong cytoplasmic L1 capsid protein mRNA expression has also been reported in a trophoblast cell culture experimentally infected with HPV.…”

Restoration of tumor suppressor p53 by differentially regulating pro- and anti-p53 networks in HPV-18-infected cervical cancer cells

“…As Cox-2 negatively regulates p53, it is reasonable to suggest that the aberrant constitutive overexpression of Cox-2 noted in various malignancies could continue to negatively affect p53 function in tumors that harbor wild-type p53. Hence the chances of Cox-2 suppressing the p53-network in cervical cancer cells appears logical and therefore its inhibition might as well improve the clinical prognosis of cervical cancer patients more because Cox-2 contributes to most of the inflammatory processes during different stages of virally infiltrated cancers (Subbaramaiah and Dannenberg, 2007).…”