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.

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Gemcitabine and 5-fluorouracil are taken up through nucleoside transporters, equilibrative nucleoside transporters (ENT) and concentrative nucleoside transporters (CNT). In CCA cells, low expression of ENT1 is associated with poor response to these drugs [276][277][278] , and CNT1 expression is also impaired 279 . Lack of sensitivity to cisplatin is due, in part, to reduced uptake through the copper transporter CTR1, whose expression in CCA is decreased 279 .…”

Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

“…Moreover, several studies in animals support the relationship between cholestasis and cholangiocarcinoma progression (5,6). On the other hand, FXR, whose expression is decreased in cholangiocarcinoma (7), is involved in liver cells chemoprotection against genotoxic compounds (8).…”

Hepatoblastoma Etiopathogenesis

“…Interestingly, some of these genes, such as BIRC5, RPL6 and MYC have been found upregulated in the C2 subtype of HB [31]. Three of these changes, namely up-regulation of BIRC5 and down-regulation of SLC22A1 and CYP1A2 were also observed in HCC and cholangiocarcinoma [28]. These phenotypic traits may be involved in the susceptibility to chemically-induced carcinogenesis and/or the lack of response to chemotherapy once the tumor has already developed.…”

“…Changes in the expression of genes involved in chemoresistance/chemoprotection in HB. [28]). *Upregulated in C2 subtype of HB [31].…”

“…The copy number variation profile of HB shows more frequent gain than losses in different studies [10,22,24]. Regarding chemoresistance, we must keep in mind that changes in expression and/or the presence of mutations in an important number of genes contributing to different mechanisms of chemoresistance in liver cancers, either affecting the intracellular amount of active drugs or affecting their effectiveness can be responsible for the lack of response to chemotherapy [28][29][30]. Using Taqman Low Density Arrays, analysis of expression profiles in HB revealed changes in mRNA abundance for 26 genes involved in chemoprotection and chemoresistance (Table 1).…”