Peroxisome Proliferator-Activated Receptor <i>α</i> Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

Shah, Yatrik M.; Morimura, Keiichirou; Yang, Qian; Tanabe, Tomotaka; Takagi, Mitsuhiro; Gonzalez, Frank J.

doi:10.1128/mcb.00317-07

Cited by 247 publications

(217 citation statements)

References 60 publications

(80 reference statements)

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“…To date, siRNAs have been used to treat many diseases effectively [138][139][140][141][142][143]. Many siRNA delivery systems have been developed, including nonselective liposomal delivery, cell-type-specific nanoparticle delivery, and lentiviral delivery.…”

Section: Discussionmentioning

confidence: 99%

The role and clinical implications of microRNAs in hepatocellular carcinoma

Zhao

Yang

et al. 2012

Sci. China Life Sci.

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Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

The role and clinical implications of microRNAs in hepatocellular carcinoma

Zhao

Yang

et al. 2012

Sci. China Life Sci.

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“…It has been demonstrated that the administration of Wy-14,643, a specific PPARα agonist, to mice for 2 weeks caused changes (>1.5-fold) in the expression of 27 miRNAs (12 miRNAs were decreased and 15 miRNAs were increased) (Shah et al, 2007), but greater changes in 707 mRNAs (671 mRNAs were decreased and 36 mRNAs were increased, >4-fold). When rat primary thymocytes were treated with dexamethasone, a synthetic glucocorticoid that binds to GR, the expression of 56 out of 350 miRNAs was altered (44 miRNAs were decreased and 12 miRNAs were increased) (Smith et al, 2010).…”

Section: Vreugdenhil Et Al (2009) Have Reported That Rat and Human Glmentioning

confidence: 99%

“…As described above, the chronic administration of NNK, a tobacco-specific carcinogen, to rats reduced the expression of several miRNAs in lung (Kalscheuer et al, 2008). There is accumulating evidence that these up-regulated or down-regulated specific miRNAs could alter the expression of target mRNAs and lead to some phenotypic changes (Shah et al, 2007;Kalscheuer et al, 2008;Maillot et al, 2009;Ribas et al, 2009). …”

Section: Vreugdenhil Et Al (2009) Have Reported That Rat and Human Glmentioning

confidence: 99%

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

Nakajima

Yokoi

2011

Pharmacology & Therapeutics

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MicroRNAs (miRNAs) are a family of short, non-coding RNA whose final product is a 22-nucleotide functional RNA molecule. They regulate the expression of target genes by binding to complementary regions of transcripts to repress their translation or promote mRNA degradation. Since miRNAs regulate every aspect of cellular function, their dysregulation is associated with a variety of diseases including cancer, diabetes, and cardiovascular diseases.Therefore, miRNAs are now considered new therapeutic targets. However, the roles of miRNAs in the metabolism of xenobiotics and endobiotics have only recently been revealed.This review describes the current knowledge on the regulation of cytochrome P450s and nuclear receptors by miRNAs, the physiological and clinical significance. The miRNA expression is readily altered by chemicals, carcinogens, drugs, hormones, stress, or diseases, and the dysregulation of specific miRNAs might lead to changes in the drug metabolism potency or pharmacokinetics as well as pathophysiological changes. In the field of pharmacogenomics, the evaluation of miRNA-related polymorphisms would provide useful information for personalized medicine. Utilizing miRNAs opens a new era in the fields of drug metabolism and pharmacokinetics as well as toxicology.

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“…Modulation of cyclin G1, a cell cycle modulator, is the mechanism by which decreased miR122a expression was reported to be hepatocarcinogenic. Another study analyzing the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in hepatocarcinogenesis showed that this protein is an important regulator of hepatic miRNA expression [49] . Of particular significance was PPARalpha inhibition of let-7C-mediated signaling and c-myc induction, which leads to hepatocyte proliferation and transformation.…”

Section: Hcc and Mirsmentioning

confidence: 99%

Harnessing the RNA interference pathway to advance treatment and prevention of hepatocellular carcinoma

Arbuthnot

Thompson²

2008

WJG

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INTRODUCTIONGlobally, hepatocellular carcinoma (HCC) is a major cause of mortality [1,2] . It is the commonest primary liver cancer and accounts for 80%-90% of this class of malignancy. HCC is characterized by a very poor prognosis and is associated with high mortality. Annual mortality from HCC is virtually the same as its annual incidence, attesting to its rapid course and grave prognosis. Moreover, although HCC is the fifth most common cancer worldwide, it is the third most common cause of cancer-related mortality [3] . Recent observations have shown that incidence and mortality from liver cancer in the United States is the fastest growing of all cancers [2] . This is despite a decline in the overall cancer mortality rate that has occurred during the past 20 years. Currently available treatments of HCC are largely inadequate. However, with better understanding of the molecular pathogenesis of the cancer and significant advances in gene silencing technology, improved approaches are being devised to counter the malignancy. In particular, harnessing the RNA interference (RNAi) pathway to inhibit expression of genes that are implicated in transformation of hepatocytes is an exciting new approach to treating HCC. Therapeutic gene silencing technology is however at an early stage of development and there are several important hurdles that need to be overcome before this approach becomes a reality for treating HCC. In this review, we summarize HCC molecular pathogenesis as a background to discussing the interesting prospects of RNAi-based drugs for treating HCC. CaUses aND mOleCUlaR paThOgeNesIs Of hCCThere are several etiological agents and risk factors that AbstractPrimary liver cancer is the fifth most common malignancy in the world and is a leading cause of cancer-related mortality. Available treatment for hepatocellular carcinoma (HCC), the commonest primary liver cancer, is rarely curative and there is a need to develop therapy that is more effective. Specific and powerful gene silencing that can be achieved by activating RNA interference (RNAi) has generated enthusiasm for exploiting this pathway for HCC therapy. Many studies have been carried out with the aim of silencing HCC-related cellular oncogenes or the hepatocarcinogenic hepatitis B virus (HBV) and hepatitis C virus (HCV). Proof of principle studies have demonstrated promising results, and an early clinical trial assessing RNAi-based HBV therapy is currently in progress. Although the data augur well, there are several significant hurdles that need to be overcome before the goal of RNAi-based therapy for HCC is realized. Particularly important are the efficient and safe delivery of RNAi effectors to target malignant tissue and the limitation of unintended harmful non-specific effects.

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Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

Cited by 247 publications

References 60 publications

The role and clinical implications of microRNAs in hepatocellular carcinoma

The role and clinical implications of microRNAs in hepatocellular carcinoma

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

Harnessing the RNA interference pathway to advance treatment and prevention of hepatocellular carcinoma

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