MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14)

Accumulating evidence suggests that microRNAs (miRNAs) are important gene regulators, which can have critical roles in diverse biological processes including tumorigenesis. In this study, we analyzed the miRNA expression profiles in non-small cell lung carcinoma (NSCLC) by use of a miRNA microarray platform and identified 40 differentially expressed miRNAs. We showed that miRNA (miR)-451 was the most downregulated in NSCLC tissues. The expression level of miR-451 was found to be significantly correlated with tumor differentiation, pathological stage and lymph-node metastasis. Moreover, low miR-451 expression level was also correlated with shorter overall survival of NSCLC patients (P<0.001). Ectopic miR-451 expression significantly suppressed the in vitro proliferation and colony formation of NSCLC cells and the development of tumors in nude mice by enhancing apoptosis, which might be associated with inactivation of Akt signaling pathway. Interestingly, ectopic miR-451 expression could significantly inhibit RAB14 protein expression and decrease a luciferase-reporter activity containing the RAB14 3′-untranslated region (UTR). In addition,, RNA interference silencing of RAB14 gene could recapitulate the tumor suppressor function of miR-451, whereas restoration of RAB14 expression could partially attenuate the tumor suppressor function of miR-451 in NSCLC cells. Furthermore, we also showed that strong positive immunoreactivity of RAB14 protein was significantly associated with downregulation of miR-451 (P=0.01). These findings suggest that miR-451 regulates survival of NSCLC cells partially through the downregulation of RAB14. Therefore, targeting with the miR-451/RAB14 interaction might serve as a novel therapeutic application to treat NSCLC patients.

[1]  F. Djouad,et al.  Concerted stimuli regulating osteo-chondral differentiation from stem cells: phenotype acquisition regulated by microRNAs , 2009, Acta Pharmacologica Sinica.

[2]  P. Dennis,et al.  Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. , 2001, Cancer research.

[3]  Wei Shi,et al.  Comprehensive MicroRNA Profiling for Head and Neck Squamous Cell Carcinomas , 2010, Clinical Cancer Research.

[4]  J. Haier,et al.  MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. , 2010, European journal of cancer.

[5]  G. Yousef.  microRNAs: a new frontier in kallikrein research , 2008, Biological chemistry.

[6]  Kishore Guda,et al.  The noncoding RNA, miR‐126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3‐kinase signaling and is frequently lost in colon cancers , 2008, Genes, chromosomes & cancer.

[7]  S. Baylin,et al.  Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  K. Kaibuchi,et al.  Small GTP-binding proteins. , 1992, International review of cytology.

[9]  Jackeline Agorreta,et al.  microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells , 2009, Clinical Cancer Research.

[10]  G. Mills,et al.  Emerging role of RAB GTPases in cancer and human disease. , 2005, Cancer research.

[11]  J. Rehwinkel,et al.  MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay. , 2006, Cold Spring Harbor symposia on quantitative biology.

[12]  G. Tsujimoto,et al.  MicroRNA-338-3p and microRNA-451 contribute to the formation of basolateral polarity in epithelial cells , 2009, Nucleic acids research.

[13]  Olga Kovalchuk,et al.  Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin , 2008, Molecular Cancer Therapeutics.

[14]  Mark M Perry,et al.  microRNA expression in the aging mouse lung , 2007, BMC Genomics.

[15]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[16]  J. Lorens,et al.  MicroRNAs in tumorigenesis. , 2007, Current pharmaceutical biotechnology.

[17]  Guohong Li,et al.  Role of specific microRNAs for endothelial function and angiogenesis. , 2009, Biochemical and Biophysical Research Communications - BBRC.

[18]  Robert H. Moore,et al.  Regulation of G-protein-coupled receptor activity by rab GTPases. , 2002, Receptors & channels.

[19]  R. Khanin,et al.  Dynamic Changes in Lung MicroRNA Profiles During the Development of Pulmonary Hypertension due to Chronic Hypoxia and Monocrotaline , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[20]  C. Stournaras,et al.  Control of transforming growth factor β signal transduction by small GTPases , 2009, The FEBS journal.

[21]  J. Yun,et al.  MicroRNA‐195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells , 2009, Hepatology.

[22]  S. Shenouda,et al.  MicroRNA function in cancer: oncogene or a tumor suppressor? , 2009, Cancer and Metastasis Reviews.

[23]  Dong Li,et al.  DIFFERENTIAL microRNA EXPRESSION IN CHILDHOOD B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA , 2009, Pediatric hematology and oncology.

[24]  J. Minna,et al.  Focus on lung cancer. , 2002, Cancer cell.

[25]  E. Medrano,et al.  The cytotoxicity and apoptosis induced by 4-tertiary butylphenol in human melanocytes are independent of tyrosinase activity. , 2000, The Journal of investigative dermatology.

[26]  Chaojun Li,et al.  Knockdown of c-Met by adenovirus-delivered small interfering RNA inhibits hepatocellular carcinoma growth in vitro and in vivo , 2005, Molecular Cancer Therapeutics.

[27]  S. Alahari,et al.  miRNA control of tumor cell invasion and metastasis , 2010, International journal of cancer.

[28]  D. Lin,et al.  Overexpression of Osteopontin Is Associated with More Aggressive Phenotypes in Human Non–Small Cell Lung Cancer , 2005, Clinical Cancer Research.

[29]  C. Croce,et al.  MicroRNAs in cancer: small molecules with a huge impact. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Gideon Rechavi,et al.  MIR-451 and Imatinib mesylate inhibit tumor growth of Glioblastoma stem cells. , 2008, Biochemical and biophysical research communications.

[31]  M. Peter,et al.  Targeting of mRNAs by multiple miRNAs: the next step , 2010, Oncogene.

[32]  G. Mills,et al.  The Emerging Role of the RAB25 Small GTPase in Cancer , 2009, Traffic.

[33]  Yiming Wu,et al.  Analysis and Identification of Tumor Marker in Lung Cancer using Two-dimensional Gel Electrophoresis and Matrix-assisted Laser Desorption Ionization Time of Flight Mass Spectrometry , 2009 .

[34]  Xiuping Liu,et al.  Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. , 2008, Biochemical pharmacology.

[35]  J. Inazawa,et al.  Down‐regulation of SKP2 induces apoptosis in lung‐cancer cells , 2003, Cancer science.

[36]  K. Chaudhuri,et al.  MicroRNA detection and target prediction: integration of computational and experimental approaches. , 2007, DNA and cell biology.

[37]  Eva E. Rufino-Palomares,et al.  MicroRNAs as Oncogenes and Tumor Suppressors , 2013 .

[38]  Koichiro Muta,et al.  Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. , 2007, Biochemical and biophysical research communications.