OCTs have been extensively studied in many tissues and tumor cell lines, but only few data exist about the presence and their role in human malignancies. In colorectal cancer, Zhang et al. found a mRNA expression of OCT2 (SLC22A2) in tumor samples, whereas this transporter was not expressed in normal colon tissue . SNPs in OCT3 (SLC22A3) were reported to contribute to the risk of distal colon cancer in an Asian population .
To our knowledge, this is the first study analyzing the expression profiles of the OCTs in a larger series of human hepatocellular carcinomas with direct correlation to clinical and tumor-specific data.
The human HCC samples analyzed, revealed different intensities of OCT1 (SLC22A1) and OCT3 (SLC22A3) expression ranging from absent to strong. We did not examine OCT2 in light of the absent to very rare and low expression in the human liver. Expression rates in RT-PCR were too low to establish meaningful statistical results.
We showed a significant downregulation for both transporters in HCC compared to the corresponding TST (p ≤ 0.001). Downregulation of SLC22A1 mRNA expression in primary human HCC is in line with previously published microarray findings by Park et al., where SLC22A1 showed a significantly reduced expression in HCC .
Our results provide first evidence that the downregulation of SLC22A1 mRNA expression is associated with advanced tumor stages and worse patient survival (Table 2 Figure 2A). Furthermore, these tumors had significantly higher T values (p = 0.025), G values (p = 0.001) and median tumor diameters (p = 0.035, Table 2). In tumors with lower stages, who underwent transarterial chemoembolization and liver transplantation, SLC22A1 was less frequently downregulated (p < 0.001). In our center transarterial chemoembolization is performed with lipiodol (20 mL) and mitomycin c (10 mg in 20 mL water) every six weeks until transplantation. Both substances are not known to be substrates for OCTs. The response to transarterial chemoembolization is discussed to represent a biological selection criterion for patients with HCC during the waiting time for liver transplantation . Whether OCT1 might be a molecular marker involved in mechanisms influencing the response to transarterial chemoembolization or a marker to predict the tumor biology and the risk of recurrence after liver transplantation remains to be determined.
Interestingly, tumors with a low SLC22A1 expression showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001), which is in contrast to the physiological state with high SLC22A1 and low SLC22A3 expression. The importance of these findings, especially with regard to tumor therapy needs to be defined in future.
Although OCTs are functionally influenced by many endogenous and exogenous substances, to date there are no data about pathways and mechanisms of the regulation of OCT expression in cancer. The transporters are located on the chromosomal locus 6q26-27 in a conserved gene cluster and influenced by genomic imprinting mechanisms involving the well known IGF2R tumor suppressor gene [19, 20]. This may contribute to complex genetic and epigenetic regulations in the context of human malignancy.
Interestingly, the OCTs could also be directly associated with mechanisms of tumor development by influence of environmental factors and carcinogens. In HepG2 cells expression of SLC22A3 correlates with the carcinogenic potency after treatment with polycyclic aromatic hydrocarbons (PAH), which are known to be potential carcinogens .
Furthermore, OCTs may play an important role in the therapy of malignant tumors. They are held responsible for the cytotoxicity of platin derivatives and are predictors of responses to small molecules [11, 22–24]. Downregulation in HCC could be responsible for a worse or lacking response towards platin treatment. In colorectal cancer OCTs are determinants of oxaliplatin cytotoxicity [11, 25–27]. Moreover, SLC22A3 expression in renal cell carcinoma cell lines enhances the sensitivity towards chemotherapeutics as melphalan, irinotecan and vincristin .
In patients with chronic myeloid leukaemia SLC22A1 expression is associated with treatment response to the tyrosine kinase inhibitor (TKI) imatinib [13, 22, 29]. Another multi-tyrosine kinase inhibitor sorafenib, which is used as systemic therapy in HCC, reduces the cellular uptake of platin and the platin-induced cytotoxicity in human colorectal cancer cell lines . Recently, it has been shown, that oxaliplatin uptake in CRC is attenuated by the TKI saracatinib via inhibition of OCT2 . These findings elucidate the crucial role of OCTs in different treatment protocols affecting classical chemotherapeutics as platin derivatives as well as small molecules like TKI. It is still unknown whether the presence of OCTs in tumors is beneficial with regard to therapy or deleterious by supporting tumor growth. Our data suggest, that a downregulation of OCT1 in the liver with possibly lacking function is associated with a worse outcome regardless of TKI treatment, since none of our patients has received a systemic therapy.
Whether OCTs are associated with treatment response to Sorafenib has not been investigated yet. To date, to the best of our knowledge, there exist no data regarding the clinical, prognostic and therapeutical relevance of OCTs in HCC. Because of the impact of OCT1 on tumor characteristics and patient survival we focused on this transporter on protein level. The relevance of OCT3 needs to be further investigated. Future studies will be necessary to evaluate possible diagnostic and therapeutic consequences.