Seo Satoru, Hatano Etsuro, Higashi Tatsuya, Nakajima Akio, Nakamoto Yuji, Tada Masaharu, Tamaki Nobuyuki, Iwaisako Keiko, Kitamura Koji, Ikai Iwao, Uemoto Shinji
Department of Surgery, Graduate School of Medicine Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Int J Oncol. 2009 May;34(5):1303-12.
18F-fluorodeoxyglucose (FDG) uptake in hepatocellular carcinoma (HCC) is associated with tumor differentiation and expression of P-glycoprotein (P-gp), a drug efflux pump that plays an important role in chemoresistance. The aim of the study was to clarify the factors that affects FDG uptake in HCC in vivo and in vitro. The standardized uptake value (SUV) and the tumor to non-tumor SUV ratio (TNR) for FDG uptake in HCC in vivo was determined by FDG-PET in 28 patients. Expression levels of glucose transporter-1 (GLUT-1), GLUT-2 and type II hexokinase (HK-II) were examined immunohistochemically in resected specimens. The glucose-6-phosphatase (G-6-Pase) activity was determined in tissue homogenates. In vitro, PLC/PRF/5 cells and doxorubicin-resistant PLC/DOR cells were used to examine the effect of P-gp on FDG uptake. The effects of two P-gp inhibitors, verapamil and cepharanthine, on accumulation of FDG were also examined. in vivo, GLUT-1 expression was low in HCCs, but was significantly higher in poorly differentiated HCCs than in moderately differentiated HCCs (P=0.043) and was positively correlated with SUV (r=0.75, P<0.0001) and TNR (r=0.7, P<0.0001). GLUT-2 and HK-II expression and G-6-Pase activity were not correlated with tumor differentiation, SUV or TNR. P-gp was over-expressed in PLC/DOR cells, and accumulation of FDG was significantly higher in PLC/PRF/5 cells than in PLC/DOR cells (P=0.04). Verapamil and cepharanthine restored FDG uptake in PLC/DOR cells, but not in PLC/PRF/5 cells. Collectively, our results show that FDG uptake in HCC is weakly correlated with GLUT-1 expression, and that FDG could be a substrate of P-gp, which may act as an efflux pump to reduce FDG accumulation.
18F-氟脱氧葡萄糖（FDG）在肝细胞癌（HCC）中的摄取与肿瘤分化及P-糖蛋白（P-gp）的表达相关，P-gp是一种药物外排泵，在化疗耐药中起重要作用。本研究的目的是阐明体内和体外影响HCC中FDG摄取的因素。通过FDG-PET测定了28例患者体内HCC中FDG摄取的标准化摄取值（SUV）和肿瘤与非肿瘤SUV比值（TNR）。采用免疫组织化学方法检测了切除标本中葡萄糖转运蛋白-1（GLUT-1）、GLUT-2和Ⅱ型己糖激酶（HK-II）的表达水平。测定了组织匀浆中葡萄糖-6-磷酸酶（G-6-Pase）的活性。在体外，使用PLC/PRF/5细胞和阿霉素耐药的PLC/DOR细胞来研究P-gp对FDG摄取的影响。还检测了两种P-gp抑制剂维拉帕米和千金藤素对FDG蓄积的影响。在体内，HCC中GLUT-1表达较低，但在低分化HCC中显著高于中分化HCC（P=0.043），且与SUV呈正相关（r=0.75，P<0.0001）和TNR呈正相关（r=0.7，P<0.0001）。GLUT-2、HK-II表达及G-6-Pase活性与肿瘤分化、SUV或TNR均无相关性。P-gp在PLC/DOR细胞中过度表达，PLC/PRF/5细胞中FDG蓄积显著高于PLC/DOR细胞（P=0.04）。维拉帕米和千金藤素可恢复PLC/DOR细胞中的FDG摄取，但不能恢复PLC/PRF/5细胞中的FDG摄取。总体而言，我们的结果表明，HCC中FDG摄取与GLUT-1表达弱相关，且FDG可能是P-gp的底物，P-gp可能作为外排泵减少FDG蓄积。
