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Unveiling the role of Ape1 in regulating tumor cell resistance to chemotherapy through miRNAs processing in HCC and NSCL
Universita degli Studi di Udine
Università di Udine - Dipartimento di Area Medica, Piazzale Massimiliano Kolbe, 4, Udine, 33100, Italia
Prof. Gianluca Tell; Dr. Giulia Antoniali
Prof. Gianluca Tell; Dr. Giulia Antoniali
Type of Research Project
- Basic science
What is the background of the project?
miRNA processing and genome stability are interconnected pathways playing an unpredicted role in tumors. Ape1 is essential in cancer cells influencing genome stability, through BER, and the expression of oncogenes. Ape1 overexpression in hepatocellular (i.e. HCC) and lung (i.e. NCSLC) cancers is a predictive and prognostic factor. Circulating Ape1 in NCSLC is a novel biomarker of progression disease. Ape1 is an emerging target for combination cancer therapy by means of specific inhibitors of DNA-repair or redox functions. Our recent data show that unexplored non-canonical roles of Ape1, associated with miRNA metabolism and its interactome network, may play an essential function in tumor biology and cancer resistance. Hypothesis: The Ape1 miRNA processing activity may be associated with cancer development and chemoresistance through specific gene alterations. In the previous AIRC project (IG-14038), using HeLa cells, we unexpectedly found a number of miRNAs directly regulated by Ape1 under genotoxic stress conditions, suggesting its contribution in post-transcriptional gene regulation through miRNA-processing/decay. We found some Ape1 cancer variants with altered protein interaction abilities and causing persistent genomic instability.
What is the aim of the project?
1. Identify the miRNAs directly processed by Ape1 in HCC and NCSLC cell lines involved in the regulation of chemoresistance genes; 2. Define the molecular mechanisms responsible for the Ape1 function in miRNA metabolism focused on pri-miRNA-processing and -decay; 3. Evaluate the effects of selected Ape1 functional inhibitors on miRNAs and respective target genes expression; 4. Correlate the expression of Ape1 with its own regulated miRNAs and target genes in NCSLC specimens to identify new prognostic biomarkers; 5. Correlate circulatory Ape1 and Ape1-regulated miRNAs levels with response rate/survival of HCC patients receiving chemo- and radiotherapy to identify new predictive biomarkers. 6. Better knowledge of Ape1’s roles in miRNA metabolism represents the basis to powerful strategies for cancer combination therapy impairing the Ape1 network.
What techniques and methods are used?
The student will use also cellular and molecolar techniques like proteomic technique and gene silencing. The process includes: gene expression analyses through Q-PCR (quantitative polymerase chain reaction) and cell biology assays (viability, colony formation assay, metabolic viability assays). Extensive use of different cancer cell lines and genotoxic treatments will be also performed, as immunofluorescence confocal analyses and proximity ligation analyses.
What is the role of the student?
- The student will mainly observe
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will be included in a team already working in this project. The student will work in pair with the tutor if she/he is able, or he/she will follow the work of the tutor. It is expected that the student will be able to perform and analyse at the molecular and biological levels the effect of genotoxic damages to cancer cells. The student will achieve a methodological approach to the lab work including ethical issue as well as technical methods.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Specific theoretical and practical training will be delivered to the students
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
It will be appreciated if the student has basic knowledge of molecular biology and biochemistry.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students
- 1: Pascut D; Sukowati CHC; Antoniali G; Mangiapane G; Burra S; Mascaretti LG; Buonocore MR; Crocè LS; Tiribelli C; Tell G. Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma. Oncotarget. 2019 Jan 8;10(3):383-394. doi: 10.18632/oncotarget.26555. eCollection 2019 Jan 8. PubMed PMID: 30719231; PubMed Central PMCID: PMC6349448.
- 2: Frossi B; Antoniali G; Yu K; Akhtar N; Kaplan MH; Kelley MR; Tell G; Pucillo CEM. Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination. J Biol Chem. 2019 Mar 29;294(13):5198-5207. doi: 10.1074/jbc.RA118.006601. Epub 2019 Jan 31. PubMed PMID: 30705092; PubMed Central PMCID: PMC6442068.
- 3: Burra S; Marasco D; Malfatti MC; Antoniali G; Virgilio A; Esposito V; Demple B; Galeone A; Tell G. Human AP-endonuclease (Ape1) activity on telomeric G4 structures is modulated by acetylatable lysine residues in the N-terminal sequence. DNA Repair (Amst). 2019 Jan;73:129-143. doi: 10.1016/j.dnarep.2018.11.010. Epub 2018 Nov 22. PubMed PMID: 30509560; PubMed Central PMCID: PMC6420783.
- 4: Yang X; Peng Y; Jiang X; Lu X; Duan W; Zhang S; Dai N; Shan J; Feng Y; Li X; Cheng Y; Yang Y; Baugh L; Tell G; Wang D; Li M. The regulatory role of APE1 in epithelial-to-mesenchymal transition and in determining EGFR-TKI responsiveness in non-small-cell lung cancer. Cancer Med. 2018 Sep;7(9):4406-4419. doi: 10.1002/cam4.1717. Epub 2018 Aug 14. PubMed PMID: 30109782; PubMed Central PMCID:PMC6144255.
- 5: Antoniali G; Serra F; Lirussi L; Tanaka M; D'Ambrosio C; Zhang S; Radovic S; Dalla E; Ciani Y; Scaloni A; Li M; Piazza S; Tell G. Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nat Commun. 2017 Oct 6;8(1):797. doi: 10.1038/s41467-017-00842-8. PubMed PMID: 28986522; PubMed Central PMCID: PMC5630600.
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