The role of stat3 phosphorylation state in clear cell renal cell carcinoma (ccrcc)

• Autores: Jazmine Paola Arevalo Bautista
• Directores de la Tesis: Anna Messeguer Navarro (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Joan Xavier Comella i Carnicé (presid.), Diego Arango del Corro (secret.), Núria Montserrat Pulido (voc.)
• Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • The signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor that regulates downstream genes involved in essential biological processes such as cell differentiation, proliferation, migration, apoptosis inhibition, and survival. The aberrant activation of STAT3 has been related to the development of near 50% of all human cancers including clear cell renal cell carcinoma (ccRCC). To date, the oncogenic properties of STAT3 are attributed to the phosphorylation of its Tyr705, however, the phosphorylation of its Ser727 has recently emerged as an event that enhances STAT3 transcriptional activity, in addition to non-genomic activities that promote cancer development. Our group was one of the pioneers in bringing the Ser727 phosphorylation to light by demonstrating that nuclear pSer727 expression levels, in tissue samples of ccRCC patients, correlated with poor prognosis and low overall survival. Since ccRCC is the most prevalent and lethal histological subtype of renal cell carcinoma (RCC) and the molecular mechanisms behind its tumorigenesis remain unclear, we aimed to elucidate the role of STAT3 phosphorylation state in ccRCC development, and especially the contribution of pSer727 to tumor progression. For that purpose, we generated simple and double STAT3 phosphomutants (Tyr705Phe, Ser727Ala, Ser727Asp, Tyr705Phe/Ser727Ala, and Tyr705Phe/Ser727Asp) transduced in human-derived ccRCC cell lines (769-P and 786-O), and we evaluated their functional behavior as well as their differential gene expression through microarray analysis. Our data demonstrated that STAT3 mutants carrying a phosphomimetic substitution for Ser727 (Ser727Asp) promote a pro-tumoral phenotype in vitro in a Tyr705-independent manner. Moreover, we describe that the overall STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pSer727-dependent genes the most related to cellular hallmarks of cancer development. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pSer727 activates STAT3 signaling through transcription of a specific subset of target genes that are clinically relevant as potential therapeutic targets and novel biomarkers for ccRCC.