The Role of MicroRNAs in Human Liver Cancers

doi:10.1053/j.seminoncol.2011.08.001

Seminars in Oncology

Volume 38, Issue 6, December 2011, Pages 752-763

https://doi.org/10.1053/j.seminoncol.2011.08.001 Get rights and content

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver of global importance. Recent studies of the expression and role of microRNA (miRNA) in HCC are providing new insights into disease pathogenesis. In addition, therapeutic efforts targeting specific miRNAs are being evaluated in animal models of HCC. The potential of miRNAs as biomarkers of disease or prognostic markers is being explored. Herein, we review studies of miRNA expression in human HCC, and discuss recent advances in knowledge about the involvement and role of selected miRNAs in disease pathogenesis, as biomarkers, or as therapeutic targets for HCC.

Section snippets

microRNA Expression in Liver Cancers

MicroRNAs (miRNAs) are a family of genes encoding small RNA molecules that play key roles in controlling gene expression. Mature miRNAs are the result of sequential processing of primary miRNA transcripts (pri-miRNA), mediated by two RNA III enzymes that act either in the nucleus (Drosha) or in the cytoplasm (Dicer).² Mature miRNAs can negatively regulate protein expression of specific mRNA by either translational inhibition or mRNA degradation. These mechanisms have been extensively reviewed

Genetic and Epigenetic Alterations

The causes of the widespread miRNA mis-expression in cancers are not clearly understood; however, the origins of such abnormalities seem to be multiple.

Calin et al⁹ investigated the association between various cytogenetic and molecular abnormalities and the location of miRNA genes and found that more than half of miRNA genes were located in cancer-associated genomic regions. Sixty-five miRNAs were located exactly in minimal regions of loss of heterozygosity (LOH) and 15 miRNAs in minimal

miR-221/-222

miR-221 and miR-222 are encoded in tandem from a gene cluster located on chromosome X (Xp11.3) and have identical 5′ regions that enable them to target the same genes.³⁰ They behave as oncogenes in several malignancies. In HCC miR-221 and miR-222 were found to be significantly upregulated when compared with adjacent liver tissues (Table 1). Murakami et al⁴ compared miRNA expression in tumors with different degrees of differentiation and found miR-222 as one of those miRNAs that significantly

miRNA in Diagnosis and Prognosis of HCC

Several recent studies have been performed of miRNA profiling in human HCC. Similar to observations in other cancers, these studies have revealed altered expression of several miRNAs (Table 1). Further definition of the miRNAs that are aberrantly expressed in HCC and elucidation of their contribution to the pathophysiology of HCC is likely to be useful in establishing a role for miRNA. On the basis of these profiling studies, signatures that are associated with cancer or precancerous changes

miRNA as Therapeutic Targets for HCC

A therapeutic approach for HCC that targets miRNA would be highly innovative. Such an approach would be promising given the evidence to date of the involvement of miRNA in HCC pathogenesis and biology. Systemic administration of antisense LNA (locked nucleic acid) oligonucleotides to miR-122 was recently shown to modulate miRNA and target gene expression in the liver and result in the loss of HCV with minimal toxicities in a non-human primate.⁸⁴ This study showed the feasibility of this

