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: Nobutaka Furuya, Takao Kamai, Hiromichi Shirataki, Yoshiaki Yanai, Takehiko Fukuda, Tomoya Mizuno, Fumihiko Nakamura, Tsunehito Kambara, Kimihiro Nakanishi, Hideyuki Abe, Ken-Ichiro Yoshida
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 60 Issue 6 Pg. 793-808 (Jun 2011) ISSN: 1432-0851 [Electronic] Germany
• PMID: 21350947 (Publication Type: Journal Article)

Chemical References

• Benzenesulfonates
• IFNAR2 protein, human
• Interferon-alpha
• Phenylurea Compounds
• Pyridines
• RNA, Messenger
• Receptor, Interferon alpha-beta
• Niacinamide
• Sorafenib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Benzenesulfonates (administration & dosage)
• Carcinoma, Renal Cell (blood, drug therapy, genetics, pathology)
• Female
• Humans
• Interferon-alpha (administration & dosage)
• Kidney Neoplasms (blood, drug therapy, genetics, pathology)
• Male
• Middle Aged
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Prognosis
• Pyridines (administration & dosage)
• RNA, Messenger (blood, genetics, metabolism)
• Receptor, Interferon alpha-beta (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sorafenib