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.

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 glutathione S-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) and Nrf2 siRNA 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, Nrf2 siRNA, radiation therapy (RT) and RT + Nrf2 siRNA 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-Nrf2 siRNA group had downregulated cell viability. Compared with the HSC-4-RR-NC and HSC-4-RR-blank groups, the HSC-4-RR-Nrf2 siRNA group had lower cell viability. However, the HSC-4-RR-Nrf2 siRNA group had elevated cell viability than the HSC-4-Nrf2 siRNA group. Tumor volume and tumor weight in the RT and RT + Nrf2 siRNA groups decreased evidently. The RT + Nrf2 siRNA 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.

Definitive chemoradiotherapy with capecitabine and cisplatin for elder patients with locally advanced squamous cell esophageal cancer.

PURPOSE: The aim of this retrospective study is to evaluate the feasibility and efficacy of concurrent chemoradiotherapy (CCRT) or sequential chemoradiotherapy (SCRT) with capecitabine and cisplatin for elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 75 patients elder than 65 years with histologically proven stage II-III ESCC were enrolled, in whom 40 patients were treated with CCRT consisted of two cycles of intravenous cisplatin and oral capecitabine during and after radiotherapy and 35 patients were treated with SCRT as two cycles of capecitabine plus cisplatin before and after radiotherapy. Response rate, overall survival, progression-free survival and toxicity were compared. RESULTS: The overall response rate (CR + PR) in the CCRT group (91.6 %) was significantly higher than that in the SCRT group (67.7 %), P = 0.023. The median PFS and median OS were significantly higher in CCRT group (19.7 and 33.6 months) than those in SCRT group (11.6 and 15.7 months), P < 0.05. The acute toxic effect was more severe in the CCRT group than in the SCRT group, but the grade 3-4 acute toxicities were similar in two groups. CONCLUSIONS: It suggested that both CCRT and SCRT with capecitabine and cisplatin are tolerable and effective for elderly patients with locally advanced ESCC. Concurrent CRT might be superior to SCRT.

Application of serial section method to determine the radiotherapy target volume for esophageal squamous carcinoma.

The three-dimensional conformal radiotherapy (3D CRT) plays an important role in the combination treatment of esophageal carcinoma. However, an accurate estimation of the clinical target volume (CTV) of esophageal squamous carcinoma (ESCC) by 3D CRT is still problematic. This study aimed to provide reference values for CTV estimation. The serial section method was applied to observe the range of the microscopic spread proximally and distally from the tumor. Further, relationships between clinicopathological features and the microscopic spread were analyzed. The positive ratio of the proximal microscopic spread was significantly higher than in the distal spread, especially in the specimens sampled 1 and 2 cm away from the tumor (p < 0.05). Probability of infiltration and metastases was still high in the proximal "3 cm" and distal "4 cm" groups, and became much lower in more distant specimens. Further, ESCC tended to exhibit stronger ascending invasion ability. A single factor analysis showed that tumors with the length of longer than 5 cm, poorer differentiation, lymph nodes metastasis, and more aggressive phase had significantly higher microscopic spread ratio (p < 0.05). A multiple factors analysis showed that differentiation degree and tumor length were the major factors affecting the microscopic spread of ESCC. In conclusion, to cover 95 % of the microscopic spread, a proximal margin of 3.0 cm and a distal margin of 4.0 cm are needed. In order to cover 90 %, proximal and distal 3-cm margins are needed. Clinicopathological features of patients can affect the range of the microscopic spread.

Contribution of SDF-1α/CXCR4 signaling to brain development and glioma progression.

The SDF-1α/CXCR4 signaling maintains central nervous system homeostasis through the interaction with the neurotransmitter and neuropeptide systems, the neuroendocrine systems. Recently, the SDF-1α/CXCR4 signaling has been reported to present nonrandom distribution in brain development and glioma progression, which exerts differential regulations on the assembly, differentiation, and function of neural precursors, neurons, glial cells, as well as glioma cells. In the present review, we highlight current knowledge about multiple molecular signaling pathways associated with the SDF-1α/CXCR4 signaling in glioma. Not only is the expression of CXCR4 a key determinant of glioma progression, but SDF-1α is essential for site-specific invasive or metastatic processes. SDF-1α is the switch of the SDF-1α/CXCR4 signaling from the endocrine loop to the autocrine and/or local paracrine loop in glioma progression and brain development. Studies of SDF-1α/CXCR4 signaling in the field of brain development may provide valuable tactics for glioma treatment.

