Download PDF
Semin Liver Dis 2021; 41(01): 028-041
DOI: 10.1055/s-0040-1722645
Review Article

Molecular Mechanisms of Hepatoblastoma

Yi Zhang
1   Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
2   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
,
Antonio Solinas
3   Department of Biomedical Sciences, University of Sassari, Sassari, Italy
,
Stefano Cairo
4   XenTech, Evry, France
5   Istituto di Ricerca Pediatrica, Padova, Italy
,
Matthias Evert
6   Institute of Pathology, University of Regensburg, Regensburg, Germany
,
Xin Chen
2   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
,
Diego F. Calvisi
6   Institute of Pathology, University of Regensburg, Regensburg, Germany
› Author Affiliations Funding This work was supported by NIH grant R01CA204586 (to X.C.), P30DK026743 for UCSF Liver Center, and a China Scholarship Council PhD fellowship (to Y.Z.; 201806050132).
› Further Information
    Permissions and Reprints

Abstract

Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.

Keywords

hepatoblastoma - Wnt/β-catenin - Hippo - NRF2


Publication History

Article published online:
20 January 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 2003; 38 (03) 560-566
    CrossrefPubMedGoogle Scholar
  • 2 Feng J, Polychronidis G, Heger U, Frongia G, Mehrabi A, Hoffmann K. Incidence trends and survival prediction of hepatoblastoma in children: a population-based study. Cancer Commun (Lond) 2019; 39 (01) 62
    CrossrefPubMedGoogle Scholar
  • 3 Celotti A, D'Amico G, Ceresoli M. et al. Hepatoblastoma of the adult: a systematic review of the literature. Surg Oncol 2016; 25 (03) 339-347
    CrossrefPubMedGoogle Scholar
  • 4 Mussa A, Ferrero GB. Screening hepatoblastoma in Beckwith-Wiedemann syndrome: a complex issue. J Pediatr Hematol Oncol 2015; 37 (08) 627
    CrossrefPubMedGoogle Scholar
  • 5 Trobaugh-Lotrario AD, López-Terrada D, Li P, Feusner JH. Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: clinical characteristics and rationale for surveillance screening. Pediatr Blood Cancer 2018; 65 (08) e27103
    CrossrefPubMedGoogle Scholar
  • 6 Clericuzio CL, Martin RA. Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 2009; 11 (03) 220-222
    CrossrefPubMedGoogle Scholar
  • 7 Ito E, Sato Y, Kawauchi K. et al. Type 1a glycogen storage disease with hepatoblastoma in siblings. Cancer 1987; 59 (10) 1776-1780
    CrossrefPubMedGoogle Scholar
  • 8 Farmakis SG, Barnes AM, Carey JC, Braddock SR. Solid tumor screening recommendations in trisomy 18. Am J Med Genet A 2019; 179 (03) 455-466
    CrossrefPubMedGoogle Scholar
  • 9 Spector LG, Feusner JH, Ross JA. Hepatoblastoma and low birth weight. Pediatr Blood Cancer 2004; 43 (06) 706
    CrossrefPubMedGoogle Scholar
  • 10 Sharma D, Subbarao G, Saxena R. Hepatoblastoma. Semin Diagn Pathol 2017; 34 (02) 192-200
    CrossrefPubMedGoogle Scholar
  • 11 Qiao GL, Chen Z, Wang C. et al. Pure fetal histology subtype was associated with better prognosis of children with hepatoblastoma: a Chinese population-based study. J Gastroenterol Hepatol 2016; 31 (03) 621-627
    CrossrefPubMedGoogle Scholar
  • 12 López-Terrada D, Alaggio R, de Dávila MT. et al. Towards an international pediatric liver tumor consensus classification: Proceedings of the Los Angeles COG Liver Tumors Symposium. Mod pathology 2014; 27 (03) 472-491
    CrossrefPubMedGoogle Scholar
  • 13 Fazlollahi L, Hsiao SJ, Kochhar M, Mansukhani MM, Yamashiro DJ, Remotti HE. Malignant rhabdoid tumor, an aggressive tumor often misclassified as small cell variant of hepatoblastoma. Cancers (Basel) 2019; 11 (12) E1992
    CrossrefPubMedGoogle Scholar
