Novo estudo revela que a proteína de ligação ao ARN, YTHDF3, afeta a migração das células do cancro gástrico e a resposta ao paclitaxel, através da regulação da EZRINA

Investigadores do grupo “Differentiation and Cancer” do i3S, em colaboração com os grupos “Cancer Metastasis” e “Cell Division & Genomic Stability” e a Prof. Carmen Jerónimo do IPO-Porto, elucidaram o papel da YTHDF3, uma proteína chave que faz a "leitura" do RNA modificado com N6-metiladenosina (m6A), na progressão do cancro gástrico (GC) e da sensibilidade ao paclitaxel. Este novo estudo, intitulado: " A proteína de ligação ao ARN, YTHDF3, afeta a migração das células do cancro gástrico e a resposta ao paclitaxel através da regulação da EZRINA", foi recentemente publicado na revista "Gastric Cancer". O cancro gástrico continua a ser um problema de saúde global, muitas vezes diagnosticado em fases avançadas, com mau prognóstico. Os investigadores descobriram, através da análise de amostras de tumor de 331 pacientes, que a YTHDF3 é significativamente sobre-expressa no CG e os casos com níveis elevados de YTHDF3 beneficiam mais do tratamento com quimioterapia. Além disso, o silenciamento da YTHDF3 em células de CG por CRISPR-Cas9 afeta a migração, a formação de metástases, a orientação mitótica e a organização do citoesqueleto, melhorando a sensibilidade ao paclitaxel. Dados mecanísticos revelaram que a YTHDF3 regula a EZRINA através da modificação m6A do RNA, estabelecendo um eixo YTHDF3-EZRINA que influencia o comportamento tumoral, possibilitando uma potencial estratégia terapêutica.

Autores e afiliações:

Patrícia Mesquita^1,2 , Alexandre Coelho^1,3 , Ana S. Ribeiro^1,2 , Luís F. C. Póvoas^1,4 , Catarina de Oliveira¹ , Nelson Leça^1,4 , Sara Silva¹ , Diana Ferreira¹ , Diana Pádua^1,3 , Ricardo Coelho⁶ , Carmen Jerónimo^3,7 , Joana Paredes^1,2,8 , Carlos Conde^1,3,5 , Bruno Pereira^1,2 , Raquel Almeida^1,2,4

¹ i3S ‑ Institute for Research and Innovation in Health, University of Porto, 4200‑135 Porto, Portugal

² IPATIMUP ‑ Institute of Molecular Pathology and Immunology, University of Porto, 4200‑465 Porto, Portugal

³ ICBAS – School of Medicine and Biomedical Sciences, University of Porto, 4050‑313 Porto, Portugal

⁴ Biology Department, Faculty of Sciences, University of Porto, 4169‑007 Porto, Portugal

⁵ IBMC ‑ Institute of Molecular and Cell Biology, University of Porto, 4200‑135 Porto, Portugal

⁶ Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland

⁷ Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI‑IPOP)/RISE@CI‑IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200‑072 Porto, Portugal

⁸ Pathology Department, Faculty of Medicine, University of Porto, 4200‑319 Porto, Portugal

Abstract:

Background: Gastric cancer (GC) is the fourth most common cause of cancer-related mortality and the fifth most common cancer worldwide. Despite efforts, the identification of biomarkers and new therapeutic approaches for GC remains elusive. Recent studies have begun to reveal the role of N6-adenosine methylation (m6A) in the regulation of gene expression.

Methods: The expression of the reader YT521-B homology domain-containing family 3 (YTHDF3) in GC was assessed in 331 patients using immunohistochemistry. GC cell lines depleted of YTHDF3 using CRISPR-Cas9 were evaluated for migration, metastasis, orientation of the mitotic spindle, and response to paclitaxel. The association between YTHDF3 and EZRIN (EZR) mRNA was shown using RNA sequencing, immunofluorescence, real-time PCR, and RNA immunoprecipitation. The single-base elongation- and ligation-based qPCR amplification (SELECT) method was used to map m6A in the EZR transcript.

Results: YTHDF3 was significantly overexpressed in GC, and high levels of YTHDF3 were predictive of the response to chemotherapy. In GC cell lines, YTHDF3 was the most highly expressed reader protein. YTHDF3 depletion impaired cytoskeleton organization, cell migration and metastasis, and orientation of the mitotic spindle, leading to an increased response to paclitaxel. EZR was one of the downregulated targets in the YTHDF3 knockout cell models and was associated with the observed phenotype.

Conclusion: YTHDF3 contributes to cell motility and response to paclitaxel in GC cell lines, at least in part through EZR regulation. The YTHDF3-EZR regulatory axis is a novel molecular player in GC, with clinical relevance and potential therapeutic utility.

Revista: Gastric Cancer

Link: https://link.springer.com/article/10.1007/s10120-025-01620-y