Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1

Lace, Michael J.; Anson, James R.; Klingelhutz, Aloysius J.; Harada, Hisashi; Taniguchi, Tadatsugu; Bossler, Aaron D.; Haugen, Thomas H.; Turek, Lubomír P.

doi:10.1093/carcin/bgp150

Cited by 22 publications

(14 citation statements)

References 54 publications

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“…Notably, there are complex interactions between HPV and IRFs. IRF1 and 2 can activate the HPV16 oncogene promoter (43,44) and the E5 oncoprotein induces IRF1 (45). In contrast, the E7 oncoprotein can suppress IFNg-induced IRF1 expression and interferes with the effectiveness of the immune response (46,47).…”

Section: Discussionmentioning

confidence: 99%

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

et al. 2016

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Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from lowgrade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo. Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

et al. 2016

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“…Under optimal conditions, such cells harbor extrachromosomal plasmid HPV genomes, exhibit an extended life span in vitro, undergo dysplastic differentiation in organotypic "raft" cultures, and have been used to dissect early and late events of the viral life cycle, including viral gene expression, vegetative viral DNA replication, and virion synthesis (16,17,26,35,46,47). Similar analyses have been extended to cervical keratinocytes (3,63) and airway epithelial cells (39).…”

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confidence: 99%

Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs

Lace

Anson

Klingelhutz

et al. 2009

J Virol

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Mucosal high-risk (HR) human papillomaviruses (HPVs) that cause cervical and other anogenital cancers also are found in ϳ25% of head and neck carcinomas (HNCs), especially those arising in the oropharynx and the tonsils. While many HR HPV types are common in anogenital cancer, over 90% of HPV-positive HNCs harbor HPV type 16 (HPV-16). Using a quantitative colony-forming assay, we compared the ability of fulllength mucosal HPV genomes, i.e., the low-risk HPV-11 and HR HPV-16, -18, and -31, to persist in and alter the growth of primary human keratinocytes from the foreskin, cervix, and tonsils. The HR HPV types led to the formation of growing keratinocyte colonies in culture independent of the site of epithelial origin. However, HPV-18 induced colony growth in all keratinocytes >4-fold more effectively than HPV-16 or HPV-31 and >20-fold more efficiently than HPV-11 or controls. HPV-11-transfected or control colonies failed to expand beyond 32 to 36 population doublings postexplantation. In contrast, individual HR HPV-transfected clones exhibited no apparent slowdown of growth or "crisis," and many maintained HPV plasmid persistence beyond 60 population doublings. Keratinocyte clones harboring extrachromosomal HR HPV genomes had shorter population doubling times and formed dysplastic stratified epithelia in organotypic raft cultures, mirroring the pathological features of higher-grade intraepithelial lesions, yet did not exhibit chromosomal instability. We conclude that, in culture, the HR HPV type, rather than the site of epithelial origin of the cells, determines the efficacy of inducing continued growth of individual keratinocytes, with HPV-18 being the most aggressive mucosal HR HPV type tested.Human papillomaviruses (HPVs) are small DNA tumor viruses that infect, persist in, and cause proliferative lesions in the epithelial cells of the skin, ectoderm-derived mucosae, and their adnexa. Mucosal HPV types are associated with most if not all carcinomas of the uterine cervix, many anogenital cancers, and ϳ25% of head and neck cancers (HNCs) (reviewed in reference 55). HNCs arising in the oropharynx or tonsils are HPV positive in over 50% of the cases. Although the same oncogenic or "high-risk" (HR) HPV types are found in the cervix, in the anogenital area, and in HNC, their prevalence is strikingly different: in cervical and anogenital cancers, HPV type 16 (HPV-16) is found in ϳ50% of the tumors, followed by HPV-18 (ϳ20%), while the remaining cases harbor over 15 other HR HPV types, including HPV-31 and other well-characterized as well as additional, novel HPV types. In contrast, over 90 to 95% of HPV-positive HNCs contain HPV-16, whereas HPV-18, HPV-31, or other HR HPVs are infrequent (10,

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“…IFN also inhibits HPV replication. Although transient increase in viral replication upon IFN treatment has been observed 246 , high and prolonged treatment with IFNβ promotes growth arrest of cells containing HPV31 episomes and reduces episome levels 247 . Although episomally replicating HPV is decreased by IFNβ treatment 247 , emergence of integrated viral genomes is associated with activation of ISGs by type I IFN 101,248 .…”

Section: Immune Interactionsmentioning

confidence: 99%

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Woodby

Scott

Bodily

2016

Progress in Molecular Biology and Translational Science

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Human papillomaviruses (HPV) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection.

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Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1

Cited by 22 publications

References 54 publications

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

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