  • 14 Zimmermann A. Hepatoblastoma with cholangioblastic features (‘cholangioblastic hepatoblastoma’) and other liver tumors with bimodal differentiation in young patients. Med Pediatr Oncol 2002; 39 (05) 487-491
    CrossrefPubMedGoogle Scholar
  • 15 Towbin AJ, Meyers RL, Woodley H. et al. 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 2018; 48 (04) 536-554
    CrossrefPubMedGoogle Scholar
  • 16 Maibach R, Roebuck D, Brugieres L. et al. Prognostic stratification for children with hepatoblastoma: the SIOPEL experience. Eur J Cancer 2012; 48 (10) 1543-1549
    CrossrefPubMedGoogle Scholar
  • 17 Trobaugh-Lotrario AD, Meyers RL, Feusner JH. Outcomes of patients with relapsed hepatoblastoma enrolled on Children's Oncology Group (COG) phase I and II studies. J Pediatr Hematol Oncol 2016; 38 (03) 187-190
    CrossrefPubMedGoogle Scholar
  • 18 Fuchs J, Rydzynski J, Von Schweinitz D. et al; Study Committee of the Cooperative Pediatric Liver Tumor Study Hb 94 for the German Society for Pediatric Oncology and Hematology. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 2002; 95 (01) 172-182
    CrossrefPubMedGoogle Scholar
  • 19 Hiyama E, Hishiki T, Watanabe K. et al. Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol. J Pediatr Surg 2016; 51 (12) 2053-2057
    CrossrefPubMedGoogle Scholar
  • 20 Meyers RL, Maibach R, Hiyama E. et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic Tumors International Collaboration. Lancet Oncol 2017; 18 (01) 122-131
    CrossrefPubMedGoogle Scholar
  • 21 Czauderna P. Hepatoblastoma throughout SIOPEL trials - clinical lessons learnt. Front Biosci (Elite Ed) 2012; 4: 470-479
    CrossrefPubMedGoogle Scholar
  • 22 Malogolowkin MH, Katzenstein HM, Meyers RL. et al. Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 2011; 29 (24) 3301-3306
    CrossrefPubMedGoogle Scholar
  • 23 Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013; 45 (10) 1127-1133
    CrossrefPubMedGoogle Scholar
  • 24 Thorsson V, Gibbs DL, Brown SD. et al; Cancer Genome Atlas Research Network. The immune landscape of cancer. Immunity 2019; 51 (02) 411-412
    CrossrefPubMedGoogle Scholar
  • 25 Zanfardino M, Pane K, Mirabelli P, Salvatore M, Franzese M. TCGA-TCIA impact on radiogenomics cancer research: a systematic review. Int J Mol Sci 2019; 20 (23) E6033
    CrossrefPubMedGoogle Scholar
  • 26 Cairo S, Armengol C, De Reyniès 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 (06) 471-484
    CrossrefPubMedGoogle Scholar
  • 27 Cairo S, Wang Y, de Reyniès 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 (47) 20471-20476
    CrossrefPubMedGoogle Scholar
  • 28 Hooks KB, Audoux J, Fazli H. et al. New insights into diagnosis and therapeutic options for proliferative hepatoblastoma. Hepatology 2018; 68 (01) 89-102
    CrossrefPubMedGoogle Scholar
  • 29 Carrillo-Reixach J, Torrens L, Simon-Coma M. et al. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol 2020; 73 (02) 328-341
    CrossrefPubMedGoogle Scholar
  • 30 Sumazin P, Chen Y, Treviño LR. et al. Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology 2017; 65 (01) 104-121
    CrossrefPubMedGoogle Scholar
  • 31 Nakagawa H, Fujita M, Fujimoto A. Genome sequencing analysis of liver cancer for precision medicine. Semin Cancer Biol 2019; 55: 120-127
    CrossrefPubMedGoogle Scholar
  • 32 Liotta L, Petricoin E. Molecular profiling of human cancer. Nat Rev Genet 2000; 1 (01) 48-56
    CrossrefPubMedGoogle Scholar
  • 33 Mavila N, Thundimadathil J. The emerging roles of cancer stem cells and Wnt/beta-catenin signaling in hepatoblastoma. Cancers (Basel) 2019; 11 (10) E1406
    CrossrefPubMedGoogle Scholar
  • 34 Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011; 25 (10) 1010-1022
