MicroRNA-384 inhibits the progression of esophageal squamous cell carcinoma through blockade of the LIMK1/cofilin signaling pathway by binding to LIMK1

Biomed Pharmacother. 2019 Jan:109:751-761. doi: 10.1016/j.biopha.2018.09.110. Epub 2018 Nov 5.

Abstract

Introduction: Esophageal squamous cell carcinoma (ESCC) represents an aggressive malignancy often accompanied with a poor prognosis. Owing to the poor mortality and morbidity rates associated with this malignancy, a deeper understanding of the finer molecular changes that occur in ESCC is required in order to identify novel potential targets for early detection and therapy. At present the mechanism by which ESCC functions on a molecular level is not fully understood. Hence, the aim of the present study was to ascertain as to whether microRNA-384 (miR-384) influences the progression of ESCC.

Material and methods: Bioinformatics analysis was initially conducted to identify ESCC-related differentially expressed genes and predict regulatory miRs. After the target relationship between miR-384 and LIMK1 had been verified, the expression of miR-384 and LIMK1 in the EC9706 cell line was altered in an attempt to investigate the regulatory roles of miR-384 in the expression of the LIMK1/cofilin signaling pathway-related genes, cell proliferation, invasion, cell cycle distribution and apoptosis, in addition to lymph node metastasis (LNM) and tumor growth in nude mice.

Results: Microarray-based gene expression profiling indicated that miR-384 affected the progression of ESCC through the LIMK1-mediated LIMK1/cofilin signaling pathway. Furthermore, miR-384 and Bax were observed to be poorly expressed, while LIMK1, cofilin and Bcl-2 were highly expressed in ESCC. The obtained evidences indicating that miR-384 targeted and negatively regulated LIMK1. Upregulation of miR-384 or LIMK1 inhibition was determined to block the LIMK1/cofilin signaling pathway, repress cell proliferation, invasion, cell cycle, LNM and tumor growth, while promote cell apoptosis in ESCC.

Conclusion: Collectively, based on the key findings of the study, miR-384 could sequester LIMK1, which acts to suppress activation of the LIMK1/cofilin signaling pathway, thus ultimately inhibiting the development and progression of ESCC.

Keywords: Cell apoptosis; Cell proliferation; Esophageal squamous cell carcinoma; LIMK1; LIMK1/cofilin signaling pathway; Lymph node metastasis; microRNA-384.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Line, Tumor
  • Cofilin 1 / antagonists & inhibitors
  • Cofilin 1 / metabolism*
  • Disease Progression*
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / prevention & control
  • Esophageal Squamous Cell Carcinoma / metabolism*
  • Esophageal Squamous Cell Carcinoma / pathology
  • Esophageal Squamous Cell Carcinoma / prevention & control
  • Female
  • Humans
  • Lim Kinases / antagonists & inhibitors
  • Lim Kinases / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / biosynthesis*
  • Middle Aged
  • Protein Binding / physiology
  • Rats
  • Rats, Nude
  • Signal Transduction / physiology

Substances

  • Cofilin 1
  • MIRN384 microRNA, human
  • MicroRNAs
  • LIMK1 protein, human
  • Lim Kinases