ABSTRACT
Non-small cell lung cancer (NSCLC) accounts for â¼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.
Subject(s)
MicroRNAs/genetics , Proto-Oncogene Proteins c-met/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , 3' Untranslated Regions/genetics , Apoptosis/drug effects , Apoptosis/genetics , Binding Sites/genetics , Blotting, Western , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cysteine Proteinase Inhibitors/pharmacology , Down-Regulation , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Humans , JNK Mitogen-Activated Protein Kinases/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mutation , Oligopeptides/pharmacology , Proto-Oncogene Mas , Proto-Oncogene Proteins c-met/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The mitotic cell cycle is a tightly regulated process that ensures the correct division of one cell into two daughter cells. Progress along the different phases of the cell cycle is positively regulated by the sequential activation of a family of serine-threonine kinases called CDKs (Cyclin Dependent Kinases). Their activity is counteracted by small proteins known as CDK inhibitors (CKI) that ensure the correct timing of CDK activation in the different phases of the cell cycle. The present review will deal with the role of one of this CKI, p27(kip1), in human cancer, focusing in particular on the mechanisms underlying its functional inactivation in tumor cells. p27(kip1) protein downregulation is usually achieved by proteasomal degradation and is often correlated to a worse prognosis in several types of human cancers, resulting in the reduction of disease free and overall survival. More recently, it has been proposed that p27(kip1) protein, rather than degraded, can be functionally inactivated. The mechanisms and the implications of these two types of p27(kip1) deregulation will be discussed and some potential therapeutic approaches targeting p27(kip1) functions will be proposed.
Subject(s)
Cell Cycle Proteins/physiology , Cell Cycle/physiology , Neoplasms/pathology , Tumor Suppressor Proteins/physiology , Animals , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Division/physiology , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Gene Expression Regulation, Neoplastic , Gene Silencing , Genetic Therapy/methods , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
The aim of the present study was to examine the immediate effect of smoking a cigarette on gingival crevice fluid (GCF) flow-rate. The study involved 17 healthy volunteers (6 male, 11 female) aged 19-57 years (mean 34.5 years) who regularly smoked cigarettes. All were periodontally healthy. GCF was collected at the mesio-buccal aspects of the right and left maxillary 2nd premolar teeth, using filter-paper strips left in place for 3 min. Samples were taken at baseline and subsequently at 10 min intervals for 70 min. Each subject sham smoked an unlit standard cigarette for 7 min after the 20 min recording, and smoked the same cigarette for 7 min to within 1 cm of the filter, following the 40 min recording. The results showed that following sham smoking (30 min recording) GCF volume increased by a mean of 16.7% (p = 0.057), and following smoking (50 min recording) GCF volume increased by a mean of 89.7%, over the previous recording (p < 0.0001). The increase following smoking was greater than that following sham smoking (p < 0.0001). Flow-rate returned to near resting levels within the experimental period. The results indicate that smoking produces a marked transient increase in GCF flow-rate, which might reflect changes in blood flow known to be produced by nicotine.
