* Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
† Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Am J Chin Med. 2018;46(4):891-910. doi: 10.1142/S0192415X18500477. Epub 2018 May 24.
The hierarchical tumor propagation or cancer stem cells (CSCs) model of carcinogenesis postulates that like physiologic adult stem cell (ASC), the CSCs positioned at the apex of any tumor population form the crux of tumor evolution with a constitutive regenerative capacity and differentiation potential. The propagation and recurrence of the characteristically heterogeneous and therapy-resistant hepatocellular carcinoma (HCC), adds to accumulating evidence to support this CSCs model. Based on the multi-etiologic basis of HCC formation which among others, focuses on the disruption of the canonical Wnt signaling pathway, this study evaluated the role of cembrane-type phytochemical, Ovatodiolide, in the modulation of the Wnt/[Formula: see text]-catenin pathway, and its subsequent effect on liver CSCs' activities. Our fluorescence-activated cell sorting (FACS) and quantitative RT-PCR analyses of side population (SP) indicated that CD133+ cells were [Formula: see text]-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to [Formula: see text]-catenin-downregulated group. We demonstrated that marked upregulation of [Formula: see text]-catenin and its downstream targets effectively enhanced hepatosphere formation, with an associated induction of CD133, OCT4 and Sox2 expression and also caused an significant enhancement of HCC proliferation. However, treatment with Ovatodiolide induced downregulation of [Formula: see text]-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the [Formula: see text]-catenin-associated enhancement of HCC growth. In summary, we demonstrated for the first time that Ovatodiolide suppressed the canonical Wnt signaling pathway, and inhibited the generation of liver CSCs; Thus, projecting Ovatodiolide as a putatively effective therapeutic agent for anti-HCC target therapy.
肿瘤发生的层级肿瘤传播或癌症干细胞 (CSC) 模型假定，与生理成体干细胞 (ASC) 一样，位于任何肿瘤群体顶端的 CSCs 构成了肿瘤进化的核心，具有组成性的再生能力和分化潜力。特征异质性和治疗耐药性肝癌 (HCC) 的传播和复发，增加了支持该 CSCs 模型的累积证据。基于 HCC 形成的多病因基础，其中重点关注经典 Wnt 信号通路的破坏，本研究评估了 cembrane 型植物化学物质 Ovatodiolide 在调节 Wnt/β-catenin 通路及其对肝 CSCs 活性的后续影响中的作用。我们的荧光激活细胞分选 (FACS) 和侧群 (SP) 的定量 RT-PCR 分析表明，与β-catenin 下调组相比，CD133+细胞表达更多的β-catenin，侵袭性更强，对常规抗癌药物顺铂和阿霉素耐药。我们证明，β-catenin 及其下游靶标的显著上调有效增强了肝球体形成，伴随着 CD133、OCT4 和 Sox2 表达的诱导，并且还导致 HCC 增殖的显著增强。然而，Ovatodiolide 处理诱导β-catenin 及其下游效应基因下调，消除肝球体形成并逆转β-catenin 相关的 HCC 生长增强。总之，我们首次证明 Ovatodiolide 抑制了经典 Wnt 信号通路，并抑制了肝 CSCs 的产生；因此，Ovatodiolide 被预测为 HCC 靶向治疗的有效治疗剂。
