miR-203 Inhibits the Proliferation and Self-Renewal of Esophageal Cancer Stem-Like Cells by Suppressing Stem Renewal Factor Bmi-1
miR-203 Inhibits the Proliferation and Self-Renewal of Esophageal Cancer Stem-Like Cells by Suppressing Stem Renewal Factor Bmi-1
复制标题
miR-203通过抑制干更新因子Bmi-1来抑制食管癌干细胞样细胞的增殖和自我更新。
DOI：
10.1089/scd.2013.0308
复制
发表时间：
2014-03-15
影响因子：
4
通讯作者：
Lu, Shih-Hsin
中科院分区：
文献类型：
--
作者：
Yu, Xiying;Jiang, Xingran;Lu, Shih-Hsin
癌症干细胞样细胞存在于许多恶性肿瘤中，并且通过基因微阵列或测序分析，一些干细胞相关基因和microRNA（例如Bmi-1和miR-203）已被鉴定为癌症干细胞样细胞调节剂。此前，我们使用侧群（SP）分选来富集食管鳞状细胞癌（ESCC）细胞系 EC9706 中的癌症干细胞样细胞。我们的结果表明 EC9706 SP 细胞具有癌症干细胞样细胞的共同特征。在这项研究中，我们检测了 ESCC SP 和非 SP (NSP) 细胞中 Bmi-1 和 miR-203 的表达。我们的结果表明，与 NSP 细胞相比，SP 细胞中 Bmi-1 上调，miR-203 下调。在SP细胞向NSP细胞分化的过程中，Bmi-1的表达水平逐渐下降。 miR-203 的过表达导致 EC9706 细胞中内源性 Bmi-1 蛋白水平显着降低。 SP和NSP分析表明，miR-203过表达的细胞中SP细胞分数显着降低。 miR-203过表达的细胞还表现出集落形成显着减少，对化疗药物治疗和裸鼠的致瘤性具有抵抗力。拯救实验表明，miR-203 过表达细胞中 Bmi-1 的异位表达增加了 SP 分数并恢复了细胞增殖。综上所述，这些结果表明干更新因子 Bmi-1 是 miR-203 的直接靶标。 miR-203对Bmi-1的调控可能在控制食管癌干细胞样细胞的增殖和自我更新中发挥重要作用。它还可能促进针对食管鳞癌干细胞样细胞的新治疗策略和有效药物的开发。
Cancer stem-like cells exist in many malignancies and several stem cell-related genes and microRNAs, such as Bmi-1 and miR-203, have been identified as cancer stem-like cell regulators using gene microarray or sequencing analysis. Previously, we used side population (SP) sorting to enrich cancer stem-like cells from esophageal squamous cell carcinoma (ESCC) cell line EC9706. Our results demonstrated that EC9706 SP cells shared common features of cancer stem-like cells. In this study, we examined the expression of Bmi-1 and miR-203 in ESCC SP and non-SP (NSP) cells. Our results showed that, when compared with NSP cells, Bmi-1 was up-regulated and miR-203 was down-regulated in SP cells. During the differentiation from SP to NSP cells, the expression levels of Bmi-1 were gradually decreased. Overexpression of miR-203 resulted in a significant reduction of endogenous Bmi-1 protein level in EC9706 cells. SP and NSP analyses revealed that the SP cell fraction was markedly decreased in miR-203 overexpressed cells. miR-203 overexpressed cells also showed a significant reduction in colony formation, which was resistant to chemotherapeutic drug treatment and tumorigenicity in nude mice. Rescue experiments demonstrated that ectopic expression of Bmi-1 in miR-203 overexpressed cells increased the SP fraction and restored cell proliferation. Taken together, these results indicated that stem renewal factor Bmi-1 was a direct target of miR-203. The regulation of Bmi-1 by miR-203 may play an important role in controlling cell proliferation and self-renewal of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs that target ESCC stem-like cells.