Please cite this article in press as: Marin JJG, et al. Molecular bases of the poor response of liver cancer to chemotherapy. Clin Res Hepatol Gastroenterol (2018), https://doi.org/10.1016/j.clinre.2017.12.006 ARTICLE IN PRESS +Model CLINRE-1092; No. of Pages 11 Clinics and Research in Hepatology and Gastroenterology (2018) xxx, xxx—xxx Available online at ScienceDirect www.sciencedirect.com MINI REVIEW Molecular bases of the poor response of liver cancer to chemotherapy Jose J.G. Marin a,e,∗ , Oscar Briz a,e , Elisa Herraez a,e , Elisa Lozano a,e , Maitane Asensio a , Silvia Di Giacomo b , Marta R. Romero a,e , Luis M. Osorio-Padilla a , Ana I. Santos-Llamas a , Maria A. Serrano a,e , Carolina Armengol c,e , Thomas Efferth d , Rocio I.R. Macias a,e a Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain b Department of Physiology and Pharmacology ‘‘Vittorio Erspamer’’, Sapienza University of Rome, Rome, Italy c Childhood Liver Oncology Group, Program of Predictive and Personalized Medicine of Cancer (PMPCC), Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain d Department Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany e Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain KEYWORDS Cholangiocarcinoma; Hepatoblastoma; Summary A characteristic shared by most frequent types of primary liver cancer, i.e., hep- atocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in adults, and in a lesser extent hepatoblastoma (HB) mainly in children, is their high refractoriness to chemotherapy. This is the result of synergic interactions among complex and diverse mechanisms of chemoresistance (MOC) in which more than 100 genes are involved. Pharmacological treatment, although it can be Abbreviations: ABC, ATP-binding cassette; AEG-1, astrocyte elevated gene-1; BCRP, breast cancer resistance protein; CCA, cholangio- carcinoma; DPD, dihydropyrimidine dehydrogenase; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; ERCC1, excision repair cross-complementation group; 5-FU, 5-fluorouracil; GSTP1, glutathione-S-transferase Pi 1; HIF, hypoxia-inducible transcription factor; HB, hepatoblastoma; HCC, hepatocellular carcinoma; LIF, leukemia inhibitory factor; MDR, multidrug resistance; MOC, mechanism of chemoresistance; MTs, metallothioneins; MRP, multidrug resistance-associated protein; mTOR, mammalian target of rapamycin; NER, nucleotide excision repair; NHEJ, non-homologous end joining; OATP, organic anion-transporting polypeptide; OCT, organic cation transporter; SLC, solute carrier; TKI, tyrosine kinase inhibitor; TKR, tyrosine kinase receptor; TOP, topoisomerase; TP, thymidine phos- phorylase; TS, thymidylate synthase; TSC2, tuberous sclerosis complex; UGT, uridine diphosphate-glucuronosyl transferase; VEGF, vascular endothelial growth factor; XLF, XRCC4-like factor. ∗ Corresponding author. Department of Physiology and Pharmacology, Campus Miguel de Unamuno E.D. Lab231, 37007 Salamanca, Spain. E-mail address: jjgmarin@usal.es (J.J.G. Marin). https://doi.org/10.1016/j.clinre.2017.12.006 2210-7401/© 2018 Elsevier Masson SAS. All rights reserved.