Study of Synthetic Lethality in cells infected with Human Papillomaviruses (HPV)

• Grant number: 10/20002-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: October 01, 2011 - September 30, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Enrique Mario Boccardo Pierulivo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated grant(s): 12/51017-8 - Analysis of polarity proteins expression in neoplastic processes associated with human Papillomavirus using organotypic cultures., AP.R
• Associated scholarship(s): 14/21361-4 - Effect of HPV16 oncoproteins on DNA damage repair pathways in human keratinocytes organotypic cultures, BP.IC; 12/16512-8 - Study of synthetic lethality in HPV-transformed cells, BP.DD

Abstract

Some HPV types, collectively known as high-risk types, are etiologically associated to almost all cervical tumors and more than 50% of other anogenital malignancies. Infection by these HPV types has been associated to genomic instability, a hallmark of most human malignancies. High-risk HPV types express two oncoproteins, E6 and E7, which target specific cellular factors to promote cell proliferation. Furthermore, these proteins induce structural and numerical chromosome alterations and modulate cellular response to DNA damage. Synthetic lethality describes a cellular condition in which two (or more) non-allelic and non-essential mutations, which are not lethal on their own, become deadly when present within the same cell. HPV transformed cells represent interesting models for the study of synthetic lethality since E6 and E7 oncoproteins target several signal transduction pathways such as those regulated by p53 and pRb. In this project we aim to systematically inhibit genes involved in DNA damage repair and tumor suppressor genes using lentiviral libraries expressing specific shRNA. This approach may contribute to identify genes that are essential for HPV-transformed cells survival and have potential for the development of anti-viral therapies to treat HPV infections. Besides, the results obtained during this project may prove useful for the study of other viral and non-viral associated tumors. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CABECA, TATIANE KAREN; ABREU, ALICE DE MELLO; ANDRETTE, RAFAEL; LINO, VANESCA DE SOUZA; MORALE, MIRIAN GALLIOTE; AGUAYO, FRANCISCO; TERMINI, LARA; VILLA, LUISA LINA; LEPIQUE, ANA PAULA; BOCCARDO, ENRIQUE. HPV-Mediated Resistance to TNF and TRAIL Is Characterized by Global Alterations in Apoptosis Regulatory Factors, Dysregulation of Death Receptors, and Induction of ROS/RNS. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 1, JAN 1 2019. (11/14416-9, 08/03232-1, 10/20002-0, 08/57889-1)

RABACHINI, TATIANA; BOCCARDO, ENRIQUE; ANDRADE, RUBIANA; PEREZ, KATIA REGINA; NONOGAKI, SUELY; CUCCOVIA, IOLANDA MIDEA; VILLA, LUISA LINA. HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner. BMC CANCER, v. 18, APR 27 2018. (10/20002-0, 08/57889-1, 08/03232-1)

CARRILLO-BELTRAN, DIEGO; MUNOZ, JUAN P.; GUERRERO-VASQUEZ, NAHIR; BLANCO, RANCES; LEON, OSCAR; DE SOUZA LINO, VANESCA; TAPIA, JULIO C.; MALDONADO, EDIO; DUBOIS-CAMACHO, KAREN; HERMOSO, MARCELA A.; et al. Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-kappa B Activation in Oral Cancer Cells. CANCERS, v. 12, n. 7, JUL 2020. (17/02997-3, 10/20002-0)

BRUNA PRATI; BRUNA MARANGONI; ENRIQUE BOCCARDO. Human papillomavirus and genome instability: from productive infection to cancer. Clinics, v. 73, 2018-09-06. (10/20002-0)

ABJAUDE, WALASON; PRATI, BRUNA; MUNFORD, VERIDIANA; MONTENEGRO, ALINE; LINO, VANESCA; HERBSTER, SUELLEN; RABACHINI, TATIANA; TERMINI, LARA; MENCK, CARLOS FREDERICO MARTINS; BOCCARDO, ENRIQUE. ATM Pathway Is Essential for HPV-Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation. PATHOGENS, v. 11, n. 6, p. 19-pg., 2022-06-01. (17/02997-3, 13/27006-9, 12/16512-8, 10/20002-0, 19/19435-3)

CARRILLO-BELTRAN, DIEGO; OSORIO, JULIO C.; BLANCO, RANCES; OLIVA, CAROLINA; BOCCARDO, ENRIQUE; AGUAYO, FRANCISCO. Interaction between Cigarette Smoke and Human Papillomavirus 16 E6/E7 Oncoproteins to Induce SOD2 Expression and DNA Damage in Head and Neck Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 8, p. 17-pg., 2023-04-01. (10/20002-0, 19/26065-8)

MORALE, MIRIAN GALLIOTE; ABJAUDE, WALASON DA SILVA; SILVA, ALINE MONTENEGRO; VILLA, LUISA LINA; BOCCARDO, ENRIQUE. HPV-transformed cells exhibit altered HMGB1-TLR4/MyD88-SARM1 signaling axis. SCIENTIFIC REPORTS, v. 8, FEB 22 2018. (14/21361-4, 10/20002-0, 11/14416-9, 08/57889-1, 08/03232-1)

TERMINI, LARA; BOCCARDO, ENRIQUE. Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 18, n. 4, p. 246-255, 2018. (12/16059-1, 10/20002-0, 08/57889-1)

PRATI, BRUNA; ABJAUDE, WALASON DA SILVA; TERMINI, LARA; MORALE, MIRIAN; HERBSTER, SUELLEN; LONGATTO-FILHO, ADHEMAR; LIMA NUNES, RAFAELLA ALMEIDA; CORDOBA CAMACHO, LIZETH CAROLINA; RABELO-SANTOS, SILVIA HELENA; ZEFERINO, LUIZ CARLOS; et al. Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo. SCIENTIFIC REPORTS, v. 9, JAN 23 2019. (08/57889-1, 10/20002-0, 13/27006-9, 12/16512-8, 11/14416-9)

PRATI, BRUNA; MARANGONI, BRUNA; BOCCARDO, ENRIQUE. Human papillomavirus and genome instability: from productive infection to cancer. Clinics, v. 73, n. 1, 2018. (10/20002-0)

HERBSTER, SUELLEN; TROMBETTA-LIMA, MARINA; DE SOUZA-SANTOS, PAULO THIAGO; PALADINO, ANDRESSA; SILVEIRA, CAIO RAONY FARINA; SOGAYAR, MARI CLEIDE; VILLA, LUISA LINA; LEPIQUE, ANA PAULA; BOCCARDO, ENRIQUE. Low RECK Expression Is Part of the Cervical Carcinogenesis Mechanisms. CANCERS, v. 13, n. 9, MAY 2021. (08/57889-1, 17/02997-3, 10/20002-0, 13/27006-9)