    CrossrefPubMedGoogle Scholar
  • 35 Crippa S, Ancey PB, Vazquez J. et al. Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma. EMBO Mol Med 2017; 9 (11) 1589-1604
    CrossrefPubMedGoogle Scholar
  • 36 Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 1999; 59 (02) 269-273
    PubMedGoogle Scholar
  • 37 Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC. Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett 2000; 152 (01) 45-51
    CrossrefPubMedGoogle Scholar
  • 38 Morcrette G, Hirsch TZ, Badour E. et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. OncoImmunology 2019; 8 (06) e1583547
    CrossrefPubMedGoogle Scholar
  • 39 López-Terrada D, Gunaratne PH, Adesina AM. et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol 2009; 40 (06) 783-794
    CrossrefPubMedGoogle Scholar
  • 40 Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004; 303 (5663): 1483-1487
    CrossrefPubMedGoogle Scholar
  • 41 McCrea PD, Gottardi CJ. Beyond β-catenin: prospects for a larger catenin network in the nucleus. Nat Rev Mol Cell Biol 2016; 17 (01) 55-64
    CrossrefPubMedGoogle Scholar
  • 42 Zhang W, Meyfeldt J, Wang H. et al. β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice. J Biol Chem 2019; 294 (46) 17524-17542
    CrossrefPubMedGoogle Scholar
  • 43 Bell D, Ranganathan S, Tao J, Monga SP. Novel advances in understanding of molecular pathogenesis of hepatoblastoma: a Wnt/β-catenin perspective. Gene Expr 2017; 17 (02) 141-154
    CrossrefPubMedGoogle Scholar
  • 44 Eichenmüller M, Trippel F, Kreuder M. et al. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 2014; 61 (06) 1312-1320
    CrossrefPubMedGoogle Scholar
  • 45 Gröbner SN, Worst BC, Weischenfeldt J. et al; ICGC PedBrain-Seq Project, ICGC MMML-Seq Project. The landscape of genomic alterations across childhood cancers. Nature 2018; 555 (7696): 321-327
    CrossrefPubMedGoogle Scholar
  • 46 Jia D, Dong R, Jing Y. et al. Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 2014; 60 (05) 1686-1696
    CrossrefPubMedGoogle Scholar
  • 47 Lee H, El Jabbour T, Ainechi S. et al. General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study. Hum Pathol 2017; 70: 84-91
    CrossrefPubMedGoogle Scholar
  • 48 Paz-Yaacov N, Bazak L, Buchumenski I. et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep 2015; 13 (02) 267-276
    CrossrefPubMedGoogle Scholar
  • 49 Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers (Basel) 2019; 11 (07) E926
    CrossrefPubMedGoogle Scholar
  • 50 Perugorria MJ, Olaizola P, Labiano I. et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol 2019; 16 (02) 121-136
    CrossrefPubMedGoogle Scholar
  • 51 MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17 (01) 9-26
    CrossrefPubMedGoogle Scholar
  • 52 Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8 (20) 33972-33989
    CrossrefPubMedGoogle Scholar
  • 53 Monga SP. β-Catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology 2015; 148 (07) 1294-1310
    CrossrefPubMedGoogle Scholar
  • 54 Yang A, Sisson R, Gupta A, Tiao G, Geller JI. Germline APC mutations in hepatoblastoma. Pediatr Blood Cancer 2018;65(04):
    PubMedGoogle Scholar
  • 55 Forbes SA, Beare D, Boutselakis H. et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 2017; 45 (D1): D777-D783
    CrossrefPubMedGoogle Scholar
  • 56 Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169 (06) 985-999
    CrossrefPubMedGoogle Scholar
  • 57 Ding Y, Xi Y, Chen T. et al. Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation. J Cell Biol 2008; 182 (05) 865-872
    CrossrefPubMedGoogle Scholar
