Program of Cancer Research, Affiliated Guangzhou Women and Children's Hospital, Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong, 510080, China.
State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
Mol Cancer. 2017 Jun 21;16(1):106. doi: 10.1186/s12943-017-0669-9.
The plasticity of cancer stem cells (CSCs)/tumor-initiating cells (T-ICs) suggests that multiple CSC/T-IC subpopulations exist within a tumor and that multiple oncogenic pathways collaborate to maintain the CSC/T-IC state. Here, we aimed to identify potential therapeutic targets that concomitantly regulate multiple T-IC subpopulations and CSC/T-IC-associated pathways.
A chemoresistant patient-derived xenograft (PDX) model of human esophageal squamous cell carcinoma (ESCC) was employed to identify microRNAs that contribute to ESCC aggressiveness. The oncogenic effects of microRNA-455-3p (miR-455-3p) on ESCC chemoresistance and tumorigenesis were examined by in vivo and in vitro chemoresistance, tumorsphere formation, side-population, and in vivo limiting dilution assays. The roles of miR-455-3p in activation of the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad pathways were determined by luciferase and RNA immunoprecipitation assays.
We found that miR-455-3p played essential roles in ESCC chemoresistance and tumorigenesis. Treatment with a miR-455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90 and CD271 T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/β-catenin and TGF-β signaling. Importantly, miR-455-3p exhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients.
Our results demonstrate that miR-455-3p functions as an oncomiR in ESCC progression and may provide a potential therapeutic target to achieve better clinical outcomes in cancer patients.
癌症干细胞（CSC）/肿瘤起始细胞（T-IC）的可塑性表明，肿瘤内存在多个 CSC/T-IC 亚群，并且多个致癌途径协同作用以维持 CSC/T-IC 状态。在这里，我们旨在确定同时调节多个 T-IC 亚群和 CSC/T-IC 相关途径的潜在治疗靶标。
使用人食管鳞状细胞癌（ESCC）的耐药性患者衍生的异种移植（PDX）模型来鉴定有助于 ESCC 侵袭性的 microRNAs。通过体内和体外化疗耐药性、肿瘤球形成、侧群和体内有限稀释测定，研究 microRNA-455-3p（miR-455-3p）对 ESCC 化疗耐药性和肿瘤发生的致癌作用。通过荧光素酶和 RNA 免疫沉淀测定确定 miR-455-3p 在激活 Wnt/β-catenin 和转化生长因子-β（TGF-β）/Smad 途径中的作用。
我们发现 miR-455-3p 在 ESCC 化疗耐药性和肿瘤发生中起着重要作用。用 miR-455-3p 拮抗剂处理可显著增强 ESCC 细胞的化疗敏感性，并通过失活多个干性相关途径（包括 Wnt/β-catenin 和 TGF-β 信号通路）减少 CD90 和 CD271 T-IC 亚群。重要的是，miR-455-3p 在各种人类癌症类型中表现出异常上调，并且与癌症患者总体生存率降低显著相关。
我们的研究结果表明，miR-455-3p 在 ESCC 进展中作为致癌 miRNA 发挥作用，并且可能为癌症患者提供潜在的治疗靶标，以实现更好的临床结果。
