Guidelines For Basic Science Open Access
Copyright ©2010 Baishideng. All rights reserved.
World J Hepatol. Jan 27, 2010; 2(1): 16-20
Published online Jan 27, 2010. doi: 10.4254/wjh.v2.i1.16
Targeting c-Myc as a novel approach for hepatocellular carcinoma
Che-Pin Lin, Chien-Ru Liu, Department of Medicine, Taipei City Hospital, Ren-Ai Branch, Taipei 106, Taiwan
Chun-Nin Lee, Tze-Sian Chan, Department of Medicine, Wanfang Hospital, Taipei Medical University, Taipei 116, Taiwan
H Eugene Liu, Department of Medicine, Department of Laboratory Medicine, and Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan
Author contributions: Lin CP and Liu CR contributed equally to this work; Both of them were responsible for manuscript writing; Lee CN and Chan TS were responsible for data collection and Liu HE for manuscript writing and editing.
Supported by the Grants from Taiwan Department of Health for the Center of Excellence for Clinical Trial and Research in Neuroscience (DOH99-TD-B-111-003)
Correspondence to: H Eugene Liu, MD, PhD, Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan.
Telephone: +886-2-29307930-2548 Fax: +886-2-55583019
Received: August 8, 2009
Revised: January 8, 2010
Accepted: January 15, 2010
Published online: January 27, 2010


Hepatocelluar carcinoma (HCC) is the most lethal cancer in the world. Most HCC over-express c-Myc, which plays a critical role in regulating cellular growth, differentiation and apoptosis in both normal and neoplastic cells. c-Myc is among the most frequently overexpressed genes in human cancers. Overexpression of c-Myc in hepatic cells leads to development of hepatocellular carcinoma. Here, we review the current progress in understanding physiologic function and regulation of c-Myc as well as its role in hepatic carcinogenesis and discuss the association of c-Myc activation in chronic hepatitis B infection and the upregulation of HIF-1/VEGF. We also explore the possibility of treating HCC by inhibiting c-Myc and examine the pros and cons of such an approach. Although this strategy is currently not available in clinics, with recent advances in better drug design, pharmacokinetics and pharmacogenetics, inhibition of c-Myc might become a novel therapy for HCC in the future.

Key Words: Hepatocellular carcinoma, c-Myc, Novel therapy


Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide[1]. Each year, approximately 350 000 patients are diagnosed with HCC in China, representing half of the new cases in the world. Surgical resection is the only way to cure this disease, yet most patients are not suitable for surgery because of poor hepatic reserve, comorbidity, or the presence of infiltrative and metastatic nature lesions. With less than 20% response rate, chemotherapy is not a good option either. Therefore it is imperative to develop novel therapeutics. Genetic analyses have revealed that c-Myc over-expression, which is commonly caused by genomic amplification is present in up to 70% of viral and alcohol-related HCC[2]. Furthermore, the presence of c-Myc amplification portends a more advanced and aggressive phenotype, indicating that c-Myc plays a critical role in pathogenesis of HCC[3,4]. In this review, we will focus on current understanding of c-Myc in hepatic carcinogenesis and its potential as a novel therapeutic target.


c-Myc, together with L-Myc, and N-Myc in the family of c-Myc genes, was first discovered as the cellular homolog of the v-Myc oncogene[5]. The identification of c-Myc as a target for activation by chromosomal translocation in Burkitt’s lymphoma resulted in the decade-long studies for its role in carcinogenesis[6]. In fact, c-Myc is the most commonly overexpressed gene in human cancers. In mammalian cells, c-Myc expression is highly regulated and closely tied to cell growth, apoptosis and differentiation[7]. The importance of c-Myc in development was exemplified by the embryonic lethality of c-Myc homologous knockouts[8].