  • 58 Matsumoto S, Yamamichi T, Shinzawa K. et al. GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling. Nat Commun 2019; 10 (01) 3882
    CrossrefPubMedGoogle Scholar
  • 59 Nejak-Bowen KN, Monga SP. Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol 2011; 21 (01) 44-58
    CrossrefPubMedGoogle Scholar
  • 60 Maugeri-Saccà M, De Maria R. The Hippo pathway in normal development and cancer. Pharmacol Ther 2018; 186: 60-72
    CrossrefPubMedGoogle Scholar
  • 61 Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015; 15 (02) 73-79
    CrossrefPubMedGoogle Scholar
  • 62 Zhu C, Li L, Zhao B. The regulation and function of YAP transcription co-activator. Acta Biochim Biophys Sin (Shanghai) 2015; 47 (01) 16-28
    CrossrefPubMedGoogle Scholar
  • 63 Lin KC, Park HW, Guan KL. Regulation of the Hippo pathway transcription factor TEAD. Trends Biochem Sci 2017; 42 (11) 862-872
    CrossrefPubMedGoogle Scholar
  • 64 Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005; 122 (03) 421-434
    CrossrefPubMedGoogle Scholar
  • 65 Li H, Wolfe A, Septer S. et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int 2012; 32 (01) 38-47
    CrossrefPubMedGoogle Scholar
  • 66 Tao J, Calvisi DF, Ranganathan S. et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 2014; 147 (03) 690-701
    CrossrefPubMedGoogle Scholar
  • 67 Zhang S, Zhang J, Evert K. et al. The Hippo effector transcriptional coactivator with PDZ-binding motif cooperates with oncogenic β-catenin to induce hepatoblastoma development in mice and humans. Am J Pathol 2020; 190 (07) 1397-1413
    CrossrefPubMedGoogle Scholar
  • 68 Min Q, Molina L, Li J. et al. β-Catenin and Yes-associated protein 1 cooperate in hepatoblastoma pathogenesis. Am J Pathol 2019; 189 (05) 1091-1104
    CrossrefPubMedGoogle Scholar
  • 69 Smith JL, Rodríguez TC, Mou H. et al. YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. Hepatology 2020; DOI: 10.1002/hep.31389.
    CrossrefPubMedGoogle Scholar
  • 70 Zhang J, Liu P, Tao J. et al. TEA domain transcription factor 4 is the major mediator of Yes-associated protein oncogenic activity in mouse and human hepatoblastoma. Am J Pathol 2019; 189 (05) 1077-1090
    CrossrefPubMedGoogle Scholar
  • 71 Dang CV. MYC on the path to cancer. Cell 2012; 149 (01) 22-35
    CrossrefPubMedGoogle Scholar
  • 72 Levens D. You don't muck with MYC. Genes Cancer 2010; 1 (06) 547-554
    CrossrefPubMedGoogle Scholar
  • 73 Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999; 19 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 74 Ranganathan S, Tan X, Monga SP. Beta-catenin and met deregulation in childhood hepatoblastomas. Pediatr Dev Pathol 2005; 8 (04) 435-447
    CrossrefPubMedGoogle Scholar
  • 75 Wang H, Lu J, Edmunds LR. et al. Coordinated activities of multiple Myc-dependent and Myc-independent biosynthetic pathways in hepatoblastoma. J Biol Chem 2016; 291 (51) 26241-26251
    CrossrefPubMedGoogle Scholar
  • 76 Eberherr C, Beck A, Vokuhl C. et al. Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells. Int J Oncol 2019; 54 (05) 1853-1863
    PubMedGoogle Scholar
  • 77 Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15 (23) 3059-3087
    CrossrefPubMedGoogle Scholar
  • 78 Ruiz i Altaba A, Sánchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002; 2 (05) 361-372
    CrossrefPubMedGoogle Scholar
  • 79 Eichenmüller M, Gruner I, Hagl B. et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology 2009; 49 (02) 482-490
    CrossrefPubMedGoogle Scholar
  • 80 Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg 2010; 45 (02) 387-392
    CrossrefPubMedGoogle Scholar
