ABSTRACT
MicroRNAs (miRNAs) play an important role in the development and progression of non-small cell lung cancer (NSCLC). Recently, several studies have shown that miR-99a is downregulated in various cancers, which can affect tumor initiation and maintenance. Herein, we found that miR-99a was downregulated in NSCLC tissues and suppressed tumor metastasis of NSCLC cells. Down-regulation of miR-99a is significantly associated with last-stage and tumor metastasis in NSCLC patients. Further functional experiments found that overexpression of miR-99a inhibit cell proliferation, migration, and invasion of NSCLC cells in vitro and tumor metastasis of NSCLC in vivo. In addition, we also found that AKT1 is directly involved in miR-99a-mediated tumor suppression. Restored the expression of AKT1 partially abolished the suppressive effects miR-99a on proliferation and invasion of NSCLC cells. Collectively, our data suggest that miR-99a plays an important role in the tumorigenesis and metastasis of NSCLC and may serve as a therapeutic target to avoid dissemination of NSCLC cells.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , MicroRNAs/genetics , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Immunoblotting , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Proto-Oncogene Proteins c-akt/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, HeterologousABSTRACT
The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycle regulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application.