ABSTRACT
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor mainly activated by phosphorylation in either tyrosine 705 (Y705) or serine 727 (S727) residues that regulates essential processes such as cell differentiation, apoptosis inhibition, or cell survival. Aberrant activation of STAT3 has been related to development of nearly 50% of human cancers including clear cell renal cell carcinoma (ccRCC). In fact, phosho-S727 (pS727) levels correlate with overall survival of ccRCC patients. With the aim to elucidate the contribution of STAT3 phosphorylation in ccRCC development and progression, we have generated human-derived ccRCC cell lines carrying STAT3 Y705 and S727 phosphomutants. Our data show that the phosphomimetic substitution Ser727Asp facilitates a pro-tumoral phenotype in vitro, in a Y705-phosphorylation-independent manner. Moreover, we describe that STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pS727-dependent genes the most related to cellular hallmarks of cancer. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pS727 promotes the expression of a specific subset of target genes that might be clinically relevant as novel biomarkers and potential therapeutic targets for ccRCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Phosphorylation , Serine/genetics , Serine/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Kidney Neoplasms/genetics , Cell Line, TumorABSTRACT
Contexto y objetivo: En los últimos años se han producido avances significativos en el conocimiento de la carcinogénesis renal. Hoy en día los tumores renales se clasifican en función de su perfil genético, y además se han desarrollado tratamientos específicos basados en la identificación de dianas terapéuticas. Sin embargo, todavía no se han identificado marcadores pronósticos. El objetivo de esta revisión es analizar la literatura que ha evaluado la expresión de la proteína STAT3 como marcador molecular en el carcinoma renal de célula clara (ccRCC). Adquisición de evidencia: En enero de 2018 se realizó una búsqueda sistemática de la literatura en Pubmed, Cochrane Library y Sciencedirect de las publicaciones realizadas desde 1990. Los términos de búsqueda fueron renal cell carcinoma and STAT3 or STAT-3 and prognostic factor. Se siguieron los principios de la declaración PRISMA y la estrategia de selección PICO, seleccionándose los artículos originales con series de pacientes diagnosticados de ccRCC localizado o metastásico, donde se analiza la actividad de STAT3 como marcador pronóstico. Se identificaron 132 publicaciones de las que finalmente se han revisado 10 por cumplir los criterios de inclusión. Síntesis de evidencia: La activación (fosforilación) de STAT3 (pSTAT3) en el residuo Ser727 es importante en el desarrollo y progresión de ccRCC. La expresión de pSTAT3 parece ser un marcador pronóstico y predictor de resistencia a algunos tratamientos en pacientes con enfermedad diseminada. Existe poca evidencia de su utilidad como un marcador pronóstico en pacientes con enfermedad localizada. Conclusiones: La expresión de pSTAT3(Ser727) en el núcleo de las células del ccRCC puede ser un marcador pronóstico y de respuesta al tratamiento en pacientes con ccRCC. La evidencia científica actual es limitada y son necesarios más estudios que demuestren su utilidad
Context and objective: There have been significant advances in the knowledge of renal carcinogenesis in the last years. Nowadays, renal tumours are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyze literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC). Evidence acquisition: In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were "renal cell carcinoma" and "STAT3" or "STAT-3" and prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analyzed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria. Evidence synthesis: STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease. Conclusions: STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness
Subject(s)
Kidney Neoplasms/etiology , Carcinoma, Renal Cell/diagnosis , STAT3 Transcription Factor/metabolism , Biomarkers, Tumor , Carcinoma, Renal Cell/physiopathology , Prognosis , Carcinoma, Renal Cell/etiology , STAT3 Transcription Factor/therapeutic useABSTRACT
CONTEXT AND OBJECTIVE: There have been significant advances in the knowledge of renal carcinogenesis n the last years. Nowadays, renal tumors are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyse literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC). EVIDENCE ACQUISITION: In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were"renal cell carcinoma"and"STAT3"or"STAT-3"and"prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analysed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria. EVIDENCE SYNTHESIS: STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease. CONCLUSIONS: STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness.
