Kim Ji-Young, Lee Hwa-Yong, Park Kwan-Kyu, Choi Yang-Kyu, Nam Jeong-Seok, Hong In-Sun
Center of Animal Care and Use, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea.
Oncotarget. 2016 Apr 12;7(15):20395-409. doi: 10.18632/oncotarget.7954.
Liver cancer stem cells (CSCs) are resistant to conventional chemotherapy and radiation, which may destroy tumor masses, but not all liver CSCs contribute to tumor initiation, metastasis, and relapse. In the present study, we showed that liver CSCs with elevated Wnt/β-catenin signaling possess much greater self-renewal and clonogenic potential. We further documented that the increased clonogenic potential of liver CSCs is highly associated with changes in Wnt/β-catenin signaling and that Wnt/β-catenin signaling activity is positively correlated with CD133 expression and aldehyde dehydrogenase (ALDH) enzymatic activity. Notably, the small molecule inhibitor CWP232228, which antagonizes the binding of β-catenin to TCF in the nucleus, inhibits Wnt/β-catenin signaling and depletes CD133+/ALDH+ liver CSCs, thus ultimately diminishing the self-renewal capacity of CSCs and decreasing tumorigenicity in vitro and in vivo. Taken together, our findings suggest that CWP232228 acts as a candidate therapeutic agent for liver cancer by preferentially targeting liver CSCs.
肝癌干细胞（CSCs）对传统化疗和放疗具有抗性，传统疗法虽可破坏肿瘤团块，但并非所有肝癌干细胞都参与肿瘤的起始、转移和复发过程。在本研究中，我们发现具有升高的Wnt/β-连环蛋白信号传导的肝癌干细胞具有更强的自我更新和克隆形成能力。我们进一步证明，肝癌干细胞克隆形成能力的增强与Wnt/β-连环蛋白信号传导的变化高度相关，且Wnt/β-连环蛋白信号传导活性与CD133表达和醛脱氢酶（ALDH）酶活性呈正相关。值得注意的是，小分子抑制剂CWP232228可拮抗β-连环蛋白与细胞核中TCF的结合，抑制Wnt/β-连环蛋白信号传导，并消耗CD133+/ALDH+肝癌干细胞，从而最终降低干细胞的自我更新能力，并在体内外降低致瘤性。综上所述，我们的研究结果表明，CWP232228通过优先靶向肝癌干细胞，可作为一种肝癌候选治疗药物。