  • 81 Yamanaka H, Oue T, Uehara S, Fukuzawa M. Forskolin, a hedgehog signal inhibitor, inhibits cell proliferation and induces apoptosis in pediatric tumor cell lines. Mol Med Rep 2010; 3 (01) 133-139
    PubMedGoogle Scholar
  • 82 Li YC, Deng YH, Guo ZH. et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. Eur J Med Res 2010; 15 (11) 468-474
    CrossrefPubMedGoogle Scholar
  • 83 Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends Mol Med 2016; 22 (07) 578-593
    CrossrefPubMedGoogle Scholar
  • 84 Comerford SA, Hinnant EA, Chen Y. et al. Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin. JCI Insight 2016; 1 (16) e88549
    CrossrefPubMedGoogle Scholar
  • 85 Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 2006; 12 (12) 3657-3660
    CrossrefPubMedGoogle Scholar
  • 86 von Schweinitz D, Faundez A, Teichmann B. et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 2000; 85 (02) 151-159
    CrossrefPubMedGoogle Scholar
  • 87 Grotegut S, Kappler R, Tarimoradi S, Lehembre F, Christofori G, Von Schweinitz D. Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by AKT activation. Int J Oncol 2010; 36 (05) 1261-1267
    PubMedGoogle Scholar
  • 88 Purcell R, Childs M, Maibach R. et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. J Exp Clin Cancer Res 2011; 30: 96
    CrossrefPubMedGoogle Scholar
  • 89 Monga SP, Mars WM, Pediaditakis P. et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res 2002; 62 (07) 2064-2071
    PubMedGoogle Scholar
  • 90 Vogt PK, Hart JR, Gymnopoulos M. et al. Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol 2010; 347: 79-104
    PubMedGoogle Scholar
  • 91 Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497 (7448): 217-223
    CrossrefPubMedGoogle Scholar
  • 92 Hartmann W, Küchler J, Koch A. et al. Activation of phosphatidylinositol-3′-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res 2009; 15 (14) 4538-4545
    CrossrefPubMedGoogle Scholar
  • 93 Liu P, Calvisi DF, Kiss A. et al. Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget 2017; 8 (43) 73433-73447
    CrossrefPubMedGoogle Scholar
  • 94 Adebayo Michael AO, Ko S, Tao J. et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by β-catenin mutations. Cell Metab 2019; 29 (05) 1135.e6-1150 e6
    CrossrefPubMedGoogle Scholar
  • 95 Muñoz M, Rosso M, Coveñas R. Neurokinin-1 receptor antagonists against hepatoblastoma. Cancers (Basel) 2019; 11 (09) E1258
    CrossrefPubMedGoogle Scholar
  • 96 Berger M, Neth O, Ilmer M. et al. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo. J Hepatol 2014; 60 (05) 985-994
    CrossrefPubMedGoogle Scholar
  • 97 Garnier A, Ilmer M, Kappler R, Berger M. Therapeutic innovations for targeting hepatoblastoma. Anticancer Res 2016; 36 (11) 5577-5592
    CrossrefPubMedGoogle Scholar
  • 98 Gray SG, Eriksson T, Ekström C. et al. Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer 2000; 82 (09) 1561-1567
    CrossrefPubMedGoogle Scholar
  • 99 Rainier S, Dobry CJ, Feinberg AP. Loss of imprinting in hepatoblastoma. Cancer Res 1995; 55 (09) 1836-1838
    PubMedGoogle Scholar
  • 100 Honda S, Arai Y, Haruta M. et al. Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. Br J Cancer 2008; 99 (11) 1891-1899
    CrossrefPubMedGoogle Scholar
  • 101 Regel I, Eichenmüller M, Joppien S. et al. IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors. Mol Cancer 2012; 11: 9
    CrossrefPubMedGoogle Scholar
  • 102 Akmal SN, Yun K, MacLay J, Higami Y, Ikeda T. Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum Pathol 1995; 26 (08) 846-851
    CrossrefPubMedGoogle Scholar
  • 103 Liu Z, Sun Q, Wang X. PLK1, a potential target for cancer therapy. Transl Oncol 2017; 10 (01) 22-32
    CrossrefPubMedGoogle Scholar
