miRNA splicing regulation in Cancer cells

• Grant number: 19/21874-5
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2020
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Patricia Pereira Coltri
• Grantee: Patricia Pereira Coltri
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Pre-RNA splicing is an essential step on gene regulation in eukaryotes. The removal of introns and ligation of exons in mature RNA sequences is performed by the spliceosome, a ~2 MDa macromolecular machinery composed of 5 small nuclear RNAs (snRNAs) and more than 100 proteins. Splice site choices and mutations on spliceosome components can lead to several different diseases, among which is cancer. In this context, spliceosome emerges as an important therapeutic target. More than 70% of human miRNAs are found within introns, and most of them are involved with cancer. Previous results from our research group showed hnRNP proteins are specifically found on spliceosomes assembled upon introns containing intronic miRNAs 18a and 19a. Our hypothesis is that hnRNP proteins actively participate on splicing regulation of introns containing miRNAs. Indeed, many oncogenic intronic miRNAs have binding sites for hnRNP C, K, M and U. In order to test our hypothesis, we will investigate whether over-expression and/or knock down of these proteins can modulate splicing of these miRNAs. Additionally, we will investigate if splicing inhibitory compounds affect miRNA splicing. In this case cellular kinetics assays will also be performed to better address cellular responses to these compounds. If our hypothesis holds true, oncogenic miRNAs processing state will respond to the level of proteins. Also, if miRNA maturation and function is dependent on splicing, addition of inhibitory compounds might block or delay miRNA maturation. In a broader context, these results will contribute to understand the mechanisms governing splicing regulation especially in diseases like cancer, as well as the participation of inhibitory drugs on treatment, continuing the ongoing laboratory research program. (AU)

Scientific publications

(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)

GATTI DA SILVA, GUILHERME HENRIQUE; PEREIRA DOS SANTOS, MARIA GABRIELA; NAGASSE, HELDER YUDI; COLTRI, PATRICIA PEREIRA. Human Antigen R (HuR) Facilitates miR-19 Synthesis and Affects Cellular Kinetics in Papillary Thyroid Cancer. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 56, n. 2, p. 15-pg., 2022-01-01. (17/06994-9, 19/21874-5)

CAMARGO, LIVIA DE LUCCA; TREVELIN, SILVIA CELLONE; DA SILVA, GUILHERME HENRIQUE GATTI; DIAS, ANA ALICE DOS SANTOS; OLIVEIRA, MARIA APARECIDA; MIKHAYLICHENKO, OLGA; ANDROWIKI, ALINE C. D.; DOS SANTOS, CELIO XAVIER; HOLBROOK, LISA-MARIE; CERAVOLO, GRAZIELA SCALIANTI; et al. Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension. Journal of Hypertension, v. 42, n. 6, p. 16-pg., 2024-06-01. (20/12432-6, 19/21874-5, 13/07937-8, 19/19894-8, 13/03520-5)