[Proteasome inhibitor bortezomib sensitizes Hep-2 human laryngeal squamous cell carcinoma cells to ionizing radiation in vitro and in vivo].

OBJECTIVE: To determine if proteasome inhibitor bortezomib leads to enhanced radiation sensitivity of Hep-2 human laryngeal cancer cells and the relative mechanisms. METHODS: Hep-2 cells with or without bortezomib were irradiated at 0, 2, 4, 6, 8, and 10 Gy. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a Hep-2 xenograft model. Nuclear factor-kappaB (NF-kappaB) activation was determined by Trans AM NF-kappaB P65 kit. The distribution of cell cycle and apoptosis were evaluated by flow cytometry. Morphological evidence of apoptotic cells were observed with Hochest 33342. RESULTS: It decreased cell growth and clonogenic survival. A 34% increase in radiosensitivity was observed for cells treated with bortezomib and radiation. Enhancement factor (EF) was 1.46 in Hep-2 xenografts receiving radiation and bortezomib. NF-kappaB activation was induced by radiation and inhibited by pretreatment with bortezomib, and was in a dose-dependent manner (r = 0.989, P < 0.05). Hep-2 cells treated with 100 nmol/L Bortezomib were arrested at G2-M phase (t = 22.31, P = 0.000) and resulted in all increased apoptosis with and without irradiation (P < 0.01). Morphological evidence of apoptotic cells could be distinguished under the fluorescence microscope after staining with Hochest 33342. Many nuclear fragments were observed in Hep-2 cells with bortezomib. CONCLUSION: Bortezomib could enhanced the radiosensitivity of Hep-2 laryngeal cancer cells by regulation of the distribution of cell cycle.

The symptom-to-treatment delay and stage at the time of treatment in cancer of esophagus.

OBJECTIVE: The main purpose of this investigation was to measure the delay from the first symptom to treatment in esophageal cancer and to analyse the relation between the delay and stage at the time of treatment. METHODS: A total of 80 patients who were consecutively found to have esophageal cancer between 1 January 2007 and 30 July 2007 at Qilu Hospital of Shandong University in Jinan (China) were included in the retrospective study. Two groups of patients were compared, one group with good prognosis (patients in Stages I and II) and the other group with poor prognosis (patients in Stages III and IV). The symptom-to-treatment delay between the two patient groups was compared using the Mann-Whitney U-test. RESULTS: The median symptom-to-treatment delay was 2.1 months (range from 0.5 to 24). The total symptom-to-treatment delay was made up with the following components: (i) delay from the first symptoms to first contacting the health-care system (69%); (ii) delay from first contacting the health-care system to histological diagnosis of esophageal cancer (20%); and (iii) delay from histological diagnosis to end point (11%). A significantly shorter median symptom-to-treatment delay was found for patients with Stages I and II compared with III and IV (P = 0.0177). CONCLUSIONS: Long delays still occur in patients with esophageal cancer. A few months delay before final treatment of esophageal cancer may have an impact on the stage of the cancer, and thereby on the patients' prognosis. Shorting the delay may result in early detection of esophageal cancer.

[The study of vascular endothelial growth factor in nasopharyngeal carcinoma patients before and after radiotherapy].

OBJECTIVE: The purpose of this study was to determine the serum vascular endothelial growth factor (VEGF) level before and after radiotherapy in the nasopharyngeal carcinoma. METHOD: In this study we used the methods of ELISA to test the serum VEGF level of 66 cases which including 46 cases of nasopharyngeal carcinoma and 20 cases of healthy controls. RESULT: The serum VEGF levels in nasopharyngeal carcinoma patients were significantly higher than those of healthy controls (P < 0.01). The serum levels of VEGF were significantly reduced at the end of radiotherapy (P < 0.01). The recurrence or metastasis rate was significantly higher in cases with > 150 ng/L VEGF level than those with < 150 ng/L. CONCLUSION: VEGF plays an important role in the growth and prognosis of nasopharyngeal carcinoma.