Department of Clinical Pharmacy and Diagnostics; University of Vienna, Vienna, Austria.
Cancer Biol Ther. 2011 May 1;11(9):801-11. doi: 10.4161/cbt.11.9.15176.
Organic anion transporting polypeptides (OATP, SLCO genes) mediate the uptake of endobiotics and drugs. Thus, their expression levels and pattern could be of relevance for cancer therapy. This prompted us to investigate the expression of poorly characterized OATPs, namely OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic cancer of different origin. First, mRNA levels of all eleven OATPs were determined in paired (cancerous and adjacent non-cancerous) specimens from 43 patients with primary liver cancer (hepatocellular carcinoma, HCC; cholangiocellular carcinoma, CCC) and liver metastases from colon tumors (MLT). Real-time RT-PCR analysis revealed that all OATPs, except OATP1C1 and OATP6A1, are extensively expressed in nearly all samples. In contrast to downregulated OATP1B1, OATP1B3, OATP1A2 and OATP2B1 in cancerous vs. non-cancerous samples, an increase in OATP2A1, OATP3A1, OATP4A1 and OATP5A1 mRNA levels was seen in tumors (up to 40-fold for OATP5A1 in the MLT group). Therefore, OATP2A1, OATP3A1, OATP4A1 and OATP5A1 were further investigated by immunofluorescence microscopy on paraffin-embedded cancerous and non-cancerous sections (seven per group). OATP-derived immunoreactivity was observed in plasma membranes and cytosol of hepatic tumor cells, and additionally, in various cytokeratin 19 positive bile ducts. An increased percentage of immunoreactive cells and a higher staining intensity in cancerous vs. non-cancerous paraffin sections paralleled higher mRNA levels of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in cancerous tissues of HCC, CCC and MLT patients. The extensive expression of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic tumors of different origin suggests that these transporters might be further exploited for the discovery of novel anticancer agents.
有机阴离子转运多肽 (OATP，SLCO 基因) 介导内源性物质和药物的摄取。因此，它们的表达水平和模式可能与癌症治疗有关。这促使我们研究了不同来源肝癌中表达水平较低的 OATP，即 OATP2A1、OATP3A1、OATP4A1 和 OATP5A1。首先，我们在 43 名原发性肝癌（肝细胞癌 HCC；胆管细胞癌 CCC）和结肠癌肝转移瘤（MLT）患者的配对（癌组织和癌旁非癌组织）标本中测定了所有 11 种 OATP 的 mRNA 水平。实时 RT-PCR 分析显示，除了 OATP1C1 和 OATP6A1，所有 OATP 都广泛表达于几乎所有样本中。与癌组织中下调的 OATP1B1、OATP1B3、OATP1A2 和 OATP2B1 相反，OATP2A1、OATP3A1、OATP4A1 和 OATP5A1 的 mRNA 水平在肿瘤中增加（在 MLT 组中 OATP5A1 增加了 40 倍）。因此，我们通过免疫荧光显微镜观察石蜡包埋的癌组织和癌旁组织切片（每组 7 个）进一步研究了 OATP2A1、OATP3A1、OATP4A1 和 OATP5A1。OATP 衍生的免疫反应性在肝肿瘤细胞的质膜和细胞质中观察到，此外，在各种细胞角蛋白 19 阳性的胆管中也观察到。与癌旁组织相比，癌组织中 OATP2A1、OATP3A1、OATP4A1 和 OATP5A1 的免疫反应性细胞比例增加和染色强度增强，与 HCC、CCC 和 MLT 患者癌组织中 OATP2A1、OATP3A1、OATP4A1 和 OATP5A1 的 mRNA 水平升高相平行。OATP2A1、OATP3A1、OATP4A1 和 OATP5A1 在不同来源的肝肿瘤中的广泛表达表明，这些转运体可能进一步用于发现新型抗癌药物。
