MiR-139-5p regulates VEGFR and downstream signaling pathways to inhibit the development of esophageal cancer
MiR-139-5p regulates VEGFR and downstream signaling pathways to inhibit the development of esophageal cancer
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DOI：
10.1016/j.dld.2018.07.017
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发表时间：
2019-01-01
影响因子：
4.5
通讯作者：
Jiao, Wenjing
中科院分区：
文献类型：
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作者：
Jiao, Wenpeng;Zhang, Jinyan;Jiao, Wenjing
背景：miR-139-5p在肿瘤的发生、转移和复发中起重要作用，有望成为食道癌诊断、预后和治疗的生物标志物。本研究旨在探讨miRNA-139-5p在食管癌中的作用及其机制。检测11例食管癌组织和癌旁组织中miRNA-139-5p的表达水平。本文检测了河北省食道癌高发区磁县92例食道癌患者血清中miR-139-5p的表达。检测miR-139-5p在食道癌细胞系中的表达。在miR-139-5p表达水平最低的KYSE150细胞系中，我们通过转染表达载体上调miR-139-5p的表达水平，研究miR-139-5p在食管鳞癌增殖、迁移和侵袭中的作用。我们利用miR-139-5P细胞系进行了一项基因图谱研究，以检测与肿瘤进展相关的重要基因的表达，包括细胞周期蛋白D1、E-钙粘蛋白和VEGFR-1。我们构建了含有野生型(WT)和突变型(Mut)VEGFR-1结合位点的miR-139-5p荧光素酶报告，以研究靶点。结果：11例食管癌组织中miRNA-139-5p的表达水平显著高于癌旁组织。92例食管癌患者血清中miR-139-5p的表达与性别(P=0.039)和TNM分期(P=0.015)有关。与miR-139-5p表达无关的因素有年龄(P=0.293)、吸烟史(P=0.397)、肿瘤长度(P=0.309)、肿瘤宽度(P=0.296)、肿瘤深度(P=0.724)、淋巴瘤转移(P=0.531)和术后治疗(P=0.884)。MIR-139-5P(P=0.013)与观察生存率显著相关。淋巴瘤转移(P=0.005)和TNM分期(P=0.000)与生存率显著相关。然而，未发现miR-139-5p与患者的性别、年龄、吸烟史、肿瘤大小和术后治疗等特征显著相关。在KYSE150细胞系中，miR-139-5p的表达水平最低。我们将其导入表达载体，发现细胞的增殖、转移和侵袭能力下降。MiR-139-5p上调可抑制Cyclin D1和VEGFR-1的表达，增加E-cadherin的表达。为了进一步证实，我们构建了含有miR-139-5P的荧光素酶报告，该报告含有野生型(WT)或突变型(Mut)VEGFR-1结合位点，用于靶向研究。结果表明，相应的VEGFR-1-Mut载体不再抑制miR-139-5。结论：miR-139-5p可能成为食道癌治疗的新靶点和判断预后的生物标志物。(C)2018年编辑意大利胃肠病学S.r.l.爱思唯尔有限公司出版。保留所有权利。
Background: MiR-139-5p plays a significant role in tumorigenesis, metastasis and recurrence, suggesting that it may potentially be used as a promising biomarker for esophageal cancer diagnosis, prognosis and therapy. This study aimed to investigate the role and the mechanism of miRNA-139-5p in esophageal cancer.Methods: This study included 11 patients from an area with a high incidence of esophageal cancer. The expression levels of miRNA-139-5p in esophageal cancer tissues and para-carcinoma tissues of 11 patients were measured. We examined the expression of miR-139-5p in serum obtained from 92 consecutive patients from Cixian, which is a region in Hebei Province with a high rate of histologically confirmed esophageal cancer. The expression of miR-139-5p in esophageal cancer cell lines was detected. In the KYSE150 cell line with the lowest expression level of miR-139-5p, we transfected a plasmid to upregulate the expression level and examined the role of miR-139-5p in esophageal squamous cell carcinoma proliferation, migration and invasion. We conducted a gene profiling study using miR-139-5p cell lines to detect the expression of significant genes related to tumor progression, including cyclinD1, E-cadherin and VEGFR-1. We then constructed luciferase reporters containing miR-139-5p, which contained wild-type (WT) or mutated-type (Mut) VEGFR-1 binding sites to investigate the target.Results: MiRNA-139-5p expression levels in esophageal cancer tissues from 11 patients were significantly higher than those in para-carcinoma tissues. MiR-139-5p expression in the serum of 92 patients with esophageal cancer was associated with gender (P = 0.039) and TNM stage (P = 0.015). Factors that were not correlated with miR-139-5p expression were age (P = 0.293), smoking history (P = 0.397), length of tumor (P = 0.309), width of tumor (P = 0.296), depth of tumor (P = 0.724), lymphoma metastasis (P = 0.531) and postoperative therapy (P = 0.884). MiR-139-5p (P = 0.013) correlated significantly with observed survival rates. The lymphoma metastasis (P = 0.005) and TNM stage (P = 0.000) were significantly associated with observed survival rates. However, no significant relationships were found between the miR-139-5p and patient characteristics including gender, age, smoking history, tumor size and postoperative therapy. In the KYSE150 cell line, the expression level of miR-139-5p was the lowest. We transfected a plasmid to upregulate the expression level and found that the cell proliferation, metastasis and invasion abilities decreased. Upregulation of miR-139-5p inhibited the expression of Cyclin D1 and VEGFR-1 and increased the expression of E-cadherin. For further confirmation, we constructed luciferase reporters containing miR-139-5p, which contained wild-type (WT) or mutated-type (Mut) VEGFR-1 binding sites for target investigation. The results show that the corresponding VEGFR-1-Mut construct no longer suppressed miR-139-5p.Conclusions: MiR-139-5p may be a novel therapeutic target and prognostic biomarker of esophageal cancer. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.