miR-124 Inhibits Lung Tumorigenesis Induced by K-ras Mutation and NNK
نویسندگان
چکیده
Dysregulated miRNAs play important role in K-ras mutation or smoking caused lung tumorigenesis. Here, we investigate the role and mechanism of miR-124 in K-ras mutation or smoking-caused lung tumorigenesis and evaluate the therapeutic potential of miR-124 agomiR in K-ras mutation or smoking-caused lung cancer treatment. Our data show that smoking suppresses miR-124 expression, and decreased miR-124 expression is inversely correlated with the p-Akt level and predicts poor overall survival in non-small-cell lung cancer (NSCLC) patients. The overexpression of miR-124 suppressed NSCLC growth by inhibiting the Akt pathway by targeting Akt1 and Akt2. In addition, the systemic delivery of miR-124 agomiR dramatically suppressed tumorigenesis in both NNK-induced lung cancer model and K-rasLA1 transgenic mice by increasing apoptosis and inhibiting cell proliferation. Our findings suggest that smoking inhibits the expression of miR-124, and decreased miR-124 contributes to Akt activation, thereby promoting NSCLC progression. Our findings also represent a novel potential therapeutic strategy for lung cancer.
منابع مشابه
The effect of 12 weeks of submaximal swimming training on immunoreactivity of Ras and Raf-1 in lung epithelial cells of Wistar rats exposed to carcinogen NN
The aim of this study was to investigate changes in immunoreactivity of Ras and Raf-1 in lung epithelial cells of rats exposed to carcinogen NNK after swimming training. 50 Wistar rats were randomly divided into five groups: control, training, training + NNK, NNK and sham. NNK-induced groups received NNK Subcutaneously once a week at a dose of 12/5 mg per kg body weight for 12 weeks. The exerci...
متن کاملK-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation.
BACKGROUND Chronic lung inflammation has been associated with an increased risk of lung cancer. However, it is unclear whether such an event affects the incidence of mutations in the K-ras oncogene frequently found in lung tumors and suggested to be involved in lung tumorigenesis. This study investigated potential impacts of inflammation on the incidence of lung tumors and K-ras mutations using...
متن کاملfrom A/J Mice Treated with Nitrosamines Protooncogene in Lung Tumors ras and the Activation of the K- Relationship between the Formation of Promutagenic Adducts
Lung and liver tumors were induced in female A/J mice after treatment for 7 weeks (3 times/week, i.p.) with either 4-{ALmethyl-A'-nitrosamino)l-(3-p\ridyl)-l-butanone (NNK) (50 mg/kg) or nitrosodimethylamine (NOMA) (3 mg/kg). Both compounds can be activated via a-hydroxylation to methylating agents, while NNK may also undergo hydroxylation at the /V-mcthyl carbon to form a pyridyloxobutylated a...
متن کاملmiR-200 Inhibits lung adenocarcinoma cell invasion and metastasis by targeting Flt1/VEGFR1.
The microRNA-200 (miR-200) family is part of a gene expression signature that predicts poor prognosis in lung cancer patients. In a mouse model of K-ras/p53-mutant lung adenocarcinoma, miR-200 levels are suppressed in metastasis-prone tumor cells, and forced miR-200 expression inhibits tumor growth and metastasis, but the miR-200 target genes that drive lung tumorigenesis have not been fully el...
متن کاملRelationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines.
Lung and liver tumors were induced in female A/J mice after treatment for 7 weeks (3 times/week, i.p.) with either 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (50 mg/kg) or nitrosodimethylamine (NDMA) (3 mg/kg). Both compounds can be activated via alpha-hydroxylation to methylating agents, while NNK may also undergo hydroxylation at the N-methyl carbon to form a pyridyloxobutylate...
متن کامل