  • 104 Kats D, Ricker CA, Berlow NE. et al. Volasertib preclinical activity in high-risk hepatoblastoma. Oncotarget 2019; 10 (60) 6403-6417
    CrossrefPubMedGoogle Scholar
  • 105 Viré E, Brenner C, Deplus R. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439 (7078): 871-874
    CrossrefPubMedGoogle Scholar
  • 106 Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med 2016; 22 (02) 128-134
    CrossrefPubMedGoogle Scholar
  • 107 Hajósi-Kalcakosz S, Dezső K, Bugyik E. et al. Enhancer of zeste homologue 2 (EZH2) is a reliable immunohistochemical marker to differentiate malignant and benign hepatic tumors. Diagn Pathol 2012; 7: 86
    CrossrefPubMedGoogle Scholar
  • 108 Schlachter K, Gyugos M, Halász J. et al. High tricellulin expression is associated with better survival in human hepatoblastoma. Histopathology 2014; 65 (05) 631-641
    CrossrefPubMedGoogle Scholar
  • 109 Wang Y, Xiao Y, Chen K. et al. Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells. Mol Med Rep 2016; 13 (03) 2724-2728
    CrossrefPubMedGoogle Scholar
  • 110 Lozano G, Zambetti GP. Gankyrin: an intriguing name for a novel regulator of p53 and RB. Cancer Cell 2005; 8 (01) 3-4
    CrossrefPubMedGoogle Scholar
  • 111 Higashitsuji H, Itoh K, Nagao T. et al. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 2000; 6 (01) 96-99
    CrossrefPubMedGoogle Scholar
  • 112 Valanejad L, Lewis K, Wright M. et al. FXR-Gankyrin axis is involved in development of pediatric liver cancer. Carcinogenesis 2017; 38 (07) 738-747
    CrossrefPubMedGoogle Scholar
  • 113 Cast A, Valanejad L, Wright M. et al. C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer. Hepatology 2018; 67 (05) 1857-1871
    CrossrefPubMedGoogle Scholar
  • 114 Toiyama Y, Inoue Y, Yasuda H. et al. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness. J Gastroenterol 2011; 46 (02) 153-163
    CrossrefPubMedGoogle Scholar
  • 115 Cui X, Liu X, Han Q. et al. DPEP1 is a direct target of miR-193a-5p and promotes hepatoblastoma progression by PI3K/Akt/mTOR pathway. Cell Death Dis 2019; 10 (10) 701
    CrossrefPubMedGoogle Scholar
  • 116 Gil-García B, Baladrón V. The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. Biol Cell 2016; 108 (02) 29-40
    CrossrefPubMedGoogle Scholar
  • 117 Nagai H, Naka T, Terada Y. et al. Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 2003; 48 (02) 65-69
    CrossrefPubMedGoogle Scholar
  • 118 Honda S, Miyagi H, Suzuki H. et al. RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients. Pediatr Surg Int 2013; 29 (11) 1147-1152
    CrossrefPubMedGoogle Scholar
  • 119 Gray SG, Hartmann W, Eriksson T. et al. Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas. Int J Mol Med 2000; 6 (02) 161-169
    PubMedGoogle Scholar
  • 120 Trobaugh-Lotrario AD, Venkatramani R, Feusner JH. Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment?. J Pediatr Hematol Oncol 2014; 36 (05) 369-373
    CrossrefPubMedGoogle Scholar
  • 121 Delmore JE, Issa GC, Lemieux ME. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011; 146 (06) 904-917
    CrossrefPubMedGoogle Scholar
  • 122 Ma L, Wang X, Jia T, Wei W, Chua MS, So S. Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells. Oncotarget 2015; 6 (28) 25390-25401
    CrossrefPubMedGoogle Scholar
  • 123 Jia J, Qiao Y, Pilo MG. et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One 2017; 12 (09) e0184068
    CrossrefPubMedGoogle Scholar
  • 124 Kieran MW, Chisholm J, Casanova M. et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro-oncol 2017; 19 (11) 1542-1552
    CrossrefPubMedGoogle Scholar
  • 125 Grüllich C. Cabozantinib: multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res 2018; 211: 67-75
