miRNA
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Lung cancer is the malignant transformation and expansion of lung tissue, and is the most lethal of all cancers worldwide, with some estimates citing up to 3 million deaths annually. There are two main types of lung cancer categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80%) and small-cell (roughly 20%) lung cancer. While lung cancer is typically associated with individuals who smoke, a strong genetic component has been identified, as well. Recent studies suggest that greater than 60 DNA variants (low-penetrance alleles) seem to slightly increase a person's risk of acquiring lung cancer. As the leading cause of cancer deaths in the world, there is a need for more thorough investigation into the mechanisms that underlie lung carcinogenesis. While molecular discoveries thus far have aided in characterizing the evolution of lung cancer, unknown markers will undoubtedly prove to be invaluable in gaining a complete picture of lung cancer biology. One such area offering novel opportunities in biomarker discovery involves the role of miRNA in gene regulation by epigenetic mechanisms. Traditionally, miRNA expression has been tested using low-throughput techniques such as Northern-blot analysis and real-time PCR, but new developments in microarray technology now enable global profiling of all miRNA genes and their precursors in any sample type.
Nozomu Yanaihara and colleagues (2006) examined microRNA molecular profiles in lung cancer diagnosis and prognosis to begin to gain an understanding of their involvement in lung carcinogenesis and found that miRNA expression profiles were, in fact, diagnostic and prognostic markers of lung cancer. The group used RT-PCR techniques in conjunction with microarray analysis to identify and confirm miRNA expression signatures, linking extensive alterations of miRNA expression to deregulation of cancer-related genes. The miRNA molecular signature of lung adenocarcinomas, including those without evidence of metastasis, also correlated with patient survival.
Title: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis.
Authors: Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC
Journal: Cancer Cell, Vol 9, Issue 3: 189-98
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Yoji Hayashita and researchers in Japan (2005) examined a panel of lung cancer cell lines for the presence of alterations in 21 miRNAs, which were pre-selected based on the potential significance of their putative TargetScan algorithm–predicted target genes in terms of cancer development. The group combined Northern and Southern blot analysis with real-time RT-PCR to perform comprehensive profiling of miRNAs in 19 lung cancer cell lines and two immortalized lung epithelial cell lines. This research documented the first evidence of frequent and marked overexpression, with occasional gene amplification, of clustered miRNAs (miR-17-92) within intron 3 of the C13orf25 gene at 13q31.3 in lung cancers, especially those examples with small-cell lung cancer histology. The group further showed the stimulatory activity of this miRNA cluster in lung cancer cell growth and discussed the possibility that the C13orf25 gene may serve as a vehicle for the expression of miR-17-92.
Title: A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation.
Authors: Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T
Journal: Cancer Res, Vol 65, Issue 21: 9628-32
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Steven Johnson and researchers from Yale University teamed up with scientists from Ambion, Inc. (2005) to assess the role of the lethal-7 (let-7) microRNA family in regulation of the gene associated with the signaling G-protein, RAS. The group combined Northern blot and microarray analysis, and found that the let-7 miRNA family negatively regulates RAS in two different C. elegans tissues and in two different human cell lines. Specifically, they found that expression of let-7 inversely correlated with expression of RAS protein in lung cancer tissues and overexpression of let-7 inhibited growth of a lung cancer cell line in vitro, suggesting a possible causal relationship. The combined observations that let-7 expression was reduced in lung tumors, that several let-7 genes mapped to genomic regions that are often deleted in lung cancer patients, that overexpression of let-7 could inhibit lung tumor cell line growth, that the expression of the RAS oncogene was regulated by let-7, and that RAS was significantly overexpressed in lung tumor samples strongly implicated let-7 as a tumor suppressor in lung tissue.
Title: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.
Authors: Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T
Journal: Cancer Res, Vol 64, Issue 11: 3753-6
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Title: Reduced expression of Dicer associated with poor prognosis in lung cancer patients.
Authors: Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, Yatabe Y, Takamizawa J, Miyoshi S, Mitsudomi T, Takahashi T
Journal: Cancer Sci, Vol 96, Issue 2: 111-5
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Title: MicroRNA and lung cancer.
Authors: Eder M, Scherr M
Journal: N Engl J Med, Vol 352, Issue 23: 2446-8
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Title: Small RNAs and non-small cell lung cancer.
Authors: Tong AW
Journal: Curr Mol Med, Vol 6, Issue 3: 339-49
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