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Targeting Innate Immune Response in Human Papillomavirus-Induced Cancer to Develop Novel Anticancer Strategies
Università degli studi di Novara
Department of Translational Medicine - Novara Medical School, 28100 Novara, Italy
Dr. Irene Lo Cigno / Prof. Marisa Gariglio
Dr. Irene Lo Cigno / Prof. Marisa Gariglio
Type of Research Project
- Basic science
What is the background of the project?
Subversion of innate immunity by oncoviruses, such as human papillomavirus (HPV), favors carcinogenesis because the mechanism(s) of viral immune evasion can also hamper cancer immunosurveillance. Previously, we demonstrated that high-risk HPV (hrHPV) can trigger simultaneous epigenetic silencing of multiple effectors of innate immunity to promote viral persistence (Albertini et al., 2018). Specifically, we showed that the hrHPV upregulate both SUV39H1 and SIRT1 genes (two histone modifiers), whose concerted action shuts down the host innate immune response. Loss-of-function experiments demonstrated that either SIRT1 or SUV39H1 depletion restores the innate immune response to exogenous stimuli, predominantly through RIG-I signaling (a cytosolic RNA sensor). Collectively, our findings raise the possibility that targeting the downstream effectors SUV39H1 and SIRT1 may be a viable strategy to treat viral and neoplastic disease.
What is the aim of the project?
The underlying hypothesis of this project is that HPV16 and HPV18 -the two high-risk genotypes that account for the majority of HPV-related cancers- have developed evolutionarily conserved strategies in order to epigenetically overturn key players of the innate immune response. The reversible nature of the modifications associated with SUV39H1 and SIRT1 upregulation provides a rationale for the design of anticancer and antiviral therapies targeting these molecules, alone or in combination with RIG-I agonist. Thus, we propose to define the role of human papillomavirus (HPV) oncoproteins in the epigenetic modulation of the immune response, and to find a strategy to treat viral and neoplastic disease by targeting histone modifiers.
What techniques and methods are used?
This project rely on the use of a wide range of cellular and molecular biology techniques. hrHPV (high-risk human papillomavirus) transformed keratinocytes will be use to find a strategy to treat viral and neoplastic disease through SUV39H1 and SIRT1 inhibition and exogenous DNA/RNA transfection to activate innate immune response. IFNβ and IFNλ1 release by ELISA (enzyme-linked immunosorbent assay) are employed to determine the induction of innate immune response, Western blotting to evaluate the expression of cellular and viral markers and cytofluorimetry to asses the effects of these treatments on cell cycle progression and cell death.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will perform several cellular and molecular biology techniques including DNA/RNA transfection, IFNβ and IFNλ1 ELISA to assess the innate immunity induction and wester blotting analysis. The student will acquire a lot of knowledge regarding HPV and the innate immunity through reading papers and meeting with the lab members so he can also contribute to the rationale of the project with his ideas and background.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Preliminary readings will be provided, focused on the specific topic. The student will be involved in lectures and seminars provided by collaborators or by external speakers.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Molecular and cellular biology knowledges
Are there any legal limitations in the student’s involvement
No results sharing
Type of students accepted
This project accepts: - Medical students
- HPV E7 Oncoprotein Subverts Host Innate Immunity Via SUV39H1-Mediated Epigenetic Silencing of Immune Sensor Genes. Lo Cigno I; Calati F; Borgogna C; Zevini A; Albertini S; Martuscelli L; De Andrea M; Hiscott J; Landolfo S; Gariglio M.
- HPV18 Persistence Impairs Basal and DNA Ligand-Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling. Albertini S; Lo Cigno I; Calati F; De Andrea M; Borgogna C; Dell'Oste V; Landolfo S; Gariglio M.
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