c-Myc proteins consists of over 430 amino acids with 150 amino-terminal residues in the transactivation domain and 90 carboxy-terminal amino acid in the DNA binding and dimerization domain for binding to the obligate partner, Max[5]. To transactivate its downstream genes, c-Myc has to form heterodimers with Max to bind a consensus E-box site in the target promoter. In contrast to c-Myc, Max is a ubiquitous protein, thus the transactivating activity of c-Myc/Max heterodimers relies on the sophisticated control of c-Myc expression. Yet c-Myc is not the only protein that can partner with Max. Mad is another protein that forms heterodimers with Max to regulate c-Myc/Max transactivating activity. Upon differentiation, the binding of target DNA motif switches from c-Myc/Max to Mad/Max[9-11]. Mad protein contains a Sin3-containing domain that recruits Sin3, transcription repressor N-Cor, and histone deacetylase to repress target gene expression, thus adding another layer of control for c-Myc/Max mediated transactivation[12].

However, c-Myc also acts as a transcription repressor, especially for genes regarded to be differentiation markers. For example, when it is recruited by Miz-1 to target DNA binding motif as in the scenario found in p21[13]. Recent studies have found that c-Myc interacts with Miz-1 and recruit DNA methyltransferase DNMT3 to p21 promoter to silence p21 transcription, a critical step during tumorigenesis[14]. Along with the recruitment of DNA methyltransferases, c-Myc also acts as transcription repressor by interacting with histone deacetylases[15]. Other proteins related to cellular differentiation such as CCAAT/enhancer binding proteins and AP-2 have also been shown to be modulated by c-Myc-mediated transcription repression[16,17]. Both the transactivating and transcription-repressive properties are essential for c-Myc-mediated transforming activity.

In the past decades, various approaches have been used to identify c-Myc target genes[18-22]. So far, as many as 15%-20% of human genes can be regulated directly or indirectly by c-Myc. These genes are related to cell cycle control, protein synthesis, cytoskeleton and cell motility, cell metabolism, and microRNA- the small regulatory molecules that regulate the stability and translation of target mRNA[23]. How these genes interact with each other to modulate growth, differentiation, apoptosis, and survival is largely unknown, and it will require tremendous efforts to dissect the intricate networks and elucidate their role in tumorigenesis.

In order fine tune the sophisticated cellular network, the activity of c-Myc is tightly regulated at multiple levels. The half-life of c-Myc is as short as 20-30 min, meaning that its level changes dynamically in response to a broad range of cellular activities. But in cancer cells, the delicate balance of c-Myc expression is deranged by diverse mechanisms such as unidentified epigenetic aberration, dysregulated transcription, altered protein functionality, or resistance to modulation and proteasomal degradation. The story of c-Myc-mediated tumorigenesis is further complicated by a recent finding, indicating that it is not just its overexpression that matters, the levels of expression also determine its cellular response[24]. Low levels of deregulated c-Myc induce proliferation and sensitize cells to apoptotic signals; while high levels of c-Myc activate intrinsic ARF/p53 surveillance pathways. It is conceivable that different levels of c-Myc might trigger distinct subsets of target genes to determine the cell fate.


The association of c-Myc with liver carcinogenesis was first identified by the high expression of c-Myc in chronic liver disease and HCC[25,26] and the frequent c-Myc amplification in liver cancer tissue, which is commonly seen in patients at younger age and with poor prognosis[3,4,25]. Using a chemically-induced liver cancer model, the expression of c-Myc is increased in proportion to hepatic injury but not in normal liver[27]. Studies on the HBV, whose chronic infection is often associated with HCC in Asian countries, also identified that HBx has been implicated in HBV-mediated HCC[28]. HBx transforms hepatocytes through multiple mechanisms. One of the critical genes activated by HBx is c-Myc[29,30]. In turn, activation of c-Myc accelerates HBx-mediated oncogenic potential[31], further underscoring the importance of c-Myc in HCC development. One of the downstream genes activated by c-Myc in HCC is human telomerase reverse transcriptase (hTERT), which has two c-Myc-binding E-boxes in its core promoter and is a direct target of c-Myc[32]. The activation of hTERT by c-Myc in HCC has important clinical significance. Inhibition of hTERT activity by either RNAi, or lipid-conjugated oligonucleotides leads to tumor regression in xenogenic HCC models[33,34].

