Increased expression of miR-194-5p through the circPVRL3/miR-194-5p/SOCS2 axis promotes proliferation and metastasis in pancreatic ductal adenocarcinoma by activating the PI3K/AKT signaling pathway
Bojing Chi, Yao Zheng, Fuming Xie, Wen Fu, Xianxing Wang, Jianyou Gu, Jiali Yang, Jingyang Yin, Lei Cai, Peng Tang, Jianbo Li, Shixiang Guo, Huaizhi Wang
Abstract
BACKGROUND: MicroRNAs (miRNAs), as an indispensable type of non-coding RNA (ncRNA), participate in diverse biological processes. However, the specific regulatory mechanism of certain miRNAs in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: The expression of miR-194-5p in PDAC tissue microarray and cell lines were detected by RNA-scope and real-time quantitative PCR (RT-qPCR). The function of proliferation and migration carried by miR-194-5p in vitro and vivo was observed by several functional experiments. Informatics methods and RNA sequencing data were applied to explore the target of miR-194-5p and the upstream circular RNA (circRNA) of miR-194-5p. RNA-binding protein immunoprecipitation (RIP) assay and dual-luciferase reporter assay confirmed the relationships between miR-194-5p and SOCS2 or miR-194-5p and circPVRL3. The proliferation and migration abilities of SOCS2 and circPVRL3 were accessed by rescue experiments. RESULTS: In this study, we aimed to clarify the molecular mechanisms of miR-194-5p, which has critical roles during PDAC progression. We found that the expression of miR-194-5p was significantly upregulated in PDAC tissue compared to tumor-adjacent tissue and was highly related to age and nerve invasion according to RNAscope and RT‒qPCR. Overexpression of miR-194-5p accelerated the cell cycle and enhanced the proliferation and migration processes according to several functional experiments in vitro and in vivo. Specifically, circPVRL3, miR-194-5p, and SOCS2 were confirmed to work as competing endogenous RNAs (ceRNAs) according to informatics methods, RIP, and dual-luciferase reporter assays. Additionally, the rescue experiments confirmed the relationship among miR-194-5p, circPVRL3, and SOCS2 mRNA. Finally, the circPVRL3/miR-194-5p/SOCS2 axis activates the PI3K/AKT signaling pathway to regulate the proliferation and metastasis of PDAC. CONCLUSION: Our findings indicated that an increase of miR-194-5p caused by circPVRL3 downregulation stimulates the PI3K/AKT signaling pathway to promote PDAC progression via the circPVRL3/miR-194-5p/SOCS2 axis, which suggests that the circPVRL3/miR-194-5p/SOCS2 axis may be a potential therapeutic target for PDAC patients.