    CrossrefPubMedGoogle Scholar
  • 126 Osanto S, van der Hulle T. Cabozantinib in the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor targeted therapy: clinical trial evidence and experience. Ther Adv Urol 2018; 10 (03) 109-123
    CrossrefPubMedGoogle Scholar
  • 127 Dhillon S. Ivosidenib: first global approval. Drugs 2018; 78 (14) 1509-1516
    CrossrefPubMedGoogle Scholar
  • 128 Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 2009; 280 (02) 201-210
    CrossrefPubMedGoogle Scholar
  • 129 Deroanne CF, Bonjean K, Servotte S. et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002; 21 (03) 427-436
    CrossrefPubMedGoogle Scholar
  • 130 Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M. Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J Biol Chem 1999; 274 (44) 31127-31130
    CrossrefPubMedGoogle Scholar
  • 131 Li AY, McCusker MG, Russo A. et al. RET fusions in solid tumors. Cancer Treat Rev 2019; 81: 101911
    CrossrefPubMedGoogle Scholar
  • 132 Yang Y, Zhou J, Zhou J. et al. Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial. Lancet Respir Med 2020; 8 (01) 45-53
    CrossrefPubMedGoogle Scholar
  • 133 Mesa RA. Tipifarnib: farnesyl transferase inhibition at a crossroads. Expert Rev Anticancer Ther 2006; 6 (03) 313-319
    CrossrefPubMedGoogle Scholar
  • 134 Liu M, Liu H, Chen J. Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). Oncol Rep 2018; 39 (03) 901-911
    PubMedGoogle Scholar
  • 135 Roskoski Jr R. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res 2019; 142: 151-168
    CrossrefPubMedGoogle Scholar
  • 136 Scott LJ. Larotrectinib: first global approval. Drugs 2019; 79 (02) 201-206
    CrossrefPubMedGoogle Scholar
  • 137 Chen Y, Du H. The promising PARP inhibitors in ovarian cancer therapy: from Olaparib to others. Biomed Pharmacother 2018; 99: 552-560
    CrossrefPubMedGoogle Scholar
  • 138 Niu NK, Wang ZL, Pan ST. et al. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther 2015; 9: 1555-1584
    PubMedGoogle Scholar
  • 139 Garbe C, Eigentler TK. Vemurafenib. Recent Results Cancer Res 2018; 211: 77-89
    CrossrefPubMedGoogle Scholar
  • 140 Duvoux C, Toso C. mTOR inhibitor therapy: does it prevent HCC recurrence after liver transplantation?. Transplant Rev (Orlando) 2015; 29 (03) 168-174
    CrossrefPubMedGoogle Scholar
  • 141 Zheng L, Li H, Mo Y, Qi G, Liu B, Zhao J. Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo . Oncotarget 2017; 8 (58) 98964-98973
    CrossrefPubMedGoogle Scholar
  • 142 Makita S, Tobinai K. Targeting EZH2 with tazemetostat. Lancet Oncol 2018; 19 (05) 586-587
    CrossrefPubMedGoogle Scholar
  • 143 Markham A. Erdafitinib: first global approval. Drugs 2019; 79 (09) 1017-1021
    CrossrefPubMedGoogle Scholar
  • 144 Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies?. Expert Opin Emerg Drugs 2019; 24 (03) 153-171
    CrossrefPubMedGoogle Scholar
  • 145 Al-Rasheed NM, Al-Oteibi MM, Al-Manee RZ. et al. Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway. Drug Des Devel Ther 2015; 9: 3217-3229
    PubMedGoogle Scholar
  • 146 McKian KP, Haluska P. Cixutumumab. Expert Opin Investig Drugs 2009; 18 (07) 1025-1033
    CrossrefPubMedGoogle Scholar
  • 147 Ettrich TJ, Seufferlein T. Regorafenib. Recent Results Cancer Res 2018; 211: 45-56
    CrossrefPubMedGoogle Scholar
  • 148 Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs 2012; 21 (06) 879-889
    CrossrefPubMedGoogle Scholar
  • 149 Metro G, Chiari R, Baldi A, De Angelis V, Minotti V, Crinò L. Selumetinib: a promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung cancer. Future Oncol 2013; 9 (02) 167-177
    CrossrefPubMedGoogle Scholar