Transforming growth factor-ß promotes aggressiveness and invasion of clear cell renal cell carcinoma.

Sitaram, Raviprakash T; Mallikarjuna, Pramod; Landström, Maréne; Ljungberg, Börje

Sitaram, Raviprakash T; Mallikarjuna, Pramod; Landström, Maréne; Ljungberg, Börje.

Afiliación

Sitaram RT; Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
Mallikarjuna P; Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Landström M; Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Ljungberg B; Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.

Oncotarget ; 7(24): 35917-35931, 2016 Jun 14.

Article en En | MEDLINE | ID: mdl-27166254

RESUMEN

The molecular mechanisms whereby transforming growth factor-ß (TGF-ß) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-ß type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-ß target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival. Expression of ALK5-FL, ALK5-ICD, pSmad2/3 and PAI-1 protein levels were significantly higher in higher stage and associated with adverse survival. ALK5-ICD, pSmad2/3 and PAI-1 correlated with higher grade, and ALK5-FL, pSmad2/3 and PAI-1 protein levels were significantly correlated with larger tumor size. Moreover, the functional role of the TGF-ß - ALK5-ICD pathway were investigated in two ccRCC cell lines by treatment with ADAM/MMP2 inhibitor TAPI-2, which prevented TGF-ß-induced ALK5-ICD generation, nuclear translocation, as well as cell invasion. The present study demonstrated that canonical TGF-ß Smad2/3 pathway and generation of ALK5-ICD correlates with poor survival and invasion of ccRCC in vitro.

Asunto(s)

Carcinoma de Células Renales/genética; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Neoplasias Renales/genética; Factor de Crecimiento Transformador beta/farmacología; Adulto; Anciano; Anciano de 80 o más Años; Carcinoma de Células Renales/metabolismo; Carcinoma de Células Renales/patología; Línea Celular Tumoral; Femenino; Humanos; Estimación de Kaplan-Meier; Neoplasias Renales/metabolismo; Neoplasias Renales/patología; Masculino; Persona de Mediana Edad; Invasividad Neoplásica; Inhibidor 1 de Activador Plasminogénico/genética; Inhibidor 1 de Activador Plasminogénico/metabolismo; Proteínas Serina-Treonina Quinasas/genética; Proteínas Serina-Treonina Quinasas/metabolismo; Receptor Tipo I de Factor de Crecimiento Transformador beta; Receptores de Factores de Crecimiento Transformadores beta/genética; Receptores de Factores de Crecimiento Transformadores beta/metabolismo; Proteína Smad2/genética; Proteína Smad2/metabolismo; Proteína smad3/genética; Proteína smad3/metabolismo

Palabras clave

ALK5; PAI-1; TGF-ß signaling pathway; ccRCC; pSmad2/3

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Regulación Neoplásica de la Expresión Génica / Factor de Crecimiento Transformador beta / Neoplasias Renales Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos

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