The induction of polyploidy is considered the reproductive end of cells, but there is evidence that polyploid giant cancer cells (PGCCs) contribute to cell repopulation during tumor relapse. However, the role of these cells in the development, progression and response to therapy in colon cancer remains undefined. Therefore, the main objective of this study was to investigate the generation of PGCCs in colon cancer cells and identify mechanisms of formation. Treatment of HCT-116 and Caco-2 colon cancer cells with the hypoxia mimic CoCl2 induced the formation of cells with larger cell and nuclear size (PGCCs), while the cells with normal morphology were selectively eliminated. Cytometric analysis showed that CoCl2 treatment induced G2 cell cycle arrest and the generation of a polyploid cell subpopulation with increased cellular DNA content. Polyploidy of hypoxia-induced PGCCs was confirmed by FISH analysis. Furthermore, CoCl2 treatment effectively induced the stabilization of HIF-1α, the differential expression of a truncated form of p53 (p47) and decreased levels of cyclin D1, indicating molecular mechanisms associated with cell cycle arrest at G2. Generation of PGCCs also contributed to expansion of a cell subpopulation with cancer stem cells (CSCs) characteristics, as indicated by colonosphere formation assays, and enhanced chemoresistance to 5-fluorouracil and oxaliplatin. In conclusion, the pharmacological induction of hypoxia in colon cancer cells causes the formation of PGCCs, the expansion of a cell subpopulation with CSC characteristics and chemoresistance. The molecular mechanisms involved, including the stabilization of HIF-1 α, the involvement of p53/p47 isoform and cell cycle arrest at G2, suggest novel targets to prevent tumor relapse and treatment failure in colon cancer.
IL28B gene variations independently predict SVR in HIV/HCV-coinfected patients with HCV genotype 1 and non-genotype 1 HCV infection. The association between rs12979860 and plasma low-density lipoprotein cholesterol suggests that the system low-density lipoprotein ligand/receptor might be involved in the effect of this genotype.
These results suggest that the ERAP1 gene is associated with genetic predisposition to AS and influences the functional severity of the disease in a Spanish population.
The goal of our study was to discriminate potential genetic differences between humans who are in both endpoints of the sports performance continuum (i.e. world-class endurance vs power athletes). We used DNA-microarray technology that included 36 genetic variants (within 20 different genes) to compare the genetic profile obtained in two cohorts of world-class endurance (N=100) and power male athletes (N=53) of the same ethnic origin. Stepwise multivariate logistic regression showed that the rs1800795 (IL6-174 G/C), rs1208 (NAT2 K268R) and rs2070744 (NOS3-786 T/C) polymorphisms significantly predicted sport performance (model χ(2) =25.3, df=3, P-value <0.001). Receiver-operating characteristic (ROC) curve analysis showed a significant discriminating accuracy of the model, with an area under the ROC curve of 0.72 (95% confidence interval: 0.66-0.81). The contribution of the studied genetic factors to sports performance was 21.4%. In summary, although an individual's potential for excelling in endurance or power sports can be partly predicted based on specific genetic variants (many of which remain to be identified), the contribution of complex gene-gene interactions, environmental factors and epigenetic mechanisms are also important contributors to the "complex trait" of being an athletic champion. Such trait is likely not reducible to defined genetic polymorphisms.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.