miRNA
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Both prostate and colon cancers (as well as breast and lung cancers) are epithelial forms of cancer, characterized as a malignancy of the tissue that surrounds organs, rather than organs themselves. Prostate cancer now exceeds lung cancer as the most commonly diagnosed cancer in men living in the United States and the second leading cause of cancer death. Colon cancer is the third most common form of cancer and the second leading cause of death among cancers in the Western world. While there has been significant research on both prostate and colon cancers, as well as epithelial cancers in general, little is known about the molecular causes of tumorigenesis in these cancers. Recent findings in prostate cancer suggest that chromosomal rearrangements induce specific genes to merge, creating what scientists call a gene fusion, and these fused genes present a unique molecular signature in the majority of prostate cancer tissue samples analyzed, but found no evidence of gene fusion in benign prostate tissue or in prostate tissue with non-cancerous changes. These findings may prove important as they hint at the possibility of recurrent chromosomal rearrangements in other common epithelial cancers. The role of miRNAs in these types of cancer are now under scrutiny, to determine what role, if any, these small RNA molecules may play in the manifestation of these cancer types. 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.
Michael Mattie and collaborators in the San Francisco Bay Area (2006) used optimized high-throughput microRNA expression profiles to perform novel biomarker assessment of clinical prostate and breast cancer biopsies, overcoming the obstacles that prohibit high-throughput miRNA profiling from typically small clinical samples such as excision or core needle biopsies. In this study, the group describes a novel combination of linear amplification and labeling of miRNA for highly sensitive expression microarray profiling that requires only picogram quantities of purified microRNA. Comparison of microarray and qRT-PCR measured miRNA levels from two different prostate cancer cell lines showed concordance between the two platforms (Pearson correlation R2 = 0.81); and extension of the amplification, labeling and microarray platform was successfully demonstrated using clinical core and excision biopsy samples from breast and prostate cancer patients. The findings of this group demonstrate that optimized high-throughput microRNA expression profiling using miRNA-specific microarrays offers novel biomarker identification from typically small clinical samples such as breast and prostate cancer biopsies.
Title: Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies.
Authors: Mattie MD, Benz CC, Bowers J,Sensinger K, Wong L, Scott GK, Fedele V, Ginzinger D, Getts R, Haqq C
Journal: Mol Cancer. 2006 Jun 19;5:24.
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Yukihiro Akao and colleagues (2006) examined the expression of let-7 miRNAs in human colon cancer tumors and cell lines, finding that 2 of 6 cases and 1 of 3 cell lines showed reduced expression of let-7. The group used semi-quantitative RT-PCR combined with transfection and Western blot analysis to characterize the involvement of let-7 in colon cancer. When let-7 low-expressing DLD-1 human colon cancer cells were transfected with let-7a-1 precursor miRNA (chromosome 9q22.3), the cells exhibited growth suppression and decreased levels of RAS and c-myc proteins, however the levels of associated mRNAs remained virtually unchanged. The findings of this study suggest the involvement of let-7 miRNA in the growth of colon cancer cells and underscore the potential for miRNAs to be used for the development of novel RNA anti-cancer agents.
Title: let-7 microRNA functions as a potential growth suppressor in human colon cancer cells.
Authors: Akao Y, Nakagawa Y, Naoe T
Journal: Biol Pharm Bull, Vol 29, Issue 5: 903-6
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Yaguang Xi et al (2006) investigated the differential regulation of microRNAs and actively translated messenger RNA transcripts by the tumor suppressor p53 in colon cancer using HCT-116 (wt-p53) and HCT-116 (null-p53) cell lines. The effect of p53 on the expression of miRNAs was investigated using miRNA expression array and real-time quantitative reverse transcription-PCR analysis. Results indicated that nearly 200 cellular mRNA transcripts were regulated at the posttranscriptional level, and sequence analysis revealed that some of these mRNAs may be potential targets of miRNAs, including translation initiation factor eIF-5A, eIF-4A, and protein phosphatase 1. This pioneering study was the first report demonstrating that wt-p53 and miRNAs interact in influencing gene expression, while providing insights of how p53 regulates genes at multiple levels via unique mechanisms.
Title: Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer.
Authors: Xi Y, Shalgi R, Fodstad O, Pilpel Y, Ju J
Journal: Clin Cancer Res, Vol 12, Issue 7 Pt 1: 2014-24
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Title: Reduced accumulation of specific microRNAs in colorectal neoplasia.
Authors: Michael MZ, O' Connor SM, van Holst Pellekaan NG, Young GP, James RJ
Journal: Mol Cancer Res, Vol 1, Issue 12: 882-91
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Title: Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma.
Authors: Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol RW, Dhir R
Journal: Am J Pathol, Vol 169, Issue 5: 1812-20
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Title: A microRNA expression signature of human solid tumors defines cancer gene targets.
Authors: Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM
Journal: Proc Natl Acad Sci U S A, Vol 103, Issue 7: 2257-61
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