title: No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors.
abstract: Farnesoid X receptor (FXR) has been recently reported to enhance chemoresistance through bile acid-independent mechanisms. Thus, FXR transfection plus activation with GW4064 resulted in reduced sensitivity to cisplatin-induced toxicity. This is interesting because primary tumors of the liver, an organ where FXR is expressed, exhibit marked refractoriness to pharmacological treatment. Here we have determined whether FXR is upregulated in hepatocellular carcinoma (HCC), cholangiocarcinoma (CGC) and hepatoblastoma (HPB) and whether this is related with the expression of genes involved in mechanisms of chemoresistance. Using RT-QPCR and Taqman low density arrays we have analyzed biopsies from healthy livers or surgically removed tumors from naive patients and cell lines derived from HCC (SK-HEP-1, Alexander and Huh7), CGC (TFK1) and HPB (HepG2), before and after exposure to cisplatin at IC50 for 72 h. In liver tumors FXR expression was not enhanced but significantly decreased (healthy liver > HCC > HPB ≈ CGC). Except for CGC, this was not accompanied by changes in the proportions of FXR isoforms. Changes in 36 genes involved in drug uptake/efflux and metabolism, expression/function of molecular targets, and survival/apoptosis balance were found. Changes affecting SLC22A1, CYP2A1 and BIRC5 were shared by HCC, CGC and HPB. Similarity in gene expression profiles between cell lines and parent tumors was found. Pharmacological challenge with cisplatin induced changes that increased this resemblance. This was not dependent upon FXR expression. Thus, although FXR may play a role in inducing chemoresistance under certain circumstances, its upregulation does not seem to be involved in the multidrug resistance phenotype characteristic of HCC, CGC and HPB.
authors.affiliation: Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Martinez-Becerra
authors.forename: J
authors.initials: J
authors.lastname: Vaquero
authors.forename: M R
authors.initials: MR
authors.lastname: Romero
authors.forename: E
authors.initials: E
authors.lastname: Lozano
authors.forename: C
authors.initials: C
authors.lastname: Anadon
authors.forename: R I R
authors.initials: RI
authors.lastname: Macias
authors.forename: M A
authors.initials: MA
authors.lastname: Serrano
authors.forename: N
authors.initials: N
authors.lastname: Grañé-Boladeras
authors.forename: L
authors.initials: L
authors.lastname: Muñoz-Bellvis
authors.forename: L
authors.initials: L
authors.lastname: Alvarez
authors.forename: B
authors.initials: B
authors.lastname: Sangro
authors.forename: M
authors.initials: M
authors.lastname: Pastor-Anglada
authors.forename: J J G
authors.initials: JJ
authors.lastname: Marin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated