title: Cyclophilin B expression is associated with in vitro radioresistance and clinical outcome after radiotherapy.
abstract: The tools for predicting clinical outcome after radiotherapy are not yet optimal. To improve on this, we applied the COXEN informatics approach to in vitro radiation sensitivity data of transcriptionally profiled human cells and gene expression data from untreated head and neck squamous cell carcinoma (HNSCC) and bladder tumors to generate a multigene predictive model that is independent of histologic findings and reports on tumor radiosensitivity. The predictive ability of this 41-gene model was evaluated in patients with HNSCC and was found to stratify clinical outcome after radiotherapy. In contrast, this model was not useful in stratifying similar patients not treated with radiation. This led us to hypothesize that expression of some of the 41 genes contributes to tumor radioresistance and clinical recurrence. Hence, we evaluated the expression the 41 genes as a function of in vitro radioresistance in the NCI-60 cancer cell line panel and found cyclophilin B (PPIB), a peptidylprolyl isomerase and target of cyclosporine A (CsA), had the strongest direct correlation. Functional inhibition of PPIB by small interfering RNA depletion or CsA treatment leads to radiosensitization in cancer cells and reduced cellular DNA repair. Immunohistochemical evaluation of PPIB expression in patients with HNSCC was found to be associated with outcome after radiotherapy. This work demonstrates that a novel 41-gene expression model of radiation sensitivity developed in bladder cancer cell lines and human skin fibroblasts predicts clinical outcome after radiotherapy in head and neck cancer patients and identifies PPIB as a potential target for clinical radiosensitization.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Williams
authors.forename: Charles R
authors.initials: CR
authors.lastname: Owens
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziegielewski
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Paul W
authors.initials: PW
authors.lastname: Read
authors.forename: James M
authors.initials: JM
authors.lastname: Larner
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.forename: William A
authors.initials: WA
authors.lastname: Brock
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D021983:Cyclophilins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D053263:Gene Regulatory Networks; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D006801:Humans; D008954:Models, Biological; D010750:Phosphoproteins / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D010750:Phosphoproteins; D012269:Ribosomal Proteins; C035690:ribosomal phosphoprotein P1; C081786:cyclophilin B; D021983:Cyclophilins