Cheng Kai, Feng Lan, Yu Shuang, Yu Changhong, Chi Nannan
Department of Gastroenterology, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, People's Republic of China.
Department of Infectious Diseases, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, People's Republic of China.
Onco Targets Ther. 2019 Dec 31;12:11737-11750. doi: 10.2147/OTT.S218876. eCollection 2019.
MicroRNA-769-5p (miR-769) is aberrantly expressed and plays crucial roles in non-small cell lung cancer and melanoma. However, the expression pattern, biological role, and mechanisms of action of miR-769 in pancreatic ductal adenocarcinoma (PDAC) are yet to be fully elucidated. Therefore, we attempted to determine the potential regulatory function of miR-769 in PDAC progression and to explore the underlying mechanisms in detail.
In this study, reverse-transcription quantitative polymerase chain reaction was carried out to determine the expression profile of miR-769 in PDAC. A series of experiments, including a Cell Counting Kit-8 assay, flow-cytometric analysis, Transwell migration and invasion assays, and a xenograft animal model, were applied to test whether miR-769 affects the malignancy of PDAC.
We found that miR-769 was significantly underexpressed in PDAC tissues and cell lines. The low miR-769 expression significantly correlated with the TNM stage and lymph node metastasis. Patients with PDAC harboring low miR-769 expression showed shorter overall survival than did the patients with high miR-769 expression. Forced upregulation of miR-769 suppressed PDAC cell proliferation, migration, and invasion in vitro; promoted apoptosis in vitro; and hindered tumor growth in vivo. Experiments on the mechanism identified ETS proto-oncogene 1 () as a direct target gene of miR-769 in PDAC cells. Furthermore, ETS1 turned out to be upregulated in PDAC tissue samples, and the upregulation of ETS1 negatively correlated with miR-769 expression. Moreover, ETS1 knockdown simulated the tumor-suppressive effects of miR-769 overexpression on PDAC cells. Besides, ETS1 reintroduction attenuated the antitumor actions of miR-769 upregulation in PDAC cells.
Our findings indicate that miR-769 performs tumor-suppressive functions in PDAC by directly targeting ETS1, and this miRNA may represent a potential therapeutic target for the development of anticancer therapies.
微小RNA-769-5p（miR-769）在非小细胞肺癌和黑色素瘤中表达异常并发挥关键作用。然而，miR-769在胰腺导管腺癌（PDAC）中的表达模式、生物学作用及作用机制尚未完全阐明。因此，我们试图确定miR-769在PDAC进展中的潜在调控功能，并详细探究其潜在机制。
在本研究中，进行逆转录定量聚合酶链反应以确定miR-769在PDAC中的表达谱。应用一系列实验，包括细胞计数试剂盒-8检测、流式细胞术分析、Transwell迁移和侵袭检测以及异种移植动物模型，来测试miR-769是否影响PDAC的恶性程度。
我们发现miR-769在PDAC组织和细胞系中显著低表达。miR-769低表达与TNM分期和淋巴结转移显著相关。miR-769表达低的PDAC患者的总生存期短于miR-769表达高的患者。miR-769的强制上调在体外抑制了PDAC细胞的增殖、迁移和侵袭；促进了体外细胞凋亡；并在体内抑制了肿瘤生长。机制实验确定ETS原癌基因1（ETS1）为PDAC细胞中miR-769的直接靶基因。此外，ETS1在PDAC组织样本中上调，且ETS1的上调与miR-769表达呈负相关。此外，ETS1敲低模拟了miR-769过表达对PDAC细胞的肿瘤抑制作用。此外，重新引入ETS1减弱了miR-769上调对PDAC细胞的抗肿瘤作用。
我们的研究结果表明，miR-769通过直接靶向ETS1在PDAC中发挥肿瘤抑制功能，这种微小RNA可能代表抗癌治疗开发的潜在治疗靶点。
