Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma

Abstract

Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long‑term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum‑based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor‑surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates.

Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

“…In rat hepatocytes, Oct1 has been located at the sinusoidal membrane [51]. OCT1 is also expressed in cholangiocytes [34, 52]. Although to a lesser extent than in rodent kidney, human OCT1 is also expressed at the apical membrane of epithelial cells in the proximal and distal tubules of the nephron [7].…”

“…We have recently described that primary liver cancer derived from epithelial cells, that is, HCC, CGC, and hepatoblastoma, shares a decreased expression of OCT1 as a common feature [2]. The reduction in the expression levels of this transporter has been associated with advanced tumor stages and poorer overall patient survival rates in HCC [87] and CGC [52]. Hypermethylation of the SLC22A1 promoter has been suggested to be the mechanism accounting for the downregulation of OCT1 in HCC [77].…”

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

“…Substrates of OATP1A2, which is highly expressed in cholangiocytes, include methotrexate, taxanes and imatinib, whose uptake by CCA cells in vitro can be impaired by OATP1A2 downregulation 272 or the expression of less active genetic variants 273 . Uptake of cationic drugs (for example, platinum derivatives and tyrosine kinase inhibitors) is mediated in part by organic cationic transporters (OCT), which are downregulated (OCT3) 274 or very poorly expressed (OCT1) 275 in CCA. Gemcitabine and 5-fluorouracil are taken up through nucleoside transporters, equilibrative nucleoside transporters (ENT) and concentrative nucleoside transporters (CNT).…”

Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT)

“…OCT isoforms are considered to be key elements in responsiveness to the platinum-based therapy. Consistently, the poor expression/function of OCT1 in CCA [3] has recently been associated with tumour-progression and reduced survival of these patients [26]. In contrast, despite the existence of an important interindividual variability, owing to the preservation in CCA of ASBT expression, which is high in normal cholangiocytes [27], this could be a major route for bile acid-mediated antitumour drug delivery.…”