Department of General Surgery, En Chu Kong Hospital, New Taipei City, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Toxicol In Vitro. 2018 Sep;51:74-82. doi: 10.1016/j.tiv.2018.04.010. Epub 2018 Apr 24.
The cancer stem cells (CSCs) theory recently became a focus of heightened attention in cancer biology, with the proposition that CSCs may constitute an important therapeutic target for effective anticancer therapy, because of their demonstrated role in tumor initiation, chemo-, and radio-resistance. Liver CSCs are a small subpopulation of poorly- or undifferentiated liver tumor cells, implicated in tumorigenesis, metastasis, resistance to therapy and disease relapse, enriched with and associated with the functional markers corresponding to the CSCs-enriched side population (SP), high aldehyde dehydrogenase (ALDH) activity, and enhanced formation of in vitro liver CSCs models, referred to herein as hepatospheres. In this study, we found YAP1 was significantly expressed in the SP cells, as well as in generated hepatospheres compared to non-SP or parental HCC cells, at transcript and/or protein levels. In addition, downregulation of YAP1 expression levels by small molecule inhibitor and siRNA transfection, in the HCC cell lines, PLC/PRF/5 and Mahlavu, were associated with marked loss of ability to form hepatospheres and increased sensitivity to sorafenib. Consistent with the above, we demonstrated that YAP1 expression positively correlated with that of Sox2, Oct4, c-Myc and GRP78, markers of stemness and drug resistance. This is suggestive of YAP1's role as a modulator of cancer stemness, ER stress and chemoresistance. For the first time, we demonstrate that Ovatodiolide significantly attenuates YAP1 expression and subsequently suppressed YAP1-modulated CSCs phenotypes and associated disease progression, consistent with our previous finding in breast cancer. Taken together, our findings suggest that YAP1, highly expressed in malignant liver tumours, contributes to hepatocellular CSCs phenotype and is a molecular target of interest for CSCs targeted therapy in liver cancer patients.
癌症干细胞 (CSCs) 理论最近成为癌症生物学研究的焦点，因为它们在肿瘤起始、化疗和放疗耐药性方面的作用，CSCs 可能构成有效抗癌治疗的重要治疗靶点。肝 CSCs 是一小部分分化不良或未分化的肝肿瘤细胞，参与肿瘤发生、转移、对治疗的耐药性和疾病复发，与功能标记物富集相关，这些功能标记物对应于 CSCs 富集的侧群 (SP)、高醛脱氢酶 (ALDH) 活性和体外肝 CSCs 模型的增强形成，在此称为肝细胞球体。在这项研究中，我们发现 YAP1 在 SP 细胞以及与非 SP 或亲本 HCC 细胞相比，在转录和/或蛋白水平上在 SP 细胞和生成的肝细胞球体中均有显著表达。此外，在 HCC 细胞系 PLC/PRF/5 和 Mahlavu 中，小分子抑制剂和 siRNA 转染下调 YAP1 表达水平与明显丧失形成肝细胞球体的能力和增加对索拉非尼的敏感性相关。与上述结果一致，我们证明 YAP1 的表达与 Sox2、Oct4、c-Myc 和 GRP78 的表达呈正相关，这些标志物是干性和耐药性的标志物。这表明 YAP1 作为癌症干性、内质网应激和化疗耐药性的调节剂的作用。这是我们首次证明 Ovatodiolide 显著减弱 YAP1 表达，随后抑制 YAP1 调节的 CSCs 表型和相关疾病进展，与我们之前在乳腺癌中的发现一致。总之，我们的研究结果表明，在恶性肝肿瘤中高度表达的 YAP1 有助于肝细胞 CSCs 表型，是肝癌患者 CSCs 靶向治疗的有价值的分子靶点。
