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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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2012; 7(7):1069-77. · 4.55 Impact Factor
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ABSTRACT: To review selected biomarkers of DNA repair and related pathways as they relate to the management of patients with non-small cell lung cancer (NSCLC), emphasizing the role of individualized, chemotherapy for advanced disease, and discussing potential applications in early disease.
The activity of molecular-targeted agents in NSCLC patients whose tumor possesses relevant biomarkers [such as epidermal growth factor receptor (EGFR) activating mutations and ALK translocations] has made personalized therapy possible. In addition, preclinical and clinical studies have shown that histopathological and biomolecular factors can correlate with clinical outcome in patients with NSCLC treated with chemotherapy. As a result, tumor histology is now routinely considered in selecting chemotherapy for NSCLC patients, such as pemetrexed for nonsquamous histology. Molecular tumor and host factors, including genes involved in DNA-repair and synthesis, are potentially even more relevant as predictive biomarkers of tumor response to chemotherapy. However, individual molecular markers and gene signatures need further validation and standardization, before routine use in the clinic can be recommended.
In the era of molecular-targeted agents, individualized therapy based on molecular biomarkers has become a reality in the treatment of patients with advanced NSCLC. Further studies are needed to optimize current treatment algorithms with regard to biomarkers for chemotherapy benefit, to refine molecular markers, and to translate these findings to early stage NSCLC.
Current opinion in oncology 03/2011; 23(2):150-7. · 4.09 Impact Factor
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ABSTRACT: Inhibitor of differentiation 1 (ID1) plays a role in cellular differentiation, proliferation, angiogenesis and tumor invasion. As shown recently, ID1 is positively regulated by the tyrosine kinase SRC in lung carcinoma cell lines and with that appears as a potential new therapeutic target in non-small cell carcinoma (NSCLC). To substantiate this hypothesis we examined ID1, SRC and matrix metalloproteinase-9 (MMP-9) immunohistochemically in human NSCLC specimens.
From 61 consecutive patient tissue samples of a tumor tissue bank a one core tissue microarray (TMA) was produced and whole slide tissue samples of preinvasive lesions used. The staining of commercial antibodies was assessed by the H-score. Statistical analyses based on Spearman's rank correlation coefficient.
ID1 was expressed in the nucleus in 70% of squamous cell carcinomas and 50% of non-squamous cell carcinomas and in vascular endothelium of non-tumor tissue. Cytoplasmic staining was found in all samples for SRC and in 93% for MMP-9. ID1-positive tissue samples co-expressed SRC and MMP-9 in 94%. In non-squamous cell carcinomas, H-scores of ID1 and SRC correlated with each other (p=0.04). H-score of MMP-9 correlated with tumor grade (p=0.04). The carcinoma findings were reflected in preinvasive lesions.
We describe for the first time the immunohistochemical expression of ID1 in the majority of NSCLC samples. The almost general co-expression of ID1, SRC and MMP-9 supports their cooperation in vivo and warrants further investigation of ID1 as a therapeutic target.
Lung cancer (Amsterdam, Netherlands) 03/2011; 71(3):306-11. · 3.14 Impact Factor
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ABSTRACT: Src tyrosine kinases regulate multiple genetic and signaling pathways involved in the proliferation, survival, angiogenesis, invasion, and migration of various types of cancer cells They are frequently expressed and activated in many cancer types, including lung cancer. Several Src inhibitors, including dasatinib, saracatinib, bosutinib, and KX2-391, are currently being investigated in clinical trials. Preliminary results of the use of single-agent Src inhibitors in unselected patients with lung cancer show that these inhibitors have a favorable safety profile and anticancer activity. Their combination with cytotoxic chemotherapy, other targeted therapy, and radiation therapy is currently being explored. In this review, we summarize the rationale for and the current status of Src inhibitor development and discuss future directions based on emerging preclinical data.
Clinical Lung Cancer 07/2010; 11(4):238-42. · 2.94 Impact Factor
