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• W2063032852 abstract "Primary liver cancer is a disease arising from malignant transformation of hepatocytes, which account for up to 80% of the liver tissue. In infants, the most common form of liver tumor is hepatoblastoma (HB), a rare childhood tumor that mostly affects kids <3 years old. In adults, hepatocellular carcinoma (HCC) is by far the most common form of liver malignancy. HB is an embryonal tumor characterized by proliferation of immature hepatoblasts, frequently associated with malignant mesenchymal tissue, which suggests that it derives from uncommitted progenitor cells. HB occurrence has a strong genetic footprint. Deregulation of the progenitor cell differentiation program is in most cases determined by the alteration of the Wnt pathway. Activating mutation of β-catenin, which leads to sustained Wnt signaling, is observed in up to 80% of tumors. Inactivating mutation of Axin and APC, 2 proteins involved in β-catenin degradation, is also observed in HB. Children with familial adenomatous polyposis, a genetic syndrome caused by germline APC mutation, have an increased risk of developing HB. Furthermore, the Beckwith–Wiedemann syndrome, a genetic disease related to loss of genomic imprinting, is also associated with elevated HB incidence. In addition to genetic alterations, some environmental events are also associated with HB development. Eclampsia during pregnancy and very low weight at birth are the environmental factors with the strongest association with HB described so far.1Schnater J.M. Kohler S.E. Lamers W.H. et al.Where do we stand with hepatoblastoma? A review.Cancer. 2003; 98: 668-678Crossref PubMed Scopus (146) Google Scholar HCC is a world-wide emergency. In the last decade, HCC prevalence increased continuously and at present HCC is the 5th most frequent form of cancer and the 3rd leading cause of cancer-related death. Differently from HB, where primary genetic events that predispose to HCC are unknown. The etiologic factors that are most frequently associated with HCC occurrence are well described. Exposure to viral pathogens such as hepatitis B (HBV) and C (HCV) viruses, to environmental factors such as aflatoxin B1, and alcohol consumption, strongly enhance the probability of developing HCC.2Yang J.D. Roberts L.R. Hepatocellular carcinoma: a global view.Nat Rev Gastroenterol Hepatol. 2010; 7: 448-458Crossref PubMed Scopus (1088) Google Scholar Despite the profound difference existing between HB and HCC in terms of etiology, genetic background, and histologic phenotype, the development of both diseases has been found tightly associated with functional hyperactivation of the Myc oncogene. Myc is a transcription factor of the basic helix–loop–helix leucine zipper (bHLHZ) family. It was originally identified as the cellular homolog of v-Myc, a viral protein of the avian myelocytomatosis virus. Three Myc homologs exist in the human genome, c-Myc, N-Myc, and L-Myc, and their involvement from early steps of carcinogenesis to evolution and metastatic spread in ≥50% of human cancers is well documented. Myc binds to a 6-nucleotide DNA consensus sequence, CACGTG, called E-Box, which is present in approximately one-third of human gene promoters. Binding of Myc to this sequence requires dimerization with the Max protein, another bHLHZ protein. Myc/Max complex, induces transcriptional activation of target genes and microRNAs (miRs). Competitive binding to Max by other bHLHZ, such as transcriptional repressors of the Mad family or Mnt, antagonizes Myc activity, as binding of a Mad/Max or Mnt/Max dimer to E-box inhibits gene transcription. In addition, many other constitutive or tissue-specific bHLH or bHLHZ transcription factors can compete for binding to E-box sequences. In addition to its transactivation properties, Myc can also exert a Max-independent repressive function by interacting with several transcription factors such as Miz1, Sp1, Smad proteins, and several others to impair the recruitment of the transcriptional machinery on several gene promoters. Overall, it has been estimated that Myc participates to the regulation of ≥15% of all coding genes and of numerous miR clusters. Beside its role as a transcription factor, Myc takes part in the modulation of