3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells
3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells
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DOI：
10.1002/ijc.26264
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发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Yokosuka, Osamu
中科院分区：
文献类型：
--
作者：
Chiba, Tetsuhiro;Suzuki, Eiichiro;Yokosuka, Osamu
干细胞生物学的最新进展已经在包括肝细胞癌（HCC）在内的多种癌症中鉴定出肿瘤起始细胞（TIC）。Polycomb组基因产物如BMI 1和EZH 2已被表征为广泛的正常干细胞和TIC中的一般自我更新调节剂。我们以前报道Ezh 2紧密调节小鼠肝干/祖细胞的自我更新和分化。然而，EZH 2在肿瘤起始HCC细胞中的作用仍不清楚。在这项研究中，我们使用短发夹RNA进行EZH 2的功能丧失测定，并通过S-腺苷高半胱氨酸水解酶抑制剂3-deazaneplanocin A（DZNep）对EZH 2进行药理学抑制。EZH 2敲低和DZNep处理均损害培养物中HCC细胞的细胞生长和非锚定依赖性球体形成。流式细胞仪分析显示，这两种方法减少了上皮细胞粘附分子（EpCAM）+肿瘤起始细胞的数量。5-氟尿嘧啶（5-FU）或DZNep的给药抑制了非肥胖糖尿病/严重联合免疫缺陷小鼠中植入HCC细胞的肿瘤。然而，值得注意的是，DZNep而不是5-FU主要减少了EpCAM+细胞的数量，并降低了这些细胞的自我更新能力，如通过球体形成测定所判断的。我们的研究结果表明，肿瘤起始HCC细胞高度依赖于EZH 2的致瘤活性。尽管对原发性HCC的TIC的进一步分析是必要的，但对EZH 2的药理学干扰可能是靶向肿瘤起始HCC细胞的有希望的治疗方法。
Recent advances in stem cell biology have identified tumor-initiating cells (TICs) in a variety of cancers including hepatocellular carcinoma (HCC). Polycomb group gene products such as BMI1 and EZH2 have been characterized as general self-renewal regulators in a wide range of normal stem cells and TICs. We previously reported that Ezh2 tightly regulates the self-renewal and differentiation of murine hepatic stem/progenitor cells. However, the role of EZH2 in tumor-initiating HCC cells remains unclear. In this study, we conducted loss-of-function assay of EZH2 using short-hairpin RNA and pharmacological inhibition of EZH2 by an S-adenosylhomocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep). Both EZH2-knockdown and DZNep treatment impaired cell growth and anchorage-independent sphere formation of HCC cells in culture. Flow cytometric analyses revealed that the two approaches decreased the number of epithelial cell adhesion molecule (EpCAM)+ tumor-initiating cells. Administration of 5-fluorouracil (5-FU) or DZNep suppressed the tumors by implanted HCC cells in non-obese diabetic/severe combined immunodeficient mice. Of note, however, DZNep but not 5-FU predominantly reduced the number of EpCAM+ cells and diminished the self-renewal capability of these cells as judged by sphere formation assays. Our findings reveal that tumor-initiating HCC cells are highly dependent on EZH2 for their tumorigenic activity. Although further analyses of TICs from primary HCC would be necessary, pharmacological interference with EZH2 might be a promising therapeutic approach to targeting tumor-initiating HCC cells.