title: Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer.
abstract: The identification of predictive biomarkers for neoadjuvant chemoradiation therapy (CRT) is a current clinical need. The heterodimer Ku70/80 plays a critical role in DNA repair and cell death induction after damage. The aberrant expression and localization of these proteins fail to control DNA repair and apoptosis. sClusterin is the Ku70 partner that sterically inhibits Bax-dependent cell death after damage in some pathologic conditions. This study sought to evaluate the molecular relevance of Ku70-Ku80-Clu as a molecular cluster predicting the response to neoadjuvant CRT in patients with locally advanced rectal cancer (LARC).
  
  
  
  Patients enrolled in this study underwent preoperative CRT followed by surgical excision. A retrospective study based on individual response, evaluated by computed tomography and diffusion-weighted magnetic resonance imaging, identified responder (56%) and no-responder patients (44%). Ku70/80 and Clu expression were observed in biopsy specimens obtained before and after treatment with neoadjuvant CRT from the same LARC patients. In vitro studies before and after irradiation were also performed on radioresistant (SW480) and radiosensitive (SW620) colorectal cancer cell lines, mimicking sensitive or resistant tumor behavior.
  
  
  
  We found a conventional nuclear localization of Ku70/80 in pretherapeutic tumor biopsies of responder patients, in agreement with their role in DNA repair and regulating apoptosis. By contrast, in the no-responder population we observed an unconventional overexpression of Ku70 in the cytoplasm (P<.001). In this context we also overexpression of sClu in the cytoplasm, which accorded with its role in stabilizing of Bax-Ku70 complex, inhibiting Bax-dependent apoptosis. Strikingly, Ku80 in these tumor tissues was lost (P<.005). In vitro testing of colon cancer cells finally confirmed the results observed in tumor biopsy specimens, proving that Ku70/80-Clu deregulation is extensively involved in the resistance mechanism.
  
  
  
  These results strongly suggest a potential role of these proteins as a new prognostic tool to predict the response to chemoradiation in LARC.
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy. Electronic address: sabina.pucci@uniroma2.it.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pucci
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Polidoro
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Joubert
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mastrangeli
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tolu
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Michaela
authors.initials: M
authors.lastname: Benassi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Fiaschetti
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Greco
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Miceli
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Floris
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Hospital Foundation Policlinico Tor Vergata, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Santoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D059248:Chemoradiotherapy / Q000379:methods*; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods*; D051152:Clusterin / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011300:Preoperative Care; D011836:Radiation Tolerance; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D009363:Neoplasm Proteins; D000072200:Ku Autoantigen