ABSTRACT
BACKGROUND: Gene targeted therapy refers to any therapy focused on one of the many biological features of the tumor. Such features are mediated by specific genes that are involved in tumor metastasis, recurrence, poor response to chemotherapy and others. Hypoxia is an important pathognomonic feature of many malignant tumors including SCLC (small cell lung cancer). HIF-1alpha, which is induced by hypoxia, is the most important regulatory factor of many specific genes that can influence the biological features of tumors. METHODS: In this study, we tried to elucidate the changes in gene expression profiles of SCLC NCI-H446 cells mediated by HIF-1alpha. According to different treatments of cells, three experimental pairwise comparisons were designed: hypoxia group vs. control group, Ad5-HIF-1alpha group vs. Ad5 group, and Ad5-siHIF-1 alpha group Vs Ad5 group. RESULTS: Results from the analysis of gene expression profiles indicated that there were 65 genes upregulated and 28 genes downregulated more than two-fold in all three experimental pairwise comparisons. These genes were involved in transport, signal-transduction, cell adhesion/motility, growth factor/cytokines, transcription, inflammatory response, metabolic process, in addition to others. SOCS1, IGFBP5, IL-6 and STAT3 were also upregulated at protein level. SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells but HIF-1alpha could induce growth and suppress apoptosis. CONCLUSIONS: Through this research, we are trying to find novel functional genes that are mediated by HIF-1alpha and provide the theoretical basis for new therapeutic targets. HIF-1 alpha maybe upregulate the expression of SOCS1 through mediation of STAT3 and IL-6. In addition, SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells. This was contrary to HIF-1alpha and it indicated that there might be an antagonism effect between HIF-1alpha and SOCS1 on regulating growth and apoptosis of NCI-H446 cells.
Subject(s)
Carcinoma, Small Cell/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Lung Neoplasms/genetics , Apoptosis/genetics , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , Cell Growth Processes/genetics , Cell Hypoxia/genetics , Cell Line, Tumor , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Insulin-Like Growth Factor Binding Protein 5/biosynthesis , Insulin-Like Growth Factor Binding Protein 5/genetics , Interleukin-6/biosynthesis , Interleukin-6/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Microarray Analysis , STAT3 Transcription Factor/biosynthesis , STAT3 Transcription Factor/genetics , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins/biosynthesis , Suppressor of Cytokine Signaling Proteins/genetics , TransfectionABSTRACT
Forty-five patients (20 men and 25 women) with a median age of 46.5 years, who were diagnosed with esophageal achalasia by clinical history, esophagoscopy, and barium esophagogram, underwent thoracoscope-assisted Heller myotomy with a minimal incision. Esophageal pressure and pH were monitored. Two patients were excluded because of mucosal perforation during the operation, requiring conversion to an open procedure. There was no postoperative esophageal leakage or hospital death. All patients resumed a normal diet as soon as gastrointestinal function recovered, and their symptoms disappeared completely. The mean operative time was 1.2 hours (range, 0.5-3.8 hours). After 2.1 years of follow-up, the outcome was rated excellent in 33 (77%) patients, good in 7 (16%), and fair in 3 (7%). Esophageal dilation was required in 3 patients because of relapsing dysphagia within 3 months after the operation. Four (9%) patients had some regurgitation but no further surgical or medical treatment was needed. Esophageal pressure and pH correlated with the clinical manifestations. Our modified Heller myotomy with the assistance of thoracoscopy is effective for achalasia.
