Ohata Yoshiteru, Shimada Shu, Akiyama Yoshimitsu, Mogushi Kaoru, Nakao Keisuke, Matsumura Satoshi, Aihara Arihiro, Mitsunori Yusuke, Ban Daisuke, Ochiai Takanori, Kudo Atsushi, Arii Shigeki, Tanabe Minoru, Tanaka Shinji
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Mol Cancer Ther. 2017 Jun;16(6):1155-1165. doi: 10.1158/1535-7163.MCT-16-0728. Epub 2017 Feb 28.
Antiangiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma; however, they finally relapse and progress, resulting in poor prognosis. We here established drug-tolerant subclones of human hepatocellular carcinoma cells by long-term treatment with VEGF receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tβ4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tβ4 in hepatocellular carcinoma cells could significantly enhance sphere-forming capacities and infiltrating phenotypes , and promote growth of tumors refractory to the VEGFR multikinase inhibitor sorafenib Clinically, sorafenib failed to improve the progression-free survival in patients with Tβ4-high hepatocellular carcinoma, indicating that Tβ4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma. .
抗血管生成疗法最初对包括肝细胞癌在内的几种实体瘤有效；然而，这些肿瘤最终会复发并进展，导致预后不良。我们通过用血管内皮生长因子受体（VEGFR）抑制剂长期处理并在免疫缺陷小鼠中进行连续移植（共12个月），建立了人肝癌细胞的耐药物亚克隆，然后在分子和生物学特征方面将它们与亲代细胞进行比较。基因表达谱表明，一种G-肌动蛋白单体结合蛋白胸腺素β4（Tβ4）是相对于最初敏感的癌细胞而言，在耐药癌细胞中富集的基因之一。突出显示与耐药性相关的表观遗传改变，我们发现Tβ4可能在启动子区域DNA去甲基化和组蛋白H3活性修饰后异常表达。在肝癌细胞中异位过表达Tβ4可显著增强成球能力和浸润表型，并促进对VEGFR多激酶抑制剂索拉非尼耐药的肿瘤生长。临床上，索拉非尼未能改善Tβ4高表达的肝癌患者的无进展生存期，这表明Tβ4表达可作为对该药物敏感性的替代标志物。这项研究表明，表观遗传改变触发的Tβ4表达可能通过获得干性而导致对抗血管生成疗法耐药性的发展，并且表观遗传调控可能是调节肝癌耐药性的关键靶点之一。