Another gene that interacts with c-Myc during hepatocarcinogenesis is HIF-1α, which is upregulated during hypoxia and induces angiogenesis. HIF-1α cooperates with c-Myc to enhance the expression of vascular-endothelial growth factor-A (VEGFA), a critical gene for angiogenesis[35]. Both HBx and HCV infection have been found to stabilize HIF-1α expression in HCC cells[36,37]. Such stabilization could be critical in promoting hepatic carcinogenesis and be responsible for the drug resistance in HCC[38].


Given the importance of c-Myc in HCC carcinogenesis, it is not surprising that c-Myc is an attractive target for developing novel therapies. The first evidence that down-regulation of c-Myc can be used as a strategy to treat HCC comes from an inducible c-Myc animal model, in which inactivation of c-Myc induced the regression and differentiation of liver tumors[39], yet could not eradicate them. This finding also echoes the recent discovery that, among the four factors required to maintain stem cell phenotypes, c-Myc is crucial[40-42]. Subsequent studies have indicated that in cells with intact p53, Rb and p16 signaling, inactivation of c-Myc leads to cell senescence[43]. This is also consistent with current knowledge on the relationship between cell senescence and hTERT. In addition, using antisense oligonucleotide strategies to downregulate c-Myc also inhibits HCC growth in vitro[44]. Recently small-molecule inhibitors that interfere with the c-Myc/Max heterodimerization have also been developed to block c-Myc-mediated transactivation[45]. Testing one of these small molecule c-Myc inhibitors, 10058-F4, in HCC reveals that 10058-F4 inhibited the growth of HCC cells in vitro, blocked the binding of E-box, and downregulated hTERT activity. Furthermore, c-Myc inhibition further sensitizes the chemotherapeutic agents against HCC[46]. However, the use of these small molecule c-Myc inhibitors in vivo has been less encouraging, probably due to rapid metabolism, resulting in low concentrations in tumors[47]. Subsequent development of c-Myc-Max inhibitors has tried to improve the activity with better pharmacokinetic profiles[48]. Hopefully these new compounds could better inhibit HCC in future in vivo studies.

Currently another small molecule compound, CX-3453 (Quarfloxin), which targets c-Myc by reducing c-Myc mRNA, is now in phase II clinical trials (NCT00780663) for neuroendocrine carcinoma. Likewise, CX-3543 also inhibits VEGF expression. Since the small molecule VEGFR inhibitor, sorafenib, has been approved for treating advanced HCC[49]. Testing this compound in HCC might shed more light on its potential for future HCC therapy.

However, some caveats are noteworthy in targeting c-Myc in HCC. First, in a transgenic model, re-activation of c-Myc leads to regrowth of tumors, indicating that this approach might target more mature cancer cells, instead of cancer stem cells. A combination with other strategies, such as chemotherapy or agents that target other critical pathways might be needed to enhance anti-cancer effects. In addition, there is concern about systemic toxicity upon c-Myc inhibition, especially in patients with impaired hepatic reserve. In an animal model, knocking down c-Myc expression does not impair liver regeneration, but the architecture of c-Myc-deficient hepatic tissues is disorganized with hypertrophied hepatocytes[50]. The less-than-anticipated toxicity in adult animals indicates that c-Myc might be dispensable in adult but not in neonatal tissues. Further investigation is crucial to determine whether the disorganized hepatic tissues still function like normal tissues and whether disorganized hepatic cells are prone to transformation.


Since the first discovery of its oncogenic properties in Burkitt’s lymphoma more than two decades ago, the role of c-Myc in normal and neoplastic cells has been extensively studied[51]. Although its critical functions in regulating cell physiology and in carcinogenesis have been well-recognized, the development of c-Myc as a therapeutic target lags far behind basic research. Reasons for such a slow progress are related to the sophisticated regulation of its expression and concerns of potential catastrophic events upon its inhibition. Indeed, even minor differences in its expression level might have divergent consequences[24]. Yet, with the advances in drug design, and in imaging tools to monitor cellular activity, it is now possible to better target c-Myc and investigate its potential as a novel therapeutic agent for HCC.


