The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma

Oesophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy. Although many molecular alterations have been observed in ESCC, the mechanisms underlying the development and progression of this disease remain unclear. In the present study, miR-1224-5p was identified to be downregul...

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Bibliographic Details
Published in:Cell death & disease 2020-07, Vol.11 (7), p.597, Article 597
Main Authors: Shi, Zhi-Zhou, Wang, Wen-Jun, Chen, Yun-Xia, Fan, Ze-Wen, Xie, Xiu-Feng, Yang, Li-Yan, Chang, Chen, Cai, Yan, Hao, Jia-Jie, Wang, Ming-Rong, Bai, Jie
Format: Article
Language:English
Subjects:
Animals
Autophagy - genetics
Base Sequence
Carcinogenesis - genetics
Carcinogenesis - pathology
Cell Line, Tumor
Cell migration
Cell Movement - genetics
Cell proliferation
Cell Proliferation - genetics
Disease Progression
EphA2 protein
Ephrin-A1 - metabolism
Epidermal growth factor receptors
ErbB Receptors - metabolism
Esophageal cancer
Esophageal Neoplasms - genetics
Esophageal Neoplasms - pathology
Esophageal Squamous Cell Carcinoma - genetics
Esophageal Squamous Cell Carcinoma - pathology
Esophagus
Female
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Kinases
Lymph nodes
Male
Malignancy
Medical prognosis
Metastases
Mice, Inbred BALB C
Mice, Nude
MicroRNAs - genetics
MicroRNAs - metabolism
Middle Aged
Neoplasm Invasiveness
Prognosis
Proteolysis
Receptor, EphA2 - metabolism
Signal Transduction
Squamous cell carcinoma
Tensins - metabolism
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
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Summary:Oesophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy. Although many molecular alterations have been observed in ESCC, the mechanisms underlying the development and progression of this disease remain unclear. In the present study, miR-1224-5p was identified to be downregulated in ESCC tissues compared to normal tissues, and its low expression was correlated with shorter survival time in patients. In vitro experiments showed that miR-1224-5p inhibited the proliferation, colony formation, migration and invasion of ESCC cells. Mechanistic investigation revealed that miR-1224-5p directly targeted TNS4 and inhibited its expression, which led to the inactivation of EGFR-EFNA1/EPHA2-VEGFA (vascular endothelial growth factor A) signalling. Experiments in vivo confirmed the suppressive effect of miR-1224-5p on oesophageal cancer cells. By immunohistochemistry analysis of ESCC specimens, we found that TNS4 expression was positively correlated with that of VEGFA, and was significantly associated with lymph node metastasis and shorter survival time in patients. Together, our data suggest that miR-1224-5p downregulation is a frequent alteration in ESCC that promotes cell proliferation, migration, invasion and tumour growth by activating the EGFR-EFNA1/EPHA2-VEGFA signalling pathway via inhibition of TNS4 expression. Decreased miR-1224-5p and elevated TNS4 are unfavourable prognostic factors for ESCC patients.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-02801-6