Geier Andreas, Macias Rocio I R, Bettinger Dominik, Weiss Johannes, Bantel Heike, Jahn Daniel, Al-Abdulla Ruba, Marin Jose J G
Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, University of Salamanca, Salamanca, Spain.
Oncotarget. 2017 Feb 28;8(9):15846-15857. doi: 10.18632/oncotarget.15029.
Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response.
The multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative.
Results confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p<0.001). No association between OCT1 expression at the plasma membrane with tumor stage, previous treatment with TACE or radiological response was seen.In conclusion, these results indicate that the presence of OCT1 at the plasma membrane, rather than its expression levels, is related to better outcome of HCC patients treated with sorafenib.
索拉非尼是晚期肝细胞癌（HCC）治疗的首选药物。化疗耐药机制限制了其疗效，这些机制包括负责药物摄取的质膜转运蛋白下调和/或功能受损。有机阳离子转运体1（OCT1）在索拉非尼摄取中起主要作用，HCC中其表达降低与较差的反应相关。
多中心回顾性TRANSFER研究纳入了39例晚期HCC患者的肿瘤活检样本，这些患者接受索拉非尼治疗≥4周。终点是临床病理特征与免疫组织学结果之间的关系。使用特异性抗OCT1头部和抗OCT1尾部一抗进行免疫染色。根据简化的染色评分将肿瘤分类为无、弱、中或强，同时考虑染色在质膜上的定位为阳性或阴性。
结果证实，在所研究的病例中有一半存在OCT1下调（10%无表达，38%弱表达）。然而，仅三分之一表达OCT1的肿瘤显示质膜定位（15% vs. 36%胞质表达）。比较有和无OCT1表达的HCC时，未发现索拉非尼反应有差异。当单独考虑质膜表达OCT1的肿瘤时，发现生存期明显更长（对数秩检验p<0.001）。未发现质膜OCT1表达与肿瘤分期、既往TACE治疗或影像学反应之间存在关联。总之，这些结果表明，质膜上OCT1的存在而非其表达水平与接受索拉非尼治疗的HCC患者的更好预后相关。