Peer reviewers: Ryuichi Morisihita, Professor, Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, 565-0871, Japan; Dr. Hironori Nakagami, Assisitant Professor, Division of Gene Therapy Science, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan

S- Editor Zhang HN L- Editor Lalor PF E- Editor Liu N

1.  Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-249.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Schlaeger C, Longerich T, Schiller C, Bewerunge P, Mehrabi A, Toedt G, Kleeff J, Ehemann V, Eils R, Lichter P. Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology. 2008;47:511-520.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Kawate S, Fukusato T, Ohwada S, Watanuki A, Morishita Y. Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression. Oncology. 1999;57:157-163.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Peng SY, Lai PL, Hsu HC. Amplification of the c-myc gene in human hepatocellular carcinoma: biologic significance. J Formos Med Assoc. 1993;92:866-870.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999;19:1-11.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Battey J, Moulding C, Taub R, Murphy W, Stewart T, Potter H, Lenoir G, Leder P. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983;34:779-787.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Dang CV, O’Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol. 2006;16:253-264.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Davis AC, Wims M, Spotts GD, Hann SR, Bradley A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 1993;7:671-682.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Larsson LG, Pettersson M, Oberg F, Nilsson K, Lüscher B. Expression of mad, mxi1, max and c-myc during induced differentiation of hematopoietic cells: opposite regulation of mad and c-myc. Oncogene. 1994;9:1247-1252.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Sommer A, Bousset K, Kremmer E, Austen M, Lüscher B. Identification and characterization of specific DNA-binding complexes containing members of the Myc/Max/Mad network of transcriptional regulators. J Biol Chem. 1998;273:6632-6642.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Xu D, Popov N, Hou M, Wang Q, Björkholm M, Gruber A, Menkel AR, Henriksson M. Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc Natl Acad Sci USA. 2001;98:3826-3831.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Harper SE, Qiu Y, Sharp PA. Sin3 corepressor function in Myc-induced transcription and transformation. Proc Natl Acad Sci USA. 1996;93:8536-8540.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Wu S, Cetinkaya C, Munoz-Alonso MJ, von der Lehr N, Bahram F, Beuger V, Eilers M, Leon J, Larsson LG. Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene. 2003;22:351-360.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Brenner C, Deplus R, Didelot C, Loriot A, Viré E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T. Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J. 2005;24:336-346.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008;68:3624-3629.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Zhang Y, Sif S, DeWille J. The mouse C/EBPdelta gene promoter is regulated by STAT3 and Sp1 transcriptional activators, chromatin remodeling and c-Myc repression. J Cell Biochem. 2007;102:1256-1270.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Sakamuro D, Prendergast GC. New Myc-interacting proteins: a second Myc network emerges. Oncogene. 1999;18:2942-2954.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Eilers M, Picard D, Yamamoto KR, Bishop JM. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 1989;340:66-68.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Haggerty TJ, Zeller KI, Osthus RC, Wonsey DR, Dang CV. A strategy for identifying transcription factor binding sites reveals two classes of genomic c-Myc target sites. Proc Natl Acad Sci USA. 2003;100:5313-5318.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Guo QM, Malek RL, Kim S, Chiao C, He M, Ruffy M, Sanka K, Lee NH, Dang CV, Liu ET. Identification of c-myc responsive genes using rat cDNA microarray. Cancer Res. 2000;60:5922-5928.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Elkon R, Zeller KI, Linhart C, Dang CV, Shamir R, Shiloh Y. In silico identification of transcriptional regulators associated with c-Myc. Nucleic Acids Res. 2004;32:4955-4961.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Berns K, Hijmans EM, Koh E, Daley GQ, Bernards R. A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts. Oncogene. 2000;19:3330-3334.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762-765.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Murphy DJ, Junttila MR, Pouyet L, Karnezis A, Shchors K, Bui DA, Brown-Swigart L, Johnson L, Evan GI. Distinct thresholds govern Myc’s biological output in vivo. Cancer Cell. 2008;14:447-457.