Clinical trial of GPC3 and AKR1B10 as the novel serum marker for hepatocellular carcinoma

GPC3和AKR1B10作为肝细胞癌新型血清标志物的临床试验

• 批准号: 17591378
• 负责人: MIDORIKAWA Yutaka
• 金额: $ 2.3万
• 依托单位: Teikyo University (2006)The University of Tokyo (2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591378/
• 关键词: microarray; serum tumor marker; hepatocellular carcinoma; GPC3; AKR1B10; gene therapy; tolerance for anti-cancer drug

GPC3 and AKR1B10 were identified as candidate genes for hepatocelular carcinoma (HCC) by comprehensive expression analysis. In this study, we demonstrated that expression levels of both GPC3 and AKR1B10 in HCC by immunohistochemistry were correlated with those of serum obtained from HCC patients. Besides, we measured serum GPC3 levels from HCC patients after surgery and found that GPC3 levels were changed in accordance with relapse and the state after therapy. Furthermore, we observed that serum GPC3 levels of about 10% of patients undergoing hepatectomy were not recovered to normal range, whose recurrence rate were significantly high. On the other hand, we also investigated copy number analysis using single nucleotide polymorphism arrays and found that expression levels and copy number were significantly correlated, indicating that gene expression are subject to the chromosomal bias. As for gene therapy, we found that anti-GPC3 monoclonal antibody we established harbors anti-tumor effects, which was confirmed in vivo. We also observed that AKR1B10 would enhance the anti-tumor effect of adriamycin for HCC by siRNA experiments using nude mice to whom hepatoma cell line, PLC/PRF/5 cells were transplanted. Through these results, we hope that GPC3 and AKR1b10 are the candidate for gene therapy.

通过综合表达分析，确定GPC3和AKR1B10为肝癌（HCC）的候选基因。在本研究中，我们通过免疫组化方法证明了GPC3和AKR1B10在HCC中的表达水平与HCC患者血清中表达水平相关。此外，我们检测了术后HCC患者的血清GPC3水平，发现GPC3水平随复发和治疗后状态的变化而变化。此外，我们观察到约10%的肝切除术患者血清GPC3水平未恢复到正常范围，其复发率显著高。另一方面，我们还利用单核苷酸多态性阵列进行拷贝数分析，发现表达水平与拷贝数显著相关，表明基因表达受染色体偏倚的影响。在基因治疗方面，我们发现我们建立的抗gpc3单克隆抗体具有抗肿瘤作用，这在体内得到了证实。我们还通过移植肝癌细胞系PLC/PRF/5裸鼠的siRNA实验发现，AKR1B10可以增强阿霉素对HCC的抗肿瘤作用。通过这些结果，我们希望GPC3和AKR1b10成为基因治疗的候选物。

项目成果

肝臓癌の遺伝子異常

肝癌的基因异常

• 发表时间: 2006
• 期刊: 最新医学 61(9)
• 作者: Kimura F;Shimizu H;Yoshidome H;Kato A;Miyazaki M;et al.;緑川 泰
• 通讯作者: 緑川 泰

Microarray-based analysis for hepatocellular carcinoma: From gene expression profiling to new challenges

• DOI: 10.3748/wjg.v13.i10.1487
• 发表时间: 2007-03-14
• 期刊: WORLD JOURNAL OF GASTROENTEROLOGY
• 影响因子: 4.3
• 作者: Midorikawa, Yutaka;Makuuchi, Masatoshi;Aburatani, Hiroyuki
• 通讯作者: Aburatani, Hiroyuki

Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer.

P1 和 P2 启动子驱动的肝细胞核因子 4α 在人类癌症发病机制中的表达失调。

• 发表时间: 2006
• 期刊: J Pathol. 208(5)
• 作者: Tanaka T;Jiang S;Hotta H;Takano K;Iwanari H;Sumi K;Daigo K;Ohashi R;Sugai M;Ikegame C;Umezu H;Hirayama Y;Midorikawa Y;Hippo Y;Watanabe A;Uchiyama Y;Hasegawa G;Reid P;Aburatani H;Hamakubo T;Sakai J;Naito M;Kodama T.
• 通讯作者: Kodama T.

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

• DOI: 10.1038/sj.onc.1209537
• 发表时间: 2006-09-01
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Midorikawa, Y.;Yamamoto, S.;Aburatani, H.
• 通讯作者: Aburatani, H.

A case of cystic duct drainage into the left intrahepatic duct and the importance of Laparoscopic Fundus-First-Cholecystectomy for prevention of bile duct injury

胆囊管引流至左侧肝内管一例及腹腔镜眼底胆囊切除术预防胆管损伤的重要性

• 发表时间: 2007
• 期刊: J Laparoscopic Adv Surg Tech 17
• 作者: Yamakawa T;Tianhua Z;Midorikawa Y;Ishiyama J;Takahashi K;Sugiyama Y
• 通讯作者: Sugiyama Y