title: Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: an in vivo and in vitro study.
abstract: We aimed to investigate the relationship between the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the radiation tolerance of patients with head and neck squamous cell carcinoma (HNSCC). From January 2015 to January 2016, 117 patients with HNSCC were enrolled in our study and assigned into the sensitive and tolerance groups based on curative effect. Immunohistochemistry (IHC) was conducted to measure protein expressions of Nrf2, heme oxygenase-1 (HO1), NADPH quinine oxidoreductase 1 (NQO1) and glutathioneS-transferase (GST). Human squamous cell carcinoma cell line, HSC-4, was induced by radiation to construct the HSC-4-radiation resistance (RR) cell line. HSC-4 and HSC-4-RR were also assigned into the blank, negative control (NC) andNrf2siRNA groups. Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed to detect cell viability, mRNA expression and protein expression, respectively, of Nrf2, HO1, NQO1 and GST. A total of 40 nude mice were equally assigned into the untreated,Nrf2siRNA, radiation therapy (RT) and RT +Nrf2siRNA groups. Compared with the sensitive group, patients in the tolerance group had upregulated Nrf2, HO1, NQO1 and GST expressions. HSC-4-RR cell line had improved cell viability and higher protein and mRNA expressions of Nrf2, HO1, NQO1 and GST compared with HSC-4 cell line. Compared with the HSC-4-NC and HSC-4-blank groups, the HSC-4-Nrf2siRNA group had downregulated cell viability. Compared with the HSC-4-RR-NC and HSC-4-RR-blank groups, the HSC-4-RR-Nrf2siRNA group had lower cell viability. However, the HSC-4-RR-Nrf2siRNA group had elevated cell viability than the HSC-4-Nrf2siRNA group. Tumor volume and tumor weight in the RT and RT +Nrf2siRNA groups decreased evidently. The RT +Nrf2siRNA group exhibited decreased tumor volume and tumor weight in comparison with the RT group. Our data demonstrated that downregulation of HO1, NQO1 and GST via inhibiting Nrf2 signaling pathway reduces the radiation tolerance of patients with HNSCC.
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Jun-Peng
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Cheng
authors.affiliation: Department of Radiotherapy, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Ye-Min
authors.initials: YM
authors.lastname: Liang
keywords: NADPH quinine oxidoreductase 1; glutathione S-transferase; head and neck squamous cell carcinoma; heme oxygenase-1; nuclear factor erythroid 2-related factor 2; radiation tolerance; signaling pathway