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      Circular RNA CircCOL5A1 Sponges the MiR-7-5p/Epac1 Axis to Promote the Progression of Keloids Through Regulating PI3K/Akt Signaling Pathway

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          Abstract

          Keloids, as a result of abnormal wound healing in susceptible individuals, are characterized by the hyper-proliferation of fibroblasts and exaggerated deposition of extracellular matrix. Current surgical and therapeutic modalities provide limited satisfactory results. Growing evidence has highlighted the roles of circRNAs in acting as miRNA sponges. However, up to date, the regulatory mechanism of circRNAs in the pathological process of keloids has rarely been reported. In this study, cell proliferation, cell migration, flow cytometry, western blotting, fluorescence in situ hybridization, dual-luciferase activity, and immunohistochemistry assays were applied to explore the roles and mechanisms of the circCOL5A1/miR-7-5p/Epac1 axis in the keloid. The therapeutic potential of circCOL5A1 was investigated by establishing keloid implantation models. The RT-qPCR result revealed that circCOL5A1 expression was obviously higher in keloid tissues and keloid fibroblasts. Subsequent cellular experiments demonstrated that circCOL5A1 knockdown repressed the proliferation, migration, extracellular matrix (ECM) deposition, whereas promoted cell apoptosis, through the PI3K/Akt signaling pathway. Furthermore, RNA-fluorescence in situ hybridization (RNA-FISH) illustrated that both circCOL5A1 and miR-7-5p were located in the cytoplasm. The luciferase reporter gene assay confirmed that exact binding sites were present between circCOL5A1 and miR-7-5p, as well as between miR-7-5p and Epac1. Collectively, the present study revealed that circCOL5A1 functioned as competing endogenous RNA (ceRNA) by adsorbing miR-7-5p to release Epac1, which contributed to pathological hyperplasia of keloids through activating the PI3K/Akt signaling pathway. Our data indicated that circCOL5A1 might serve as a novel promising therapeutic target and represent a new avenue to understand underlying pathogenesis for keloids.

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          Most cited references43

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          Natural RNA circles function as efficient microRNA sponges.

          MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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            Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway

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              Upregulation of METTL14 mediates the elevation of PERP mRNA N 6 adenosine methylation promoting the growth and metastasis of pancreatic cancer

              Background Pancreatic cancer is one of the most lethal human cancers. N 6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive. Methods LC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14. Results We found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells. Conclusions Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                21 January 2021
                2021
                : 9
                : 626027
                Affiliations
                [1] 1Department of Plastic and Aesthetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST) , Wuhan, China
                [2] 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST) , Wuhan, China
                Author notes

                Edited by: Song Zhao, First Affiliated Hospital of Zhengzhou University, China

                Reviewed by: Albert Mellick, University of New South Wales, Australia; XiuKai Cao, Yangzhou University, China

                *Correspondence: Yuping Ren, yprentj@ 123456163.com

                These authors have contributed equally to this work and share first authorship

                This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2021.626027
                7859531
                33553184
                2e2888ac-68f4-46a1-b1f6-4f42ba8afe53
                Copyright © 2021 Lv, Liu, Zhang, Hu, Wu and Ren.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 November 2020
                : 04 January 2021
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 43, Pages: 17, Words: 0
                Categories
                Cell and Developmental Biology
                Original Research

                keloid,fibroblast,circcol5a1,mir-7-5p,epac1,pi3k/akt pathway
                keloid, fibroblast, circcol5a1, mir-7-5p, epac1, pi3k/akt pathway

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