title: Overexpression of sphingosine-1-phosphate receptor 1 and phospho-signal transducer and activator of transcription 3 is associated with poor prognosis in rituximab-treated diffuse large B-cell lymphomas.
abstract: BACKGROUND
  Sphingosine-1-phosphate receptor-1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) play important roles in immune responses with potential oncogenic roles.
  
  
  METHODS
  We analyzed S1PR1/STAT3 pathway activation using immunohistochemistry in rituximab-treated diffuse large B-cell lymphomas (DLBCL; N=103).
  
  
  RESULTS
  Nuclear expression of pSTAT3 (but not S1PR1) was associated with non-GCB phenotype (p=0.010). In univariate survival analysis, S1PR1 expression (S1PR1+) was a poor prognostic factor in total DLBCLs (p=0.018), as well as in nodal (p=0.041), high-stage (III, IV) (p=0.002), and high-international prognostic index (IPI; 3-5) (p=0.014) subgroups, while nuclear expression of pSTAT3 (pSTAT3+) was associated with poor prognosis in the low-stage (I, II) subgroup (p=0.022). The S1PR1/pSTAT3 risk-categories, containing high-risk (S1PR1+), intermediate-risk (S1PR1-/pSTAT3+), and low-risk (S1PR1-/pSTAT3-), predicted overall survival (p=0.010). This prognostication tended to be valid in each stage (p=0.059 in low-stage; p=0.006 in high-stage) and each IPI subgroups (p=0.055 [low-IPI]; p=0.034 [high-IPI]). S1PR1 alone and S1PR1/pSTAT3 risk-category were significant independent prognostic indicators in multivariate analyses incorporating IPI and B symptoms (S1PR1 [p=0.005; HR=3.0]; S1PR1/pSTAT3 risk-category [p=0.019: overall; p=0.024, HR=2.7 for S1PR1-/pSTAT3+ vs. S1PR1+; p=0.021, HR=3.8 for S1PR1-/pSTAT3- vs. S1PR1+]).
  
  
  CONCLUSIONS
  Therefore, S1PR1 and S1PR1/pSTAT3 risk-category may contribute to risk stratification in rituximab-treated DLBCLs, and S1PR1 and STAT3 might be therapeutic targets for DLBCL.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Paik
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Nam
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. junarplus@chol.com.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000737:chemistry; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D049349:Receptors, Lysosphingolipid / Q000032:analysis*; D018570:Risk Assessment; D000069283:Rituximab; D050796:STAT3 Transcription Factor / Q000032:analysis*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D016019:Survival Analysis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D000069283:Rituximab