RESUMO
Colon cancer is one of the most fatal cancers in the United States, and is characterized by the presence of chromosomal instability (CIN), causes of which are largely unclear. Emerging evidence indicates that abnormal spindle geometry and supernumerary centrosomes lead to CIN in cells. However, if and how spindle geometry defects and centrosomes amplification occur in colon cancer remains unknown. Here we show that decrease in the cell cycle regulatory protein, cyclin A2, induces spindle geometry defects in colon cancer cells. In mechanistic studies, we found that cyclin A2 is located at the centrosomes, and its depletion reduces phosphorylation of EG5, which is important for centrosome localization and movement of duplicated centrosomes to opposite poles. We also found that cyclin A2 silencing leads to centrosome amplification in the cells. Collectively, these findings demonstrate previously unrecognized role for cyclin A2 in preventing centrosomal defects in colon cancer cells and provide insights into mechanisms that may potentially cause CIN in these tumors.
RESUMO
Recent studies have demonstrated that the dysregulation of miRNAs are frequently associated with cancer progression including gastric cancer (GC). MiR-211 was found to act as tumor suppressor in GC, however, the functional role of miR-211 involved in GC cell epithelial-mesenchymal transition (EMT) process still to be investigated. In the study, we demonstrated that miR-211 was lower expression in gastric cancer tissues compared with adjacent normal tissues. Lower miR-211 expression was positively associated with distant metastasis and lymph node metastasis in GC patients. Survival curve by Kaplan-Meier method and log rank test revealed that lower miR-211 expression indicated a poor outcome in GC patients. Function assays showed that miR-211 inhibited cell invasion and cell epithelial-mesenchymal transition (EMT) process in GC by upregulating E-cadherin expression and down-regulating twist1 and N-cadherin expression. Furthermore, we demonstrated that miR-211 suppressed cell EMT by targeting MMP9 expression in GC. These results showed that miR-211 acted as a tumor suppressor in GC and may be a potential target of GC treatment.
RESUMO
To define the stoichiometry and molecular identity of the Cl(-)/HCO(3)(-) exchanger in the apical membrane of pancreatic duct cells, changes in luminal pH and volume were measured simultaneously in interlobular pancreatic ducts isolated from wild-type and Slc26a6-null mice. Transepithelial fluxes of HCO(3)(-) and Cl(-) were measured in the presence of anion gradients favoring rapid exchange of intracellular HCO(3)(-) with luminal Cl(-) in cAMP-stimulated ducts. The flux ratio of Cl(-) absorption/HCO(3)(-) secretion was â¼0.7 in wild-type ducts and â¼1.4 in Slc26a6(-/-) ducts where a different Cl(-)/HCO(3)(-) exchanger, most likely SLC26A3, was found to be active. Interactions between Cl(-)/HCO(3)(-) exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated ducts were examined by measuring the recovery of intracellular pH after alkali-loading by acetate prepulse. Hyperpolarization induced by luminal application of CFTRinh-172 enhanced HCO(3)(-) efflux across the apical membrane via SLC26A6 in wild-type ducts but significantly reduced HCO(3)(-) efflux in Slc26a6(-/-) ducts. In microperfused wild-type ducts, removal of luminal Cl(-), or luminal application of dihydro-4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid to inhibit SLC26A6, caused membrane hyperpolarization, which was abolished in Slc26a6(-/-) ducts. In conclusion, we have demonstrated that deletion of Slc26a6 alters the apparent stoichiometry of apical Cl(-)/HCO(3)(-) exchange in native pancreatic duct. Our results are consistent with SLC26A6 mediating 1:2 Cl(-)/HCO(3)(-) exchange, and the exchanger upregulated in its absence, most probably SLC26A3, mediating 2:1 exchange.