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Principal Investigator: Rachel Adria Katzenellenbogen
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $68,162
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
High-risk human papillomaviruses (HR HPVs) cause 5% of all cancers. There are preventive vaccines
against HPV, but less than 2% of the world's target population has received them. This leaves millions of women
and men at risk for HPV-associated cervical, anogenital, and head and neck cancers. We need to understand
how HR HPV establishes and maintains an active infection, while also driving cancer development, in order to
guide focused therapeutic interventions to prevent, arrest, and reverse disease.
The greatest clinical risk factor for cervical cancer is a persistent HR HPV infection. This persistence
occurs through coordinated dysregulation of cellular pathways, which both support the infection and foster cancer
development. Underlying this dysregulation is the requirement that the HPV oncogenes E6 and E7 partner with
cellular proteins. Our work has focused on the E6 oncogene from HPV type 16 (16E6), the most common HR
HPV type in cancers. Previously, we found that 16E6 required the cellular protein NFX1-123, and its protein
partners cytoplasmic poly(A) binding proteins (PABPCs), to fully activate telomerase and the immortalization
pathway. Our current studies revealed that NFX1-123 is highly expressed in cervical cancers, and together 16E6,
NFX1-123, and PABPCs amplify telomerase, cellular growth, and longevity over time. We also discovered that
NFX1-123 is increased during differentiation and, together with 16E6, augments cellular differentiation cascades
and their host and viral gene targets while simultaneously protecting against concomitant cellular arrest and
senescence. These findings create a sightline for a new level of investigation that will uncover the connectivity
and control of growth and differentiation and the temporal changes driving and accelerating immortalization by
PABPCs, NFX1-123, and 16E6. These results will also delineate targets for future treatments that specifically
disrupt universal pathways required for HPV and its cancers.
Our specific aims are: (1) Determine how 16E6, NFX1-123, and PABPCs work together in co-regulating
growth and differentiation to better establish a persistent infection. We will mimic the initial steps of establishing
a HR HPV infection to identify the way in which these proteins function to permit both differentiation and growth
in concert during the initial, foundational steps of a HR HPV infection. (2) Elucidate the mechanism of longitudinal,
sequential increases of hTERT and telomerase by 16E6, NFX1-123, and PABPCs. Telomerase activation leads
to cellular immortalization. We will leverage long-term cellular studies to determine the sequential changes to
hTERT, the catalytic subunit of telomerase, due to 16E6 with NFX1-123 and PABPCs and to create a roadmap
of molecular oncogenic progression that mirrors clinical chronology. Our proposed studies will elucidate the
temporal and interwoven dysregulation of oncogenic pathways by 16E6 and its host protein partners; they will
also provide foundational data on the oncogenic etiology and progression of increasingly common HPV-
associated cancers.
Terms: <Acceleration><Automobile Driving><Binding Proteins><Biologic Models><Biological Models><Cancer Treatment><Cancer cell line><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Causality><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Signaling><CellLine><Cells><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Physiology><Cellular Process><Cervical><Cervical Cancer><Cervix Cancer><Chronology><Clinical><Collaborations><Cytoplasm><Data><Development><Differentiation and Growth><Disease><Disorder><EST2><Etiology><Fostering><Future><Gene Targeting><Gene Transcription><Generalized Growth><Genetic Transcription><Genome><Goals><Growth><HPV><HPV 16><HPV E6><HPV Vaccine><HPV induced cancer><HPV infection><HPV malignancy><HPV oncogene><HPV+ cancer><HPV-16><HPV-High Risk><HPV-Related Malignancy><HPV-associated cancer><HPV-associated malignancy><HPV-related cancer><HPV16><Head and Neck Cancer><Head and Neck Carcinoma><High Risk Oncogenic HPV><High Risk Woman><High risk HPV><High risk Human Papillomavirus><High risk Human papilloma virus><Human Papilloma Virus><Human Papilloma Virus Vaccine><Human Papilloma Virus-Related Malignancy><Human Papilloma Virus-Related Malignant Neoplasm><Human Papilloma Virus-associated cancer><Human Papilloma Virus-associated malignancy><Human Papilloma Virus-related cancer><Human Papillomavirus><Human papilloma viral oncogene><Human papilloma virus infection><Human papilloma virus type 16><Human papillomavirus 16><Human papillomavirus Vaccine><Human papillomavirus cancer><Human papillomavirus induced cancer><Human papillomavirus infection><Human papillomavirus malignancy><Human papillomavirus type 16><Human papillomavirus-Related Malignancy><Human papillomavirus-Related Malignant Neoplasm><Infection><Infectious Human Wart Virus><Intracellular Communication and Signaling><Investigation><Knock-out><Knockout><Knowledge><Laboratories><Length of Life><Life Cycle><Life Cycle Stages><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Longevity><Longitudinal Studies><Maintenance><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Model System><Molecular><Oncogene Products><Oncogene Proteins><Oncogenesis><Oncogenic><Oncogenic Viruses><Oncoproteins><Papillomavirus Transforming Protein E6><Pathway interactions><Poly(A)+ mRNA Binding Protein><Poly(A)-Binding Proteins><Preventative vaccine><Preventive><Preventive vaccine><Prophylactic vaccine><Protein Binding><Proteins><RNA Expression><Regulation><Research><Risk><Risk Factors><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Subcellular Process><TCS1><TERT gene><Target Populations><Telomerase><Telomere Reverse Transcriptase><Therapeutic Intervention><Time><Tissue Growth><Transcription><Tumor Viruses><Uterine Cervix Cancer><Viral><Viral Genes><Viral Markers><Viral Oncogene><Viral Protein E6><Virus><Woman><Work><anti-cancer therapy><at-risk females><at-risk women><biological signal transduction><bound protein><cancer initiation><cancer progression><cancer risk><cancer therapy><cancer type><cancer-directed therapy><causation><cell growth><cellular differentiation><cellular longevity><cellular targeting><chronic infection><clinical risk><cultured cell line><developmental><disease causation><driving><females at high risk><head/neck cancer><high risk><high risk females><human papilloma virus 16><human papilloma virus oncogene><human papillomaviral oncogene><human papillomavirus E6 oncoprotein><human papillomavirus associated malignancy><human papillomavirus oncogene><human papillomavirus-associated cancer><human papillomavirus-related cancer><insight><intervention therapy><keratinocyte><life course><long-term study><longitudinal outcome studies><longterm study><malignancy><malignant head and neck tumor><men><mutant><neoplasm progression><neoplasm/cancer><neoplastic progression><oncogenic tumor virus><ontogeny><overexpress><overexpression><papilloma virus Transforming Protein E6><pathway><persistent infection><posttranscriptional><prevent><preventing><protein function><protein protein interaction><senescence><senescent><telomerase catalytic subunit><therapeutic agent development><therapeutic development><tumor progression><tumorigenesis><type 16 Human papilloma virus><type 16 Human papillomavirus><uptake><wart virus><women at high risk>