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Assessment of somatic genomic alterations from tumors can now be performed by sequencing circulating tumor DNA from the cell-free component of blood. This procedure, which identifies tumor-derived somatic mutations from a simple blood sample, circumvents the need for tumor tissue. A recent study highlights the promise of circulating tumor DNA to guide therapeutic decisions in a variety of solid tumors for both clinical and investigative purposes, as well as providing a tool for the early detection of cancer.
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UNLABELLED: Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P<0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice. CONCLUSION: Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Epigenómica , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , MicroARNs/antagonistas & inhibidores , MicroARNs/biosíntesis , alfa-Fetoproteínas/biosíntesis , Adulto , Animales , Carcinoma Hepatocelular/enzimología , Línea Celular Tumoral , Estudios de Cohortes , Metilación de ADN/genética , ADN Metiltransferasa 3A , Regulación hacia Abajo/genética , Femenino , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas Experimentales/enzimología , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/mortalidad , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , alfa-Fetoproteínas/genéticaRESUMEN
Recent studies have demonstrated that deregulated microRNA (miR) expression is implicated in the development of human cancers. In the aberrant miR expression, miR-301 is upregulated in cancers, such as pancreatic, colorectal and oral carcinoma. Based on this evidence, we investigated the contribution of miR-301 to pancreatic carcinoma and the novel target genes of miR-301 in pancreatic carcinoma. In this study, we analyzed the effects of enforced and inhibited expression of miR-301b expression in the Panc-1 and BxPC-3 cell lines. MiR-301b expression levels were associated with cell invasiveness in both cell lines. Additional experiments indicated that miR-301b influences invasiveness through CDH1. Moreover microRNA target search algorithms and experimental strategies suggested that miR-301b suppressed TP63 expression as a novel target of miR-301b. Remarkably, miR-301b was also found to be associated with NF-κB activity in both cell lines. In summary, overexpressed miR-301b may suppress TP63 expression and contributes to promote cell invasiveness and to enhance gemcitabine resistance in pancreatic carcinoma cells. Thus, miR-301b may have potential as a novel therapeutic target for cancer treatment due to its stimulatory effects on cell invasiveness.
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MicroARNs/genética , Invasividad Neoplásica/genética , Neoplasias Pancreáticas/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proliferación Celular , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , FN-kappa B , Invasividad Neoplásica/patología , Neoplasias Pancreáticas/patología , Gemcitabina , Neoplasias PancreáticasRESUMEN
MicroRNA (miRNA) function has been studied extensively in the last two decades. These short, non-coding RNAs influence a variety of cellular processes through repression of target genes. With the number of genes that a single miRNA can target, the biological effects of one miRNA alone can be vast. In cancer, aberrant miRNA expression is ubiquitous and consequently it can provoke progression of the disease. Though much is known about the downstream effects of miRNA, the mechanisms that control the level of miRNA expression itself are not well documented. In this review, we will focus on how miRNAs are regulated as well as potential therapeutic targets that can be exploited for cancer therapy.
