Abstract
Constitutive activation of NF-κB signaling plays vital roles in esophageal squamous cell carcinoma (ESCC) progression. The aim of this study was to evaluate the effect of miR-138 on NF-κB activation and ESCC progression. Expression of miR-138 in ESCC cell lines, ESCC tissues, and 205 archived ESSC specimens was determined using real-time PCR analysis. Anchorage-independent growth, chicken chorioallantoic membrane, Transwell matrix invasion and Annexin V-binding assays, and a xenograft tumor model were used to determine the role of miR-138 in ESCC progression. The effect of miR-138 on NF-κB activation was investigated using IKK in vitro kinase, electrophoretic mobility shift, lipid raft isolation, and luciferase reporter assays. miR-138 was downregulated and inversely correlated with tumor progression and patient survival in ESCCs. Downregulation of miR-138 enhanced, whereas upregulation of miR-138 reduced, the aggressive phenotype of ESCC cells both in vitro and in vivo. Silencing miR-138 promoted K63-linked polyubiquitination of the NF-κB signaling intermediaries TRAF2 and RIP1 and sustained NF-κB activation. Furthermore, downregulation of miR-138 induced lipid raft formation via upregulating multiple components of lipid rafts, including FLOT1, FLOT2, and caveolin-1. Importantly, the in vitro analysis was consistent with a significant inverse correlation between miR-138 expression and NF-κB hyperactivation in a cohort of human ESCC specimens. Our results show that miR-138 functions as a tumor-suppressive miRNA and that downregulation of miR-138 contributes to constitutive NF-κB activation and ESCC progression.
Highlights
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive malignancies of the gastrointestinal tract, is the sixth most common cause of cancer-related deaths worldwide [1, 2]
Our results show that miR-138 functions as a tumor-suppressive miRNA and that downregulation of miR-138 contributes to constitutive NF-kB activation and esophageal squamous cell carcinoma (ESCC) progression
By analyzing published miRNA expression profiles obtained from 153 primary ESCC tissues and 104 normal esophageal tissues (NCBI/GEO/GSE6188), miR-138 was identified to be significantly downregulated in ESCC tissues compared with normal tissues (Fig. 1A)
Summary
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive malignancies of the gastrointestinal tract, is the sixth most common cause of cancer-related deaths worldwide [1, 2].
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