Abstract
BackgroundThe 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.MethodsA 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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
Our findings provide an attractive therapeutic approach for targeting T-ICs to achieve better clinical outcomes in cancer patients
The CDDP-resistant esophageal squamous cell carcinoma (ESCC) (EC-CR) cells isolated from CDDP-treated tumors displayed much higher resistance to the chemotherapeutic drugs CDDP and docetaxel (DOC) than the CDDP-untreated ESCC (EC-UT) cells isolated from phosphate-buffered saline (PBS)-treated tumors (Fig. 1a, right)
Summary
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. Targeting a single T-IC subpopulation within a tumor may be insufficient for effective cancer treatment. Overactivated transforming growth factor-β (TGF-β) signaling is essential for the stemness of glioma-initiating cells and maintenance of skin T-ICs and leukemia-initiating cells [1,2,3]. Given the prominence of stemness-associated pathways in cancer initiation and progression, multiple inhibitors of these signaling cascades have been developed and tested in clinical trials [14]. The Wnt/β-catenin and TGF-β signaling pathways collaborate to maintain mammary T-ICs [20,21,22,23]. Targeting a single signaling pathway may be insufficient to eradicate T-ICs
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