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Identifying innovative and effective therapeutic agents is imperative for treating hepatocellular carcinoma (HCC). Natural phytochemical compounds may be a feasible glimmer of hope as more than 8,000 phenolic structures are currently known, and several of them are efficient in treating different types of cancer.
MicroRNAs can modulate tumor cell response to growth signals, apoptosis and replication rates, new blood vessel formation, tissue invasion, and dissemination. We disclosed herein how phenolic compounds, influencing miRNAs-regulated genes, may exert their antitumor activities.
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Phytochemicals such as berberine, curcumin, EGCG, luteolin, and quercetin are promising candidates capable of regulating different miRNAs while exerting their antitumoral effects through distinct molecular mechanisms. MiRNAs such as miRNA-122 and -34a deserve deep investigations, as they were found to be over and down-expressed by more than one polyphenol. MiRNA-regulated genes took part in molecular mechanisms such as cell death, through p53, bcl-2, and SMAD modulation; energy metabolism, by regulating PI3K/Akt pathway; antiproliferative events, mediated by Ras, c-Kit, and β-catenin; and epigenetics events, involving SIRT, HDAC, and DNMT family members. Tumor microenvironment modulation, by NOTCH1 and VEGFA, is also a potential mechanism related to polyphenols’ effects. We reported that polyphenols have specific drug ability and anticancer biological activities. Among the DEGs, 4 of them (e.g., EZH2, HRAS, STMN1, VEGFA), are candidate genes for miRNA modulation. The expression profile of gene subsets that are frequently altered in HCC patients was also characterized.
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Hepatocellular cancer (HCC) is the third most leading reason for carcinoma-related deaths in males, originating mainly from the liver as a complication of cirrhosis. Unfortunately, the majority of the patients diagnosed with liver cancer show poor prognosis. One of the reasons for this is the lack of availability of interventions that could reverse or halt the transformation of cirrhotic cells into cancer cells. There exists a need for the development of advanced and newer treatment strategies; such targeted therapies that focus on critical pathways at cellular level. Research on gene expression profiling has demonstrated some carcinogenic pathways in liver cancer cells that cause aberrant cell growth and inhibit apoptosis. These signaling pathways include Janus kinase–signal transducer and activator of transcription and mammalian target of rapamycin (mTOR) pathways. Latest research on the relationship of microRNA (miRNA) with HCC pathogenesis has provided new insights and paved the way for the potential for targeted therapies. While some miRNAs are downregulated, some others are overexpressed. Studies have indicated that profiling of miRNA can be a good diagnostic as well as prognostic tool in HCC. Furthermore, a profounder knowledge related to the functions of various miRNAs at cellular level can provide insights in uncovering newer therapies targeting those specific cellular pathways. The current review highlights the association of various miRNAs in disease pathogenesis, as well as the potential for developing advanced therapeutics in curbing and/or reversing the disease process.
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Liver cancer is the 7^th utmost frequent neoplasm and the 4^th principal source of cancer deaths. This malignancy is linked with several environmental and lifestyle-related factors emphasizing the role of epigenetics in its pathogenesis. MicroRNAs (miRNAs) have been regarded as potent epigenetic mechanisms partaking in the pathogenesis of liver cancer. Dysregulation of miRNAs has been related with poor outcome of patients with liver cancer. In the current manuscript, we provide a concise review of the results of recent studies about the role of miRNAs in the progression of liver cancer and their diagnostic and prognostic utility.
Hepatocyte growth control by SOCS1 and SOCS3
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Citation Excerpt :
Independent of the studies on Socs gene expression following PH and the effect of SOCS deficiency on liver regeneration, a seminal work reported frequent repression of the SOCS1 gene by promoter CpG methylation in human hepatocellular carcinoma (HCC) specimens in up to 65% of cases [46–48]. This epigenetic mechanism of SOCS1 gene repression appears to be more frequent in HCC than microRNA-mediated downmodulation, which occurs in other malignancies such as breast cancer [49,50]. SOCS3 gene was also found to be downmodulated by promoter methylation in HCC specimens, albeit at a much lower frequency (33%) compared to the SOCS1 gene [51].
The extraordinary capacity of the liver to regenerate following injury is dependent on coordinated and regulated actions of cytokines and growth factors. Whereas hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are direct mitogens to hepatocytes, inflammatory cytokines such as TNFα and IL-6 also play essential roles in the liver regeneration process. These cytokines and growth factors activate different signaling pathways in a sequential manner to elicit hepatocyte proliferation. The kinetics and magnitude of these hepatocyte-activating stimuli are tightly regulated to ensure restoration of a functional liver mass without causing uncontrolled cell proliferation. Hepatocyte proliferation can become deregulated under conditions of chronic inflammation, leading to accumulation of genetic aberrations and eventual neoplastic transformation. Among the control mechanisms that regulate hepatocyte proliferation, negative feedback inhibition by the ‘suppressor of cytokine signaling (SOCS)’ family proteins SOCS1 and SOCS3 play crucial roles in attenuating cytokine and growth factor signaling. Loss of SOCS1 or SOCS3 in the mouse liver increases the rate of liver regeneration and renders hepatocytes susceptible to neoplastic transformation. The frequent epigenetic repression of the SOCS1 and SOCS3 genes in hepatocellular carcinoma has stimulated research in understanding the growth regulatory mechanisms of SOCS1 and SOCS3 in hepatocytes. Whereas SOCS3 is implicated in regulating JAK-STAT signaling induced by IL-6 and attenuating EGFR signaling, SOCS1 is crucial for the regulation of HGF signaling. These two proteins also module the functions of certain key proteins that control the cell cycle. In this review, we discuss the current understanding of the functions of SOCS1 and SOCS3 in controlling hepatocyte proliferation, and its implications to liver health and disease.
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View all citing articles on Scopus

: This study was supported by Grant No. DK069370 from the National Institutes of Health (TP).

: Financial disclosures: None of the authors has any financial disclosures.

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MicroRNAs and cancer: From the bench to the clinicThe Role of MicroRNAs in Human Liver Cancers

Section snippets

microRNA Expression in Liver Cancers

Genetic and Epigenetic Alterations

miR-221/-222

miRNA in Diagnosis and Prognosis of HCC

miRNA as Therapeutic Targets for HCC

Mol Cell

Cell

Mutat Res

Pharmacol Ther

Hum Immunol

Cancer Cell

Cancer Lett

J Hepatol

Comput Biol Chem

Virology

Cancer Cell

Cancer Cell

J Biol Chem

Cell

Gastroenterology

J Biol Chem

Gastroenterology

Pharmacol Res

J Surg Res

Blood

Biochim Biophys Acta

Gastroenterology

Gastroenterology

J Hepatol

J Biol Chem

Mol Cell

J Hepatol

J Hepatol

J Biol Chem

Am J Pathol

Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates

Cancer

Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues

Oncogene

Identification of metastasis-related microRNAs in hepatocellular carcinoma

Hepatology

MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma

Hepatology

Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival

Clin Cancer Res

MicroRNA expression, survival, and response to interferon in liver cancer

N Engl J Med

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

Proc Natl Acad Sci U S A

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia

Proc Natl Acad Sci U S A

Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA

Nat Cell Biol

A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia

N Engl J Med

Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes

Oncogene

Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis

Cancer Res

Epigenetic activation of miR-34a contributes to an invasive phenotype in hepatocellular cancer

Hepatology

MicroRNAs and cancer: From the bench to the clinic
The Role of MicroRNAs in Human Liver Cancers