circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer

Abstract

Background Patients with lymph node (LN)-positive pancreatic ductal adenocarcinoma (PDAC) have extremely poor survival rates. Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNAs, have been proposed to mediate the progression of diverse types of tumors. However, the role and underlying regulatory mechanisms of circRNAs in the LN metastasis of PDAC remain unknown. Methods Next-generation sequencing was used to identify differentially expressed circRNAs between PDAC and normal adjacent tissues. In vitro and in vivo experiments were conducted to evaluate the functional role of circNFIB1. RNA pulldown and luciferase assays were performed to examine the binding of circNFIB1 and miR-486-5p. Results In the present study, we identified that a novel circRNA (circNFIB1, hsa_circ_0086375) was downregulated in PDAC and negatively associated with LN metastasis in PDAC patients. Functionally, circNFIB1 knockdown promoted lymphangiogenesis and LN metastasis of PDAC both in vitro and in vivo. Mechanistically, circNFIB1 functioned as a sponge of miR-486-5p, and partially reversed the effect of miR-486-5p. Moreover, circNFIB1 attenuated the oncogenic effect of miR-486-5p and consequently upregulated PIK3R1 expression, which further downregulated VEGF-C expression through inhibition of the PI3K/Akt pathway, and ultimately suppressed lymphangiogenesis and LN metastasis in PDAC. Conclusions Our findings provide novel insight into the underlying mechanism of circRNA-mediated LN metastasis of PDAC and suggest that circNFIB1 may serve as a potential therapeutic target for LN metastasis in PDAC. Graphical abstract

RETRACTED ARTICLE: CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p

“…Noncoding RNAs are classified as miRNAs, small nuclear RNAs (snRNAs), lncRNAs (long noncoding RNAs) and circRNAs. There is no doubt that lncRNAs and circRNAs have attracted increasing attention in cancer research [22][23][24]. LncRNAs are generally described as RNA transcripts of more than 200 nt in length without protein-coding potential.…”

circRNA circ_102049 Implicates in Pancreatic Ductal Adenocarcinoma Progression through Activating CD80 by Targeting miR-455-3p

“…It is widely accepted that high methylation of tumor suppressor genes and low methylation of cancer genes play significant roles in the occurrence and development of cancers [ 38 ]. Recently, a number of studies have elucidated that circRNAs, a type of covalent closed circular noncoding RNAs, are strongly implicated in tumor growth, metastasis, and proliferation through the circRNA-miRNA-mRNA axis in a wide variety of tumors [ 39 , 40 ]. circRNAs are highly stable and tissue-specific compared with linear RNAs that might be used as promising biomarkers for the detection of clinicopathological status in PDAC.…”

Screening and functional prediction of differentially expressed circular RNAs in human glioma of different grades

“…Relative to colorectal and ovarian cancer tissues, a high proportion of circRNAs are abundant in normal human tissues [ 29 ]. Many studies have revealed that certain circRNAs are downregulated in tumors compared with normal tissues and cells [ 30 – 33 ], which indicates that these circRNAs may function as suppressor genes and have a protective function in inhibiting cancer. Hence, we chose specific downregulated circRNAs for further research.…”