title: Serum interferon alpha receptor 2 mRNA may predict efficacy of interferon alpha with/without low-dose sorafenib for metastatic clear cell renal cell carcinoma.
abstract: BACKGROUND
  Interferon (IFN) alpha is one of the central agents in immunotherapy for renal cell carcinoma (RCC). It acts by binding to the IFN-alpha receptor (IFNAR). We previously reported that increased tumor expression of IFNAR2 mRNA was associated with the metastatic potential and progression of RCC, as well as with a poor response of metastatic RCC to IFN-alpha therapy. This study investigated the influence of serum IFNAR2 in RCC patients.
  
  
  METHODS
  We measured serum IFNAR2 mRNA levels and quantified IFNAR mRNA expression in paired tumor and non-tumor tissues from the surgical specimens of 66 consecutive RCC patients by the real-time reverse transcription polymerase chain reaction (RT-PCR). We also measured phosphorylated Akt (Ser-473) and phosphorylated-S6 ribosomal protein (Ser-235/236) proteins levels in paired tumor and non-tumor tissues of patients with metastatic RCC by Western blotting.
  
  
  RESULTS
  The serum level of IFNAR2 mRNA was not associated with its tumor tissue level. Serum IFNAR2 mRNA was positively correlated with tumor size (P < 0.05), but not with tumor grade, pT stage, metastasis, microscopic vascular invasion, or serum C-reactive protein. Serum levels of IFNAR2 mRNA were significantly higher in patients with a good response to IFN-alpha ± sorafenib than in those with a poor response (P < 0.0001). Tumor tissue IFNAR2 mRNA levels and phosphorylated-S6 ribosomal protein (Ser-235/236) levels were associated with metastatic potential (P < 0.001 and P < 0.01, respectively), and patients with a low IFNAR2 mRNA level and low phosphorylated Akt (Ser-473) protein level in the primary tumor showed a good response to IFN-α ± sorafenib (IFN-α ± Sor: CR-PR) (P < 0.01 and P < 0.05, respectively). Kaplan-Meier survival analysis showed that a higher serum IFNAR2 mRNA level was associated with longer overall survival of treated patients (P < 0.05), while a higher tumor tissue IFNAR2 mRNA level was related to shorter overall survival (P < 0.01).
  
  
  CONCLUSIONS
  Our findings suggest that a high serum level of IFNAR2 mRNA may be a useful marker for predicting the response of metastatic RCC to IFN-alpha ± sorafenib therapy.
authors.affiliation: Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Furuya
authors.forename: Takao
authors.initials: T
authors.lastname: Kamai
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Shirataki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yanai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nakamura
authors.forename: Tsunehito
authors.initials: T
authors.lastname: Kambara
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Abe
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta; D009536:Niacinamide; D000077157:Sorafenib