chromatin status. Myc binding to DNA throughout the genome is associated with an increased amount of euchromatin regions, whereas Myc ablation leads to progressive spread of heterochromatin. Given the pleiotropic role that Myc plays on genomic DNA and gene expression, it is not surprising that Myc activity is regulated and finely tuned by several converging upstream signaling pathways. Depending on the developmental stage, the tissue type and the cell lineage, Ras, Wnt, Notch, and PI3K pathway can converge and modulate Myc activity to regulate cell growth (proliferation vs differentiation), cell metabolism (glycolysis vs citric acid cycle), and cell survival (apoptosis vs senescence).3Meyer N. Penn L.Z. Reflecting on 25 years with MYC.Nat Rev Cancer. 2008; 8: 976-990Crossref PubMed Scopus (1185) Google Scholar In the liver, Myc plays an important role during embryonic liver development as well as in the homeostasis of adult liver. The use of animal models has provided important insights on Myc contribution to liver development and maturation. These studies showed that both N-myc and c-Myc are involved in tissue organization and in the burst of proliferation that precedes birth in rodents, with redundant as well as unique roles for each protein. In adult liver, c-Myc is involved in hepatocyte growth and is essential for achievement of polyploidy. Moreover, Myc is required to induce liver regeneration upon partial hepatectomy, as well as in response to hepatotoxic agents. These 2 properties are closely intertwined, and their relationship is well explained by the recent discovery that Myc allows cell replication under stress conditions. In this new intriguing perspective, the main functional role of Myc would be to help cells bypass the G1/S checkpoint rather than to induce proliferation.4Herold S. Herkert B. Eilers M. Facilitating replication under stress: an oncogenic function of MYC?.Nat Rev Cancer. 2009; 9: 441-444Crossref PubMed Google Scholar Myc overexpression is sufficient by itself to induce liver tumors. Support for this notion has been provided by several animal models. Among them, seminal studies in the field showed that when Myc is overexpressed in embryonic liver, mice succumb to liver cancer within a few days after birth, whereas if Myc overexpression is induced perinatally, the mean latency period between Myc induction and tumor occurrence is 8 weeks. By contrast, if activated in young adult mice, Myc induces HCC with an average latency period of 35 weeks. Concomitant administration of hepatotoxic molecules at the time of Myc activation dramatically drops this latency down to 1 week.5Shachaf C.M. Kopelman A.M. Arvanitis C. et al.MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.Nature. 2004; 431: 1112-1117Crossref PubMed Scopus (734) Google Scholar, 6Beer S. Komatsubara K. Bellovin D.I. et al.Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.PLoS One. 2008; 3: e2493Crossref PubMed Scopus (38) Google Scholar On the basis of these findings, it has been proposed that Myc oncogenic potential is fully elicited when cells are in a proliferative status. In this view, a strong requirement for HB to occur would be that aberrant Myc activation is coupled with active hepatoblast/hepatocyte proliferation at the embryonic and early postnatal stages. Accordingly, HB prevalence begins to decrease by the time children reach 3 years of age, which corresponds with the period in which most of hepatoblasts still present from fetal stages are converted into mature hepatocytes. In adults, accumulation of liver insults boosts hepatocyte regeneration and turnover. Because all these events engage Myc activation, prolonged stress increases the chances of inducing constitutive, aberrant Myc signaling, which leads to liver hyperplasia and eventually degenerates into HCC. A schematic overview of this hypothesis is depicted in Figure 1. Expression of early hepatic precursor markers such as AFP, GPC3, KRT19, and EpCAM has been observed in poorly differentiated HBs and HCCs, supporting the view that these tumor subtypes could distinguish similar molecular features. Molecular signatures that identify Myc activation in liver cancer have been recently developed. A 16-gene signature has been established in HB that identifies an HB subclass endowed with constitutive Myc activation and poor prognosis.7Cairo S. Armengol C. DeReynies A. et al.Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.Cancer Cell. 2008; 14: 471-484Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar When applied to HCC, this signature was capable of identifying invasive, poor prognosis HCC.8Villanueva A. Hoshida Y. Battiston C. et al.Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma.Gastroenterology. 2011; 140: 1501-1512Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar Similarly, a miR-based signature successfully stratified both HB and HCC based on the expression profile of 4 Myc target miRs, miR-100, let-7a, miR-371, and miR-373. These results suggest that, despite the fact that the modality of Myc engagement in tumorigenesis is different between HB and HCC, Myc oncogenic activity relies on an oncogenic program shared by both tumor types.9Cairo S. Wang Y. de Reynies A. et al.Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer.Proc Natl Acad Sci U S A. 2010; 107: 20471-20476Crossref PubMed Scopus (164) Google Scholar Beside enhancing cell proliferation and inducing improper bypass of cell cycle checkpoint, Myc carcinogenic properties rely also on their ability to block cell differentiation, alter metabolism, and induce cell survival. Recently, regulation of miR expression by Myc has emerged as a privileged strategy by which Myc intervenes into these pathways. miRs are small RNAs that in their mature form consist of single strand RNA molecule of 20–22 nucleotides. The main role demonstrated so far for these small molecules is to bind complementary mRNA and inhibit protein synthesis. By reason of their small size and of the fact that full complementarity between mRNA and miR seed sequence (7–8 nucleotides) is sufficient to induce translation inhibition, miR expression can influence the synthesis of hundreds of proteins at the same time. The aforementioned microarray-based analysis of miR profile in HB clearly identified a molecular subclass of poor prognosis tumors characterized by altered expression of direct Myc target miRs strongly associated with Myc activation. In particular, in aggressive forms of HB, down-regulation of Myc-repressed miRs (MRMs) was observed. Among them, numerous members of the let-7, miR-23, miR-26, miR-29, and miR-30 families, miR-150, already validated as direct MRMs, were negatively regulated in this tumor subclass. Among Myc-induced target miRs, miR-371-3 family was found overexpressed in the aggressive HB subtype (Figure 2). Conversely, overexpression of miR-19a, which belongs to the miR-17-92 Myc-induced target miRs cluster, the first miR cluster identified as direct Myc target in B-cell lymphoma, was found as a common trait of HB. Functional studies on miR-100/let-7a-2/miR-125b-1 and miR-371-3 validated these clusters as Myc targets in the liver and showed that these miRs play a crucial role as effectors of Myc oncogenic activity. Overexpression of miR-100/let-7a-2/miR-125b-1 cluster or inhibition of miR-371-3 cluster in liver cancer cell lines reduces their oncogenic potential in vitro and in vivo. When the 2 conditions are combined, liver cancer cell capacity of forming tumors is dramatically impaired. Interplay of the 2 miR clusters shows striking analogies between the regulation of liver cancer stem/progenitors and the expression of these clusters in embryonic stem cells (ESCs). The miR 371-3 cluster was originally found to be specifically expressed in ESCs and rapidly down-regulated in response to proliferation. Recent studies have shown that the mouse ortholog of miR 371-3, the miR-290-5 cluster, plays a crucial role in the regulation of ESCs renewal and differentiation. miR-290-5 cluster is also activated by Myc, accelerates transition through the G1/S restriction point by targeting the CDK inhibitors Cdkn1a (p21) and Rb, and can replace Myc in promoting dedifferentiation of somatic cells into induced pluripotent stem cells. Other studies have implicated the human miR-371-3 cluster in tumorigenesis. These miRs exert oncogenic potential in primary cells by allowing escape from Ras-induced senescence in wild-type p53 background and suppressing the CDK inhibitor Lats2. Moreover, they promote tumor invasion and metastasis in response to hypoxia. Expression of