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Chan KL, Guan XY, Ng IO. High-throughput tissue microarray analysis of c-myc activation in chronic liver diseases and hepatocellular carcinoma. Hum Pathol. 2004;35:1324-1331.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL. Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer. 2001;91:106-112.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Fang CH, Zhang GQ, Zhu XY, Gong JQ. Distribution of oval cells and c-myc mRNA expression in mouse hepatocarcinogenesis. Hepatobiliary Pancreat Dis Int. 2004;3:433-439.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Yu DY, Moon HB, Son JK, Jeong S, Yu SL, Yoon H, Han YM, Lee CS, Park JS, Lee CH. Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J Hepatol. 1999;31:123-132.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Balsano C, Avantaggiati ML, Natoli G, De Marzio E, Will H, Perricaudet M, Levrero M. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun. 1991;176:985-992.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Wu CG, Salvay DM, Forgues M, Valerie K, Farnsworth J, Markin RS, Wang XW. Distinctive gene expression profiles associated with Hepatitis B virus x protein. Oncogene. 2001;20:3674-3682.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P, Buendia MA. The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene. 1997;14:395-404.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R. Direct activation of TERT transcription by c-MYC. Nat Genet. 1999;21:220-224.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Zhang PH, Zou L, Tu ZG. RNAi-hTERT inhibition hepatocellular carcinoma cell proliferation via decreasing telomerase activity. J Surg Res. 2006;131:143-149.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL. Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology. 2005;42:1127-1136.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Huang LE. Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ. 2008;15:672-677.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Nasimuzzaman M, Waris G, Mikolon D, Stupack DG, Siddiqui A. Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor. J Virol. 2007;81:10249-10257.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Yoo YG, Na TY, Seo HW, Seong JK, Park CK, Shin YK, Lee MO. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene. 2008;27:3405-3413.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Han HK, Han CY, Cheon EP, Lee J, Kang KW. Role of hypoxia-inducible factor-alpha in hepatitis-B-virus X protein-mediated MDR1 activation. Biochem Biophys Res Commun. 2007;357:567-573.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, Bachmann MH, Borowsky AD, Ruebner B, Cardiff RD. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431:1112-1117.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E, Horvath S, Zhou Q, Plath K. Role of the murine reprogramming factors in the induction of pluripotency. Cell. 2009;136:364-377.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Cairo S, Armengol C, De Reyniès A, Wei Y, Thomas E, Renard CA, Goga A, Balakrishnan A, Semeraro M, Gresh L. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14:471-484.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA. 2007;104:13028-13033.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Simile MM, De Miglio MR, Muroni MR, Frau M, Asara G, Serra S, Muntoni MD, Seddaiu MA, Daino L, Feo F. Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells. Carcinogenesis. 2004;25:333-341.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Yin X, Giap C, Lazo JS, Prochownik EV. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene. 2003;22:6151-6169.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Lin CP, Liu JD, Chow JM, Liu CR, Liu HE. Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells. Anticancer Drugs. 2007;18:161-170.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Guo J, Parise RA, Joseph E, Egorin MJ, Lazo JS, Prochownik EV, Eiseman JL. Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc-Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice. Cancer Chemother Pharmacol. 2009;63:615-625.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Wang H, Hammoudeh DI, Follis AV, Reese BE, Lazo JS, Metallo SJ, Prochownik EV. Improved low molecular weight Myc-Max inhibitors. Mol Cancer Ther. 2007;6:2399-2408.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Li F, Xiang Y, Potter J, Dinavahi R, Dang CV, Lee LA. Conditional deletion of c-myc does not impair liver regeneration. Cancer Res. 2006;66:5608-5612.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, Aaronson S, Leder P. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA. 1982;79:7837-7841.  [PubMed]  [DOI]  [Cited in This Article: ]