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Human papillomavirus type 16 E6 induces cell competition.

ABSTRACT: High-risk human papillomavirus (HPV) infections induce squamous epithelial tumors in which the virus replicates. Initially, the virus-infected cells are untransformed, but expand in both number and area at the expense of uninfected squamous epithelial cells. We have developed an in vitro assay in which colonies of post-confluent HPV16 expressing cells outcompete and displace confluent surrounding uninfected keratinocytes. The enhanced colony competition induced by the complete HPV16 genome is conferred by E6 expression alone, not by individual expression of E5 or E7, and requires E6 interaction with p53. E6-expressing keratinocytes undermine and displace adjacent normal keratinocytes from contact with the attachment substrate, thereby expanding the area of the E6-expressing colony at the expense of normal keratinocytes. These new results separate classic oncogenicity that is primarily conferred by HPV16 E7 from cell competition that we show is primarily conferred by E6 and provides a new biological role for E6 oncoproteins from high-risk human papillomaviruses.

SUBMITTER: Brimer N

PROVIDER: S-EPMC8979454 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Human papillomavirus type 16 E6 induces cell competition.

Brimer Nicole N Vande Pol Scott S

PLoS pathogens 20220323 3

High-risk human papillomavirus (HPV) infections induce squamous epithelial tumors in which the virus replicates. Initially, the virus-infected cells are untransformed, but expand in both number and area at the expense of uninfected squamous epithelial cells. We have developed an in vitro assay in which colonies of post-confluent HPV16 expressing cells outcompete and displace confluent surrounding uninfected keratinocytes. The enhanced colony competition induced by the complete HPV16 genome is co ...[more]

PMID: 35320322

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Project description:High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

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Human papillomavirus type 16 E6 induces cell competition.

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Human papillomavirus type 16 E6 induces cell competition.

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