Blanca Torrejón1, Ion Cristóbal2, Cristina Caramés1, Iván Prieto-Potín3, Cristina Chamizo1, Andrea Santos1, Marta Sanz-Alvarez3, Roberto Serna-Blasco1, Melania Luque3, Juan Madoz-Gúrpide3, Federico Rojo3, Jesús García-Foncillas4. 1. Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Diaz, Autonomous University of Madrid, University Hospital "Fundación Jiménez Diaz", Avda. Reyes Católicos-2, 28040, Madrid, Spain. 2. Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Diaz, Autonomous University of Madrid, University Hospital "Fundación Jiménez Diaz", Avda. Reyes Católicos-2, 28040, Madrid, Spain. ion.cristobal@fjd.es. 3. Pathology Department, Autonomous University of Madrid, University Hospital "Fundación Jiménez Diaz", 28040, Madrid, Spain. 4. Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Diaz, Autonomous University of Madrid, University Hospital "Fundación Jiménez Diaz", Avda. Reyes Católicos-2, 28040, Madrid, Spain. jesus.garciafoncillas@oncohealth.eu.
Abstract
BACKGROUND: The functional loss of the tumor suppressor protein phosphatase 2A (PP2A) occurs in a wide variety of human cancers including colorectal cancer (CRC), and SET overexpression has been reported as a key contributing mechanism to inhibit PP2A. Although SET binding protein 1 (SETBP1) overexpression and gain of function mutations have been described in several hematological malignancies as common events that increase the expression levels of the PP2A inhibitor SET, thereby leading to PP2A inactivation, the potential existence of SETBP1 alterations in CRC still remains unexplored. METHODS: We studied the expression profile of SETBP1 by Western blot in a set of CRC cell lines and patient samples. Moreover, we performed co-immunoprecipitation assays to analyze the formation of the previously reported SETBP1-SET-PP2A inhibitory complex. Furthermore, we evaluated the mutational status of SETBP1 by pyrosequencing assays in a cohort of 55 CRC patients with metastatic disease after the immunohistochemical characterization of SET and p-PP2A expression in this cohort. RESULTS: We found high SETBP1 expression in several CRC lines but only in two of the patients analyzed. In addition, we demonstrated the formation of the SETBP1-SET-PP2A heterotrimeric complex in CRC cells. However, we failed to detect SETBP1 mutations in any of the CRC patient samples included in the study. CONCLUSIONS: Our results suggest that SETBP1 expression is mainly similar o lower in colorectal cancer tissue compared to normal colonic mucosa. However, its overexpression is a low prevalent alteration which could contribute to inhibit PP2A in CRC through the formation of a SETBP1-SET-PP2A complex in some CRC patients. Moreover, SETBP1 mutations are, if exist, rare events in CRC patients.
BACKGROUND: The functional loss of the tumor suppressor protein phosphatase 2A (PP2A) occurs in a wide variety of humancancers including colorectal cancer (CRC), and SET overexpression has been reported as a key contributing mechanism to inhibit PP2A. Although SET binding protein 1 (SETBP1) overexpression and gain of function mutations have been described in several hematological malignancies as common events that increase the expression levels of the PP2A inhibitor SET, thereby leading to PP2A inactivation, the potential existence of SETBP1 alterations in CRC still remains unexplored. METHODS: We studied the expression profile of SETBP1 by Western blot in a set of CRC cell lines and patient samples. Moreover, we performed co-immunoprecipitation assays to analyze the formation of the previously reported SETBP1-SET-PP2A inhibitory complex. Furthermore, we evaluated the mutational status of SETBP1 by pyrosequencing assays in a cohort of 55 CRC patients with metastatic disease after the immunohistochemical characterization of SET and p-PP2A expression in this cohort. RESULTS: We found high SETBP1 expression in several CRC lines but only in two of the patients analyzed. In addition, we demonstrated the formation of the SETBP1-SET-PP2A heterotrimeric complex in CRC cells. However, we failed to detect SETBP1 mutations in any of the CRC patient samples included in the study. CONCLUSIONS: Our results suggest that SETBP1 expression is mainly similar o lower in colorectal cancer tissue compared to normal colonic mucosa. However, its overexpression is a low prevalent alteration which could contribute to inhibit PP2A in CRC through the formation of a SETBP1-SET-PP2A complex in some CRC patients. Moreover, SETBP1 mutations are, if exist, rare events in CRC patients.
Authors: Ion Cristóbal; Francisco J Blanco; Laura Garcia-Orti; Nerea Marcotegui; Carmen Vicente; José Rifon; Francisco J Novo; Eva Bandres; María J Calasanz; Carmelo Bernabeu; María D Odero Journal: Blood Date: 2009-11-16 Impact factor: 22.113
Authors: Godfrey Grech; Shawn Baldacchino; Christian Saliba; Maria Pia Grixti; Robert Gauci; Vanessa Petroni; Anthony G Fenech; Christian Scerri Journal: Tumour Biol Date: 2016-07-21
Authors: I Cristóbal; R Manso; R Rincón; C Caramés; S Zazo; T G Del Pulgar; A Cebrián; J Madoz-Gúrpide; F Rojo; J García-Foncillas Journal: Br J Cancer Date: 2014-07-08 Impact factor: 7.640
Authors: Rashmi Kanagal-Shamanna; Rajyalakshmi Luthra; Cameron C Yin; Keyur P Patel; Koichi Takahashi; Xinyan Lu; John Lee; Chong Zhao; Francesco Stingo; Zhuang Zuo; Mark J Routbort; Rajesh R Singh; Patricia Fox; Farhad Ravandi; Guillermo Garcia-Manero; L Jeffrey Medeiros; Carlos E Bueso-Ramos Journal: Oncotarget Date: 2016-03-22