The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma
The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma
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miR-1224-5p/TNS4/EGFR轴抑制食管鳞状细胞癌的肿瘤进展
DOI：
10.1038/s41419-020-02801-6
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发表时间：
2020-07-30
影响因子：
9
通讯作者：
Bai, Jie
中科院分区：
文献类型：
--
作者：
Shi, Zhi-Zhou;Wang, Wen-Jun;Bai, Jie
食管鳞状细胞癌是一种常见的恶性肿瘤。尽管在ESCC中已经观察到许多分子改变，但这种疾病的发展和进展的潜在机制仍不清楚。在本研究中，与正常组织相比，miR-1224- 5 p在ESCC组织中被鉴定为下调，并且其低表达与患者较短的生存时间相关。体外实验表明，miR-1224- 5 p抑制食管鳞癌细胞的增殖、集落形成、迁移和侵袭。机制研究表明，miR-1224- 5 p直接靶向TNS 4并抑制其表达，从而导致EGFR-EFNA 1/EPHA 2-VEGFA（血管内皮生长因子A）信号转导的失活。体内实验证实了miR-1224- 5 p对食管癌细胞的抑制作用。通过免疫组化分析，我们发现TNS 4的表达与VEGFA的表达呈正相关，并与患者的淋巴结转移和较短的生存时间显著相关。总之，我们的数据表明，miR-1224- 5 p下调是ESCC中的常见改变，其通过抑制TNS 4表达激活EGFR-EFNA 1/EPHA 2-VEGFA信号通路来促进细胞增殖、迁移、侵袭和肿瘤生长。miR-1224- 5 p降低和TNS 4升高是ESCC患者的不利预后因素。
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.