Huang Wenjie, Gu Jianyou, Tao Tian, Zhang Junfeng, Wang Huaizhi, Fan Yingfang
Department of First Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.
Front Oncol. 2020 Jan 21;9:1499. doi: 10.3389/fonc.2019.01499. eCollection 2019.
Pancreatic ductal adenocarcinoma (PDAC) is associated with several genetic syndromes. However, the molecular mechanism underlying PDAC progression is still unknown. In this study, we showed that Laminin Subunit Beta 3 (LAMB3) was aberrantly overexpressed in PDAC and was closely associated with the overall survival rate of patients with PDAC. Functional studies demonstrated that LAMB3 played important roles in cell proliferation, the cell cycle, and invasion capacity. Using bioinformatics analysis, we determined that miR-24-3p was an upstream miRNA of LAMB3, and further experiments verified that miR-24-3p regulated LAMB3 expression in PDAC cells. A dual-luciferase reporter system demonstrated that miR-24-3p directly targeted the LAMB3 3'UTR, and FISH assay confirmed that miR-24-3p and LAMB3 mRNA mostly resided in cytoplasm, accounting for their post-translational regulation. Rescue assay demonstrated that miR-24-3p exerted its anti-cancer role by suppressing LAMB3 expression. Finally, by using a subcutaneous xenotransplanted tumor model, we demonstrated that miR-24-3p overexpression inhibited the proliferation of PDAC by suppressing LAMB3 expression . Collectively, our results provide evidence that the miR-24-3p/LAMB3 axis plays a vital role in the progression of PDAC and indicate that the miR-24-3p/LAMB3 axis may represent a novel therapeutic target for PDAC.
胰腺导管腺癌（PDAC）与多种遗传综合征相关。然而，PDAC进展的分子机制仍不清楚。在本研究中，我们发现层粘连蛋白β3亚基（LAMB3）在PDAC中异常过表达，且与PDAC患者的总生存率密切相关。功能研究表明，LAMB3在细胞增殖、细胞周期和侵袭能力中发挥重要作用。通过生物信息学分析，我们确定miR-24-3p是LAMB3的上游miRNA，进一步实验证实miR-24-3p在PDAC细胞中调节LAMB3表达。双荧光素酶报告系统表明miR-24-3p直接靶向LAMB3的3'UTR，荧光原位杂交分析证实miR-24-3p和LAMB3 mRNA大多位于细胞质中，这解释了它们的翻译后调控机制。拯救实验表明，miR-24-3p通过抑制LAMB3表达发挥其抗癌作用。最后，通过皮下异种移植瘤模型，我们证明miR-24-3p过表达通过抑制LAMB3表达抑制PDAC的增殖。总的来说，我们的结果提供了证据，表明miR-24-3p/LAMB3轴在PDAC进展中起关键作用，并表明miR-24-3p/LAMB3轴可能代表PDAC的一个新的治疗靶点。
