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全球癌症统计数据表明,肝癌是全球第二大癌症死亡原因,因肝癌死亡的人口数占癌症总死亡人数的8.2%。肝细胞癌是原发性肝癌最常见的形式[1],手术是其首选的治疗方法,然而只有5%~10%的肝细胞肿瘤适合切除,大多数患者(50%~70%)在手术后5年内发生肿瘤复发[2]。在小分子药物治疗方面,多激酶抑制剂索拉非尼能够延长患者近3个月中位生存期和进展时间[3],但仍无法满足临床治愈肝细胞癌的需求。因此,寻找新的肝细胞癌治疗靶点,开发新的治疗策略具有重要的临床意义。
磷脂酰肌醇蛋白聚糖(GPCs),属于硫酸乙酰肝素蛋白多糖家族,通过糖基磷脂酰肌醇(GPI)锚定于细胞膜外,是细胞外基质的主要组成部分[4]。磷脂酰肌醇蛋白聚糖由一个核心蛋白以及与其相连的两条硫酸乙酰肝素(HS)链组成,该家族包括6个成员(GPC1-6)[5]。其中GPC3研究最为广泛,其由580个氨基酸组成,表达于胎儿的肝、肺、胎盘和肾器官,由于DNA甲基化诱导的表观遗传沉默,其在成人器官中的表达明显降低[6]。在临床研究中,GPC3与肿瘤的发生发展密切相关,许多研究都报道了GPC3在肝细胞癌中表达上调[7]。本文综述了GPC3在肝细胞癌相关信号通路中的作用以及基于GPC3开发的肝癌靶向疗法。
Research Progress on Glypican-3 Targeted Therapy in Hepatocellular Carcinoma
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摘要: 肝癌是全球第二大癌症死亡原因,而肝细胞癌(HCC)是最常见的原发性肝癌形式。磷脂酰肌醇蛋白聚糖-3(GPC3)是一种细胞膜表面蛋白多糖,其在正常成人组织中几乎不表达,但在肝细胞癌中特异性表达上调,因此,GPC3成为肝细胞癌诊断和治疗的可靠靶点。综述了GPC3通过Wnt、YAP、hedgehog等信号通路调节癌症发展,总结了单克隆抗体、双特异性抗体、肿瘤疫苗、免疫毒素、CAR-T细胞、光敏剂治疗等GPC3靶向治疗方法,并对未来基于GPC3的肝细胞癌治疗策略进行展望。
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关键词:
- 肝细胞癌 /
- 磷脂酰肌醇蛋白聚糖-3 /
- 信号通路 /
- 肝细胞癌治疗
Abstract: Liver cancer is the second leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the most common form of primary liver cancer. Glypican-3 (GPC3) is a cell membrane proteoglycan which is rarely expressed in normal adult tissues but is specifically upregulated in HCC, which makes GPC3 a reliable target for the diagnosis and treatment of HCC. The role of GPC3 in the regulation of cancer development through Wnt, YAP, hedgehog and other signaling pathways were reviewed in this article. GPC3-targeted therapies, such as monoclonal antibodies, bispecific antibodies, tumor vaccines, immunotoxins, CAR-T cells, and photosensitizer therapy were also summarized. These treatment methods offered promising approaches for HCC treatment and future treatment strategies for HCC based on GPC3 were prospected in this paper.-
Key words:
- Hepatocellular carcinoma /
- Glypican-3 /
- signaling pathway /
- HCC therapy
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