MicroRNA profiling of carcinogen-induced rat colon tumors and the influence of dietary spinach
ABSTRACT MicroRNA (miRNA) profiles are altered in chronic conditions such as cardiovascular disease, diabetes, neurological disorders, and cancer. A systems biology approach was used to examine, for the first time, miRNAs altered in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine carcinogen from cooked meat.
Among the most highly dysregulated miRNAs were those belonging to the let-7 family. Subsequent computational modeling and target validation identified c-Myc and miRNA-binding proteins Lin28A/Lin28B (Lin28) as key players, along with Sox2, Nanog, and Oct-3/4. These targets of altered miRNAs in colon cancers have been implicated in tumor recurrence and reduced patient survival, in addition to their role as pluripotency factors. In parallel with these findings, the tumor-suppressive effects of dietary spinach given postinitiation correlated with elevated levels of let-7 family members and partial normalization of c-myc, Sox2, Nanog, Oct-3/4, HmgA2, Dnmt3b, and P53 expression.
We conclude that the let-7/c-Myc/Lin28 axis is dysregulated in heterocyclic amine-induced colon carcinogenesis, and that the tumor suppressive effects of dietary spinach are associated with partial normalization of this pathway.
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ABSTRACT: Background MicroRNAs (miRNAs or miRs) are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that also become dysregulated in cancer development. In the latter context, studies to date have focused on high-abundance miRNAs and their targets. We hypothesized that among the pool of low-abundance miRNAs are some with the potential to impact crucial oncogenic signaling networks in colon cancer. Results Unbiased screening of over 650 miRNAs identified miR-206, a low-abundance miRNA, as the most significantly altered miRNA in carcinogen-induced rat colon tumors. Computational modeling highlighted the stem-cell marker Krüppel-like factor 4 (KLF4) as a potential target of miR-206. In a panel of primary human colon cancers, target validation at the mRNA and protein level confirmed a significant inverse relationship between miR-206 and KLF4, which was further supported by miR-206 knockdown and ectopic upregulation in human colon cancer cells. Forced expression of miR-206 resulted in significantly increased cell proliferation kinetics, as revealed by real-time monitoring using HCT116 cells. Conclusions Evolutionarily conserved high-abundance miRNAs are becoming established as key players in the etiology of human cancers. However, low-abundance miRNAs, such as miR-206, are often among the most significantly upregulated miRNAs relative to their expression in normal non-transformed tissues. Low-abundance miRNAs are worthy of further investigation, because their targets include KLF4 and other pluripotency and cancer stem-cell factors.09/2012; 4(1). DOI:10.1186/1868-7083-4-16
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ABSTRACT: A plethora of studies have described the disruption of key cellular regulatory mechanisms involving non-coding RNAs, specifically microRNAs (miRNA) from the let-7 family, the miR-17 family, miR-21, miR-143, and the miR-200 family, which contribute to aberrant signaling and tumor formation. Certain environmental factors, such as bioactive dietary agents, e.g., folate, curcumin, polyunsaturated fatty acids, are also thought to impact the progression and severity of cancer. In terms of the chemoprotective mechanisms of action, these bioactive dietary agents appear to act, in part, by modulating tissue levels of miR-16, miR-17 family, miR-26b, miR-106b, and miR-200 family miRNAs and their target genes. However, the mechanisms of nutrient action are not yet fully understood. Therefore, additional characterization of the putative underlying mechanisms is needed to further our understanding of the biology, early diagnosis, prevention, and the treatment of cancer. For the purpose of elucidating the epigenetic landscape of cancer, this review will summarize the key findings from recent studies detailing the effect of bioactive dietary agents on miRNA regulation in cancer.Frontiers in Genetics 12/2012; 3:305. DOI:10.3389/fgene.2012.00305
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ABSTRACT: BACKGROUND: Alterations in microRNA (miRNA/miR) genes are of biological importance in the pathophysiology of cancers, including pancreatic cancer (PaCa). Although growing evidence supports the role of miRNA in cancer, their response to dietary phytochemicals is less known. Previously, we showed that garcinol induces PaCa cell growth arrest and apoptosis in vitro. The present study, discusses chemo-sensitization by garcinol in synergism with first-line PaCa drug, gemcitabine. The miRNA expression profile of gemcitabine-resistant Panc-1 cells treated with garcinol and/or gemcitabine was also evaluated. METHODS AND RESULTS: Garcinol synergizes with gemcitabine to inhibit cell proliferation and induce apoptosis in PaCa cells with significant modulation of key cancer regulators including PARP, VEGF, MMPs, ILs, caspases, and NF-κB. In addition, biostatistical analyses, quantitative reverse transcription PCR data, and in silico modeling using TargetScan5, PicTar, and DNA intelligent analysis, microT-V.B4 database showed that these two agents modulated a number of microRNAs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) linked to various canonical oncogenic signaling pathways. CONCLUSION: We identified garcinol-specific miRNA biomarkers that sensitize PaCa cells to gemcitabine treatment, thus attenuating the drug-resistance phenotype. These results prompt further interest in garcinol and gemcitabine combination strategy as a drug modality to improve treatment outcome in patients diagnosed with PaCa.Molecular Nutrition & Food Research 02/2013; 57(2). DOI:10.1002/mnfr.201200297 · 4.91 Impact Factor