PURPOSE: The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy. EXPERIMENTAL DESIGN: By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy. RESULTS: Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels. CONCLUSIONS: Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma.
PURPOSE: The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy. EXPERIMENTAL DESIGN: By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy. RESULTS: Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels. CONCLUSIONS: Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma.
Authors: Min Long; Shasha Tao; Montserrat Rojo de la Vega; Tao Jiang; Qing Wen; Sophia L Park; Donna D Zhang; Georg T Wondrak Journal: Cancer Prev Res (Phila) Date: 2015-02-23
Authors: I Ferrer; E M Verdugo-Sivianes; M A Castilla; R Melendez; J J Marin; S Muñoz-Galvan; J L Lopez-Guerra; B Vieites; M J Ortiz-Gordillo; J M De León; J M Praena-Fernandez; M Perez; J Palacios; A Carnero Journal: Oncogene Date: 2015-09-21 Impact factor: 9.867
Authors: Mujeeburahiman Cheerathodi; Naze G Avci; Paola A Guerrero; Leung K Tang; Julia Popp; John E Morales; Zhihua Chen; Amancio Carnero; Frederick F Lang; Bryan A Ballif; Gonzalo M Rivera; Joseph H McCarty Journal: Mol Cancer Res Date: 2016-09-21 Impact factor: 5.852
Authors: Daniela Schwarzenbacher; Verena Stiegelbauer; Alexander Deutsch; Anna Lena Ress; Ariane Aigelsreiter; Silvia Schauer; Karin Wagner; Tanja Langsenlehner; Margit Resel; Armin Gerger; Hui Ling; Cristina Ivan; George Adrian Calin; Gerald Hoefler; Beate Rinner; Martin Pichler Journal: Oncotarget Date: 2015-05-10
Authors: Anna Lena Ress; Verena Stiegelbauer; Daniela Schwarzenbacher; Alexander Deutsch; Samantha Perakis; Hui Ling; Cristina Ivan; George Adrian Calin; Beate Rinner; Armin Gerger; Martin Pichler Journal: Oncotarget Date: 2014-09-30
Authors: Eva M Verdugo-Sivianes; Lola Navas; Sonia Molina-Pinelo; Irene Ferrer; Alvaro Quintanal-Villalonga; Javier Peinado; Jose M Garcia-Heredia; Blanca Felipe-Abrio; Sandra Muñoz-Galvan; Juan J Marin; Luis Montuenga; Luis Paz-Ares; Amancio Carnero Journal: Oncotarget Date: 2017-10-26