Article

MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma

Department of Clinical Research, University of Bern, Bern, Switzerland.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.8). 05/2012; 7(7):1069-77. DOI: 10.1097/JTO.0b013e31824fe976
Source: PubMed

ABSTRACT MicroRNAs are small, noncoding RNAs that suppress gene expression by binding to the 3' untranslated region (UTR) and thereby repress translation or decrease messenger RNA stability. Inhibitor of differentiation 1 (ID1) is a putative stem-cell gene involved in invasion and angiogenesis. We previously showed that ID1 is regulated by Src kinases, overexpressed in human lung adenocarcinoma, and targeted by Src-dependent microRNAs. The current study focused on the association between miR-381 and ID1 in lung adenocarcinoma.
An ID1 3'UTR-luciferase reporter assay was used to determine whether miR-381 directly targets ID1. Human lung cancer cell lines were stably transduced with a precursor of miR-381 to evaluate its role on ID1 expression and to investigate changes in cell migration and invasion. The Src tyrosine kinase inhibitors saracatinib and dasatinib were used to repress ID1 expression. MiR-381 expression was measured in 18 human lung adenocarcinomas and corresponding normal lung tissue by quantitative reverse-transcription polymerase chain reaction.
ID1 is a direct target of miR-381 as shown by 3'UTR luciferase reporter assays. MiR-381 expression was negatively correlated with ID1 expression in lung cancer cell lines. Ectopic expression of miR-381 reduced ID1 mRNA and protein levels, and significantly decreased cell migration and invasion. Furthermore, miR-381 was significantly downregulated in human lung adenocarcinomas, and low miR-381 expression levels correlated with poor prognosis.
These results suggest that downregulation of miR-381 and thus induction of its target ID1 may contribute to the metastatic potential of lung adenocarcinomas. Further studies to explore potential therapeutic strategies, including Src inhibitors, are ongoing.

0 Followers
 · 
225 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Radiation resistance poses a major clinical challenge in treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms of radioresistance has not been fully elucidated. Since accumulating evidence demonstrates that aberrant expression of microRNAs (miRNAs) contributes to cancer sensitivity to radiation, we aimed to identify miRNAs associated with radioresistance of ESCC. In this study, we used GeneChip miRNA Array to perform an comparison of miRNAs expression in tissues from primary ESCC and recurrent ESCC in situ after radiotherapy. Differential expressions of miRNAs were comfirmed by quantitative Real-Time PCR in tissues and six ESCC cell lines. Cell radiosensitivity were determined by colony formation assay. Functional analyses of miRNA-381 in ESCC cells growth and metastasis were performed by MTT and Transwell Assays. In vivo assays of the functions of miRNA-381 were performed in tumor xenografts. One miRNA candidate, miRNA-381, was found to be downregulated in radiation resistance tissues and cells. Enforced expression of miRNA-381 increased radiosensitivity of ESCC cells and promoted nonaggressive phenotype including decreased cellular proliferation and migration. In contrast, inhibition of miRNA-381 in ESCC cells promoted radiation resistance and development of an aggressive phenotype. In vivo assays extended the significance of these results, showing that miRNA-381 overexpression decreased the tumor growth and the resistance to radiation treatment in tumor xenografts. Together, our work reveals miRNA-381 expression as a critical determinant of radiosensitivity in esophageal cancer cells.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNA-381 (miR-381) is a highly expressed onco-miRNA that is involved in malignant progression and has been suggested to be a good target for glioblastoma multiforme (GBM) therapy. In this study, we employed two-dimensional fluorescence differential gel electrophoresis (2-D DIGE) and MALDI-TOF/TOF-MS/MS to identify 27 differentially expressed proteins, including the significantly upregulated neurofilament light polypeptide (NEFL), in glioblastoma cells in which miR-381 expression was inhibited. We identified NEFL as a novel target molecule of miR-381 and a tumor suppressor gene. In human astrocytoma clinical specimens, NEFL was downregulated with increased levels of miR-381 expression. Either suppressing miR-381 or enforcing NEFL expression dramatically sensitized glioblastoma cells to temozolomide (TMZ), a promising chemotherapeutic agent for treating GBMs. The mechanism by which these cells were sensitized to TMZ was investigated by inhibiting various multidrug resistance factors (ABCG2, ABCC3, and ABCC5) and stemness factors (ALDH1, CD44, CKIT, KLF4, Nanog, Nestin, and SOX2). Our results further demonstrated that miR-381 overexpression reversed the viability of U251 cells exhibiting NEFL-mediated TMZ sensitivity. In addition, NEFL-siRNA also reversed the proliferation rate of U251 cells exhibiting locked nucleic acid (LNA)-anti-miR-381-mediated TMZ sensitivity. Overall, the miR-381-NEFL axis is important for TMZ resistance in GBM and may potentially serve as a novel therapeutic target for glioma.
    Oncotarget 12/2014; · 6.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cigarette smoke is associated with the majority of lung cancers: however, 25% of lung cancer patients are non-smokers, and half of all newly diagnosed lung cancer patients are former smokers. Lung tumors exhibit distinct epidemiological, clinical, pathological, and molecular features depending on smoking status, suggesting divergent mechanisms underlie tumorigenesis in smokers and non-smokers. MicroRNAs (miRNAs) are integral contributors to tumorigenesis and mediate biological responses to smoking. Based on the hypothesis that smoking-specific miRNA differences in lung adenocarcinomas reflect distinct tumorigenic processes selected by different smoking and non-smoking environments, we investigated the contribution of miRNA disruption to lung tumor biology and patient outcome in the context of smoking status.
    BMC Cancer 01/2014; 14(1):778. DOI:10.1186/1471-2407-14-778 · 3.32 Impact Factor