ABSTRACT
Deregulated microRNAs (miRNAs) are small noncoding RNAs that are involved in the carcinogenesis of various cancers, including lung cancer. HIF1a has been suggested to be a master regulator of hypoxia-induced cell proliferation. The relationship between HIF1a expression and the progression of non-small cell lung cancer (NSCLC) is not fully understood, and whether HIF1a expression is regulated by miRNAs in this process remains unclear. In this study, we found that the upregulation of HIF1a expression and the reduction in miR-199a levels were highly associated with NSCLC progression. NSCLC cells derived from cancer tissues with low miR-199a levels showed high HIF1a expression and high proliferation capacity. Moreover, HIF1a and glycolysis inhibitors suppress the proliferation of NSCLC cells. MiR-199a overexpression suppressed the hypoxia-induced proliferation of NSCLC cells through targeting elevated HIF1a and blocking the downstream upregulation of PDK1 without affecting AKT activation. Together, these results indicate that downregulation of miR-199a is essential for hypoxia-induced proliferation through derepressing the expression of HIF1a expression and affecting HIF1a mediated glycolytic pathway in NSCLC progression.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Hypoxia/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung Neoplasms/genetics , MicroRNAs/genetics , Cell Line, Tumor , Cell Proliferation , Glycolysis/genetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , MicroRNAs/metabolism , Protein Serine-Threonine Kinases/biosynthesis , Proto-Oncogene Proteins c-akt/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Up-RegulationABSTRACT
A few case-control studies were performed to assess the association between X-ray repair cross-complementing group 3 (XRCC3) rs861539 C/T polymorphism and lung cancer susceptibility, but no consistent finding was reported. In the present study, we performed a meta-analysis of 14 case-control studies with a total of 7,869 lung cancer cases and 10,778 controls to provide a comprehensive assessment of the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk. Pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs) were calculated to assess the strength of the association. Overall, there was no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models [OR (95 % CI) for T versus C, 1.00 (0.89-1.13), P = 0.99; OR (95 % CI) for TT versus CC, 1.07 (0.81-1.41), P = 0.62; OR (95 % CI) for TT/CT versus CC, 0.95 (0.84-1.07), P = 0.39; OR (95 % CI) for TT versus CT/CC, 1.10 (0.86-1.39), P = 0.62]. In the subgroup analyses of both Asians and Caucasians, there was still no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models (All P values were more than 0.05). However, there was an obvious association between XRCC3 rs861539 C/T polymorphism and decreased risk of lung cancer in the subgroup analysis of the mixed population (All P values were less than 0.05). In addition, there was some risk of publication bias in the meta-analysis, and there was obvious discrepancy in the findings between studies with large sample size and studies with small sample size in the meta-analysis. The meta-analysis indicates that the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk is still uncertain owing to the obvious discrepancy in the findings between studies with large sample size and studies with small sample size. More studies with large sample size are needed to further assess the association.