the miR-371-3 cluster is barely detectable in most human tumors, but it is highly activated in germ cell tumors, which share with HB wild type p53 and DNA damage-sensitive phenotype. Let-7 and the miR-125b Caenorhabditis elegans ortholog lin-4 have been among the first miRs discovered. Throughout species, miRs of the let-7 family have been shown to participate in cell differentiation and commitment, and to be strong determinants of tissue and organ fate. Let-7 miRs were also among the first to be identified as Myc antagonists and eventually validated as MRMs. Let-7 overexpression counteracts the oncogenic potential of Myc and Ras, and blocks the chromatin remodeling factor HMGA2 that activates pro-invasive and pro-metastatic genes. The central role of Myc in the regulation of let-7 is further strengthened by concomitant overexpression of the Myc target genes LIN28/LIN28B in aggressive HBs and HCCs. LIN28 proteins inhibit processing of let-7 precursors and therefore limit the availability of mature let-7 in cells.10Viswanathan S.R. Powers J.T. Einhorn W. et al.Lin28 promotes transformation and is associated with advanced human malignancies.Nat Genet. 2009; 41: 843-848Crossref PubMed Scopus (680) Google Scholar, 11Subramanyam D. Blelloch R. From microRNAs to targets: pathway discovery in cell fate transitions.Curr Opin Genet Dev. 2011; 21: 498-503Crossref PubMed Scopus (55) Google Scholar miR-125b and miR-100 have also been described to show tumor suppressive properties. miR-125b contributes to DNA damage response by targeting p53, whereas miR-100 acts as a potent inhibitor of the mTOR pathway.12Le M.T. Teh C. Shyh-Chang N. et al.MicroRNA-125b is a novel negative regulator of p53.Genes Dev. 2009; 23: 862-876Crossref PubMed Scopus (560) Google Scholar, 13Nagaraja A.K. Creighton C.J. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer.Mol Endocrinol. 2010; 24: 447-463Crossref PubMed Scopus (207) Google Scholar In addition to the miR-100/let-7a-2/miR-125b-1 cluster, inhibition of other MRMs as a requirement for Myc to drive its oncogenic activity is getting more and more evident.14Bui T.V. Mendell J.T. Myc: maestro of microRNAs.Genes Cancer. 2010; 1: 568-575Crossref PubMed Scopus (114) Google Scholar These miRs intervene in several cell functions that can be strategically altered to confer a selective advantage to the tumor cell. miR-23a and miR-23b (miR-23a/b) are MRMs that have been involved in glutamine metabolism. It is well established that Myc regulates both glycolysis and glutaminolysis. Myc activation leads to an increased rate of aerobic glycolysis. In the absence of metabolic precursors from glucose, tumor cell growth passes through glutamine conversion to glutamate. In these metabolic conditions, Myc increases glutamine uptake through the expression of glutamine carriers (SLC38A5 and SLC1A5), and indirectly regulates glutamine conversion to glutamate through repression of miR-23a/b expression. These miRs target glutaminase 1 (GLS1), which deaminates glutamine to produce glutamate. Loss of miR-23a/b increases glutamine/glutamate conversion rate and supplies cells with basic substrate to guarantee cell growth. miR-23a/b play therefore a crucial role in Myc-mediated shift of cell metabolic balance toward increased uptake and consumption of glutamine, thus feeding the TCA-cycle and favoring the glycolysis-prone metabolism of tumor cells. miR-26, another MRM, has also emerged as an important suppressor of Myc-mediated tumorigenesis. Overexpression of miR-26a in vitro induces cell cycle arrest, and ectopic expression of miR-26a in tumor cells inhibits cell growth and induces tumor regression. Moreover, a recent publication has inferred a role of miR-26 as a bridge between interferon and the nuclear factor (NF)-κB pathway in the liver. When overexpressed, mir-26 elicits activation of the intracellular NF-κB signaling, which in turn induces cell resistance to interferon-α–mediated cell death. HCC patients that express low levels of mir-26 either in the normal or cancerous tissue, despite showing poorer prognosis, respond better to INFα than patients with constitutively high miR-26.15Ji J. Shi J. Budhu A. et al.MicroRNA expression, survival, and response to interferon in liver cancer.N Engl J Med. 2009; 361: 1437-1447Crossref PubMed Scopus (736) Google Scholar HB and HCC display a divergent degree of response to chemotherapeutic treatment. The majority of HBs respond to chemotherapy, with a rate of complete remission at 3 years of around 70%. Conversely, HCC is refractory to chemotherapy, and the chance of surviving the disease is tightly associated with early diagnosis, which allows for operative interventions such as partial hepatectomy or orthotopic liver transplantation. The need for new therapeutic strategies is therefore a major concern. One of the main roles of the liver is to filter blood to accumulate nutrients and neutralize toxic molecules. In addition, the fetal liver harbors immature hematopoietic precursors and actively contributes to their differentiation. Exposure to the blood stream, beside allowing the execution of its function, makes the liver an easy target for intravenously injected products. Because overexpression of MRMs impairs Myc-mediated tumor growth, it is tempting to speculate that, if injected into the blood stream, these miRs could target liver tumor cells and inhibit carcinogenesis. Preliminary support to this approach has been provided by recent studies on miR-26. Overexpression of miR-26a in vitro induces cell cycle arrest, and when an adenoviral vector expressing mir-26a is injected in mice harboring Myc-induced liver tumors, ectopic expression of miR-26 in tumor cells inhibits cell growth and induces tumor regression.16Kota J. Chivukula R.R. O'Donnell K.A. et al.Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.Cell. 2009; 137: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (1516) Google Scholar Because MRMs are normally expressed at high levels in differentiated tissue, exposing the organism to a massive dose of these molecules could be tolerated with few secondary effects. Presently, the development of appropriate vectors to envelop miRs and favor their absorption in the liver is in progress, and some positive results are being obtained. Nucleic acids are hydrophilic, negatively charged, high molecular weight materials that are readily degraded by nucleases in vivo. Therefore, a number of delivery strategies have been investigated to improve both the stability and uptake of these therapeutic molecules. Viral approaches are generally the most efficient and widely used delivery systems given their highly evolved natural pathways for infection. However, issues including immunogenicity and insertional mutagenesis have led to the development of nonviral approaches, such as the use of synthetic (lipids, polymers, and organic nanoparticles) delivery systems that are able to associate with DNA or RNA molecules to form complexes. The size of the complex has a critical impact on its ability to overcome delivery barriers in cancer therapy. Nanoparticles smaller than the renal filtration cutoff of 50 kDa or 5–6 nm are rapidly removed from the bloodstream and excreted. Cells of the liver, spleen, and some tumors allow molecules up to 200 nm in diameter to enter, whereas particles <100 nm in diameter are known to have greater accumulation levels in the hepatic Kupffer cells. So the liver is a privileged organ for delivery of therapeutic RNAs. Optimization of particle size is essential to maximize the penetration and retention in tumor tissue, in which immature and porous vasculature provides access to circulating particles.17Guo J. Bourre L. Soden D.M. et al.Can non-viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics?.Biotechnol Adv. 2011; 29: 402-417Crossref PubMed Scopus (93) Google Scholar Hopefully, the availability of mouse models of Myc-induced tumorigenesis and the growing number of clinically relevant preclinical models of human liver cancer such as patient-derived HB and HCC xenografts will provide a decisive contribution to the development of this approach and will indicate if these experimental approaches could be extended to preliminary clinical studies. We would like to thank Sabrina Serpillon and Giovanna Giorgio for critical reading of the manuscript. This review is dedicated to Antonio Giorgio Jreneus." @default.
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• W2063032852 title "Myc Target miRs and Liver Cancer: Small Molecules to Get Myc Sick" @default.
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