Modulation of microRNAs and its regulatory target network with therapeutic potential in thyroid cancer: application of gene editing with CRISPR/Cas9

• Grant number: 19/25116-8
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2021 - August 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Edna Teruko Kimura
• Grantee: Edna Teruko Kimura
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Recently, the identification and clinical trials of new drugs that modulate oncogenic signaling, such as genetic alteration in the MAPK pathways that is involved in more than 70% of thyroid cancer cases, have been promoted a great advance in cancer treatment. Nevertheless, it is not rare that some tumors display resistance to these drugs due to activation of alternative signaling pathways. In this context, microRNAs (miRNAs), a class of potent post-transcriptional regulators of gene expression, emerge as potential adjuvant for conventional therapy as they exert pleiotropic effects and control several protein coding genes simultaneously. Among deregulated miRNA in thyroid cancer, miR-146b overexpression is consistent in papillary and anaplastic thyroid cancer, and is associated to clinical-pathological characteristic of tumor aggressiveness. Thus, in this project, we aim to understand the role of new molecular targets of miR-146b with therapeutic potential in thyroid cancer. For that, we will edit the MIR146B gene with CRISPR/Cas9 in thyroid cancer cell lines to evaluate the global effect of miR-146b silencing by NGS sequencing in order to identify the target's regulatory network in the process of differentiation and tumor progression. The results will be also compare with additional silencing approach such as antimiRs and functional blockade with miRNA sponges. These experimental models will help to validate the therapeutic potential of miR-146b modulation and to delineate a global panorama of molecular pathways influenced by miR-146b. Thus, we expect that the present proposal reaches a new understanding of miRNA regulatory target network and a potential application of microRNA based-molecular tool as a new adjuvant therapy in thyroid cancer. (AU)

Scientific publications

(5)

(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)

PEREIRA DOS SANTOS, MARIA GABRIELA; GATTI DA SILVA, GUILHERME HENRIQUE; NAGASSE, HELDER YUDI; FUZIWARA, CESAR SEIGI; TERUKO, KIMURA EDNA; COLTRI, PATRICIA PEREIRA. hnRNP A1 and hnRNP C associate with miR-17 and miR-18 in thyroid cancer cells. FEBS OPEN BIO, v. 12, n. 6, p. 12-pg., 2022-04-24. (19/17282-5, 17/06994-9, 19/21874-5, 19/25116-8)

DE SANTA-INEZ, DANIEL CASARTELLI; FUZIWARA, CESAR SEIGI; SAITO, KELLY CRISTINA; KIMURA, EDNA TERUKO. Targeting the Highly Expressed microRNA miR-146b with CRISPR/Cas9n Gene Editing System in Thyroid Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 15, AUG 2021. (19/25116-8, 20/10403-9, 19/17282-5)

LEITE, ANA KOBER; SAITO, KELLY CRISTINA; THEODORO, THERESE RACHELL; PASINI, FATIMA SOLANGE; CAMILO, LUANA PERRONE; ROSSETTI, CARLOS AUGUSTO; CAVALHEIRO, BEATRIZ GODOI; ALVES, VENANCIO AVANCINI FERREIRA; KOWALSKI, LUIZ PAULO; PINHAL, MARIA APARECIDA SILVA; et al. Profile of MicroRNAs Associated with Death Due to Disease Progression in Metastatic Papillary Thyroid Carcinoma Patients. CANCERS, v. 15, n. 3, p. 12-pg., 2023-02-01. (20/12459-1, 19/25116-8)

DE MELLO, DIEGO CLARO; SAITO, KELLY CRISTINA; CRISTOVAO, MARCELLA MARINGOLO; KIMURA, EDNA TERUKO; FUZIWARA, CESAR SEIGI. Modulation of EZH2 Activity Induces an Antitumoral Effect and Cell Redifferentiation in Anaplastic Thyroid Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 9, p. 22-pg., 2023-04-26. (21/01674-1, 19/25116-8, 22/09813-3, 17/01829-0, 20/10403-9, 19/17282-5)

HUTH, HUGO; FUZIWARA, CESAR; KIMURA, EDNA. The role of miR-200 in anaplastic thyroid cancer aggressiveness. Cancer Research, v. 83, n. 7, p. 2-pg., 2023-04-01. (21/12284-0, 19/25116-8, 19/17282-5)