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Mol Cancer. 2017 Jun 21;16(1):106. doi: 10.1186/s12943-017-0669-9.

Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma.

Author information

1
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.
2
State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
3
Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
4
Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
5
State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China. songlb@sysucc.org.cn.
6
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. lijun37@mail.sysu.edu.cn.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Chemoresistance; Esophageal squamous cell carcinoma; OncomiR; miR-455-3p

PMID:
28633632
PMCID:
PMC5479030
DOI:
10.1186/s12943-017-0669-9
[Indexed for MEDLINE]
Free PMC Article

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