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Principal Investigator: Rachel Adria Katzenellenbogen
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2022
Award: $67,133
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: <Automobile Driving><Cancers><Causality><Cellular Expansion><Cellular Growth><Cervical><Cervical Cancer><Cervix Cancer><Chronology><Clinical><Data><Development><Differentiation and Growth><Disease><Disorder><EST2><Etiology><Fostering><Foundations><Future><Gene Targeting><Generalized Growth><Growth><HPV><HPV 16><HPV Vaccine><HPV infection><HPV oncogene><HPV-16><HPV-Related Malignancy><HPV-associated cancer><HPV-associated malignancy><HPV-related cancer><HPV16><Head and Neck Cancer><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 infection><Human papillomavirus type 16><Human papillomavirus-Related Malignancy><Human papillomavirus-Related Malignant Neoplasm><Infection><Infectious Human Wart Virus><Investigation><Length of Life><Longevity><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><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><Molecular><Oncogenic><Pathway interactions><Poly(A)+ mRNA Binding Protein><Poly(A)-Binding Proteins><Preventative vaccine><Preventive><Preventive vaccine><Prophylactic vaccine><Proteins><Risk><Risk Factors><TCS1><TERT gene><Target Populations><Telomerase><Telomere Reverse Transcriptase><Therapeutic Intervention><Time><Tissue Growth><Uterine Cervix Cancer><Viral><Viral Genes><Woman><Work><cancer risk><causation><cell growth><chronic infection><clinical risk><developmental><disease causation><driving><head/neck cancer><high risk><human papilloma virus 16><human papilloma virus oncogene><human papillomaviral oncogene><human papillomavirus associated malignancy><human papillomavirus oncogene><human papillomavirus-associated cancer><human papillomavirus-related cancer><intervention therapy><life span><lifespan><malignancy><malignant head and neck tumor><men><men's><neoplasm/cancer><ontogeny><pathway><persistent infection><prevent><preventing><protein function><senescence><senescent><telomerase catalytic subunit><type 16 Human papilloma virus><type 16 Human papillomavirus><uptake><wart virus>