miR-139-5p 通过调控 VEGFR 及其下游信号通路抑制食管癌的发生发展。
MiR-139-5p regulates VEGFR and downstream signaling pathways to inhibit the development of esophageal cancer.
机构信息
Dept. of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
Clinical Laboratory, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
出版信息
Dig Liver Dis. 2019 Jan;51(1):149-156. doi: 10.1016/j.dld.2018.07.017. Epub 2018 Aug 27.
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.
背景
miR-139-5p 在肿瘤发生、转移和复发中起重要作用，提示其可能作为一种有前途的食管癌诊断、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。
方法
本研究纳入了 11 名来自食管癌高发地区的患者。测量了 11 名患者食管癌组织和癌旁组织中 miR-139-5p 的表达水平。我们检测了来自河北省磁县 92 例连续患者血清中的 miR-139-5p 表达水平，该地区是组织学证实食管癌发病率较高的地区。检测了食管癌细胞系中 miR-139-5p 的表达。在 miR-139-5p 表达最低的 KYSE150 细胞系中，我们转染质粒上调表达水平，并检测 miR-139-5p 在食管鳞癌细胞增殖、迁移和侵袭中的作用。我们使用 miR-139-5p 细胞系进行基因谱研究，以检测与肿瘤进展相关的显著基因的表达，包括 cyclinD1、E-cadherin 和 VEGFR-1。然后，我们构建了包含 miR-139-5p 的荧光素酶报告基因，其中包含野生型（WT）或突变型（Mut）VEGFR-1 结合位点，以进行靶标研究。
结果
11 例食管癌患者的 miR-139-5p 表达水平明显高于癌旁组织。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）相关。与 miR-139-5p 表达不相关的因素包括年龄（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）与观察生存率显著相关。然而，miR-139-5p 与患者特征（包括性别、年龄、吸烟史、肿瘤大小和术后治疗）之间没有显著关系。在 KYSE150 细胞系中，miR-139-5p 的表达水平最低。我们转染质粒上调表达水平，发现细胞增殖、迁移和侵袭能力降低。上调 miR-139-5p 抑制 Cyclin D1 和 VEGFR-1 的表达，增加 E-cadherin 的表达。为了进一步证实，我们构建了包含 miR-139-5p 的荧光素酶报告基因，其中包含野生型（WT）或突变型（Mut）VEGFR-1 结合位点，用于靶标研究。结果表明，相应的 VEGFR-1-Mut 构建体不再抑制 miR-139-5p。
结论
miR-139-5p 可能是食管癌的一种新的治疗靶点和预后生物标志物。
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