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HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation

  1. Author:
    Lou,Hong
    Boland, Joseph F
    Li,Hongchuan [ORCID]
    Burk, Robert [ORCID]
    Yeager, Meredith [ORCID]
    Anderson,Steve [ORCID]
    Wentzensen, Nicolas
    Schiffman, Mark
    Mirabello, Lisa
    Dean, Michael [ORCID]

  2. Author Address

    Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research, Rockville, MD 20850, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Departments of Pediatrics, Microbiology and Immunology, and Obstetrics & Gynecology and Women 39;s Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Laboratory of Cancer Genetics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA., Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.,
    1. Year: 2022
    2. Date: Oct 06
    3. Epub Date: 2022 10 06
  2. Journal: Cancers
    1. 14
    2. 19
  4. Type of Article: Article
  5. Article Number: 4895
  1. Abstract:

    The human papillomavirus (HPV) type 16 E7 oncogene is critical to carcinogenesis and highly conserved. Previous studies identified a preponderance of non-synonymous E7 variants amongst HPV16-positive cancer-free controls compared to those with cervical cancer. To investigate the function of E7 variants, we constructed full-length HPV16 E7 genes and tested variants at positions H9R, D21N, N29S, E33K, T56I, D62N, S63F, S63P, T64M, E80K, D81N, P92L, and P92S (found only in controls); D14E, N29H cervical intraepithelial neoplasia (CIN2), and P6L, H51N, R77S (CIN3). We determined the steady-state level of cytoplasmic and nuclear HPV16 E7 protein. All variants from controls showed a reduced level of E7 protein, with 7/13 variants having lower protein levels. In contrast, 2/3 variants from the CIN3 precancer group had near-wild type E7 levels. We assayed the activity of representative variants in stably transfected NIH3T3 cells. The H9R, E33K, P92L, and P92S variants found in control subjects had lower transforming activity than D14E and N29H variants (CIN2), and the R77S (CIN3) had activity only slightly reduced from wild-type E7. In addition, R77S and WT E7 caused increased migration of NIH3T3 cells in a wound-healing assay compared with H9R, E33K, P92L, and P92S (controls) and D14E (CIN2). These data provide evidence that the E7 variants found in HPV16-positive cancer-free women are partially defective for transformation and cell migration, further demonstrating the importance of fully active E7 in cancer development.

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External Sources

  1. View Full Text
  2. DOI: 10.3390/cancers14194895
  3. PMID: 36230818
  4. PMCID: PMC9562847
  5. PII : cancers14194895

Library Notes

  1. Fiscal Year: FY2022-2023
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