Emerging Roles for Modulation of microRNA Signatures in Cancer Chemoprevention

Amrita Institute of Medical Sciences and Research Centre, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, Kerala, India.
Current cancer drug targets (Impact Factor: 3.52). 04/2012; 12(6):716-40. DOI: 10.2174/156800912801784875
Source: PubMed


miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3-gallate, curcumin, isoflavones, indole-3-carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that lead to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance. Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets.

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    ABSTRACT: The genetic alterations and aberrant miRNA expression profiles have been identified as important events behind the emergence of cancer. This knowledge triggers the use of miRNA therapeutics as an anticancer strategy. Basically, MicroRNAs (miRNAs) are approximately 22-nucleotide long, endogenous non-protein-coding RNA molecules which function as important regulatory molecules that regulate gene and protein expression through the RNA interference (RNAi) machinery. Transcription of these molecules by RNA polymerases II and III, resulting in the generation of precursor microRNAs that undergo a series of cleavage events, consequently, generate the mature microRNA. The biogenesis pathway is mediated by the two important cleavage events such as nuclear and cytoplasmic. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC), leading to translational repression and hence, regulate the gene expression. The current progress in the development of strategies for miRNA-based anticancer therapies is due to its involvement in cellular, developmental and biological processes including regulation in cancer cell and modulation by various cancer chemoprophylaxis agents. Although miRNA therapeutics have been found to suppress gene expression effectively as compared to anti-sense oligonucleotide strategies, but it is bound with some limitations viz. identification of tissue specific miRNA, biological instability, off-target effects and delivery in the cell system. Up to certain extent, these hurdles have been resolved by chemical modifications using cholesterol conjugation, morpholinos, cationic lipids and cationic nanoparticles. Still more research is needed to understand the mechanism of action for better miRNA therapeutics. The paper discusses the potential miRNA therapeutics and diagnostic applications for cancer prevention, based on recent patents and their analysis.
    No preview · Article · Mar 2014 · Recent Patents on Anti-Cancer Drug Discovery
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    • "The miRNAs are small, endogenous non-coding RNAs (20–22 nucleotides) that are now recognized as an important component of epigenetic gene regulation in mammals, which control an array of cellular processes such as differentiation, development, hematopoiesis, cell cycle regulation, and immunity.[9293] Different cancer studies have shown that miRNAs interact with genes in diverse cellular pathways, resulting in differential gene expression profiles of normal and tumor tissues and among tumor types.[8294] "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs) act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC) cells and the possible role of miRNA in controlling BMI-1 expression. We evaluated the expression of BMI-1 gene in a panel of EC cell lines, and detected a strong association with invasive capability. Stable silencing of BMI-1 in invasive mesenchymal-type EC cells up-regulated the epithelial marker E-cadherin, down-regulated mesenchymal marker Vimentin, and significantly reduced cell invasion in vitro. Furthermore, we discovered that the expression of BMI-1 was suppressed by miR-194 via direct binding to the BMI-1 3'-untranslated region 3'-UTR). Ectopic expression of miR-194 in EC cells induced a mesenchymal to epithelial transition (MET) by restoring E-cadherin, reducing Vimentin expression, and inhibiting cell invasion in vitro. Moreover, BMI-1 knockdown inhibited in vitro EC cell proliferation and clone growth, correlated with either increased p16 expression or decreased expression of stem cell and chemoresistance markers (SOX-2, KLF4 and MRP-1). These findings demonstrate the novel mechanism for BMI-1 in contributing to EC cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis.
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