title: Spinophilin loss correlates with poor patient prognosis in advanced stages of colon carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Instituto de Biomedicina de Sevilla, HUVR/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Purificacion
authors.initials: P
authors.lastname: Estevez-Garcia
authors.forename: Iker
authors.initials: I
authors.lastname: Lopez-Calderero
authors.forename: Sonia
authors.initials: S
authors.lastname: Molina-Pinelo
authors.forename: Sandra
authors.initials: S
authors.lastname: Muñoz-Galvan
authors.forename: Ana
authors.initials: A
authors.lastname: Salinas
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gomez-Izquierdo
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucena-Cacace
authors.forename: Blanca
authors.initials: B
authors.lastname: Felipe-Abrio
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D000099273:Neurabins
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D000099273:Neurabins