CircRNA cPWWP2A: an emerging player in diabetes mellitus

Abstract

Circular RNAs(CircRNAs), a new class of non-coding RNAs, possess significant capabilities of gene regulation and are disrupted in various diseases, including diabetes mellitus (DM). However, the underlying mechanism of CircRNAs in DM and diabetic complications remains illusive. A recent study published by Liu et al. (Proc Natl Acad Sci USA 116:7455–7464, 2019) shown that a novel diabetic retinopathy (DR)-associated CircRNA cPWWP2A, which could act as a competing endogenous RNA interacting with miR-579 to promote the DR-induced retinal vascular dysfunction through up-regulating the expression of Angiopoietin 1, Occludin, and SIRT1. Their findings may provide new insight into the potential use of CircRNA cPWWP2A for the targeted therapy of DR. However, those promising findings may need to be further evaluated detailedly for the following reason. (1) This study doesn’t well clarify why the most significantly up-regulated CircRNA mmu _circ_0000254 the fold change of which is 160.581 is excluded,while the cPWWP2A the fold change of which is only 3.487 is chosen. (2) It is difficult to conclude that cPWWP2A competing with miR-579 only by the analysis of colocalization in pericytes.

Diabetes mellitus (DM), with the chronic hyperglycaemia, is a complex multifactorial metabolic disorder, which is associated with the dysfunction and failure of multiple organ systems, especially the eyes, kidneys, heart, blood vessels and nerves (Daneshgari and Moore 2006; He et al. 2017). Currently, DM has become the third most prevalent non-infective disease (NCD) exceeded only by cardiovascular diseases and cancer (Wang et al. 2005), that is affecting more than 400 million people worldwide. The development of DM is accompanied by a series of complications, such as diabetic retinopathy (DR), diabetic nephropathy (DN), diabetic neuropathic pain (DNP) and diabetic cardiomyopathy (DCM). Deeper investigation into the molecular mechanisms of DM is highly worthwhile for improving the chances of an early diagnosis, monitoring cancer progression, and detecting recurrence.

Non-coding RNAs (ncRNAs), which include microRNA (miRNAs), Long non-coding RNA (LncRNAs), and Circular RNAs (CircRNAs), are key elements that play a crucial role in cellular development and homeostasis (He et al. 2019; Meng et al. 2017). CircRNAs are a new class of non-coding RNAs that are composed of > 200 nucleotides. CircRNAs possess significant capabilities of gene regulation and are disrupted in various diseases, including tumors (Zhou et al. 2018). The most important function of CircRNAs is that they can act as a competing endogenous RNA interacting with miRNAs (Ou et al. 2020). Recently, several databases have been developed as convenient tools for the miRNAs-CircRNAs association prediction (Table 1). For example, (Shan et al. 2017) reported that a novel CircRNA circ-HIPK3 is significantly elevated in diabetic retinas, and it can act as a competing endogenous RNA interacting with miR-30a to increase endothelial proliferation and vascular dysfunction.

Table 1.

Databases were available for miRNA-circRNA association prediction

Database	Functions of database	Subgroup analysis
circRNABase	Constructing a network of predicted interactions between miRNAs and circRNAs	http://starbase.sysu.edu.cn/ mirCircRNA.php
starBase v3.0	Providing an open-source platform for studying the miRNA- circular RNAs and mRNA	http://starbase.sysu.edu.cn/
Circ2Traits	Constructing a network of predicted interactions between miRNAs and protein coding, long non-coding and circular RNAs	http://gyanxet-beta.com/circdb/
circNet	Providing novel circRNAs and constructing the circRNA-miRNA-target network	http://circnet.mbc.nctu.edu.tw/
CircInteractome	Constructing a network of predicted interactions between miRNAs and circRNAs	http://circinteractome.nia.nih.gov
CSCD	Providing novel cancer-specific circRNAs and constructing the circRNA-miRNA network	http://gb.whu.edu.cn/CSCD

In a recent publication (Liu et al. 2019), Liu and co-authors from Yan’s group at the Shanghai Medical College, Fudan University elegantly addressed the role of the CircRNA cPWWP2A in diabetic retinopathy (DR). The authors showed that cPWWP2A (CircBase ID: mmu_circ_0000254), a CircRNA derived from the host gene PWWP2A, was up-regulated in DR, was associated with the DR-induced retinal vascular dysfunction. Functionally, the up-regulation of cPWWP2A in DR regulates retinal pericyte function and vascular integrity, thereby promoting the DR-associated microvascular complications. Mechanistically, the authors demonstrated that cPWWP2A could act as a competing endogenous RNA interacting with miR-579 to up-regulate the expression of Angiopoietin 1/Occluding/SIRT1. This study indicated that the “cPWWP2A-miR-579-Angiopoietin 1/Occluding/SIRT1” axis plays a role in promoting the progression of DR-induced retinal vascular dysfunction, which may provide a novel perspective on the use of CircRNAs in therapy strategies for DR. However, the conclusion drawn by Liu et al. needs to be further validated for the following reason. Firstly, it is hard to convince people to choose the CircRNA cPWWP2A as the object of this research. The CircRNAs expression profiling between diabetic retinas and non-diabetic retinas were shown in the Table S1 (Liu et al. 2019). The most significantly up-regulated CircRNA in Table S1 (Liu et al. 2019) was mmu _circ_0015546 and the fold change is 160.581 while the fold change of cPWWP2A expression is only 3.487. However, the authors did not explain why those significantly up-regulated CircRNAs the fold change of which was from 3.487 to 160.581 were excluded in this study. Secondly, there was little evidence to conclude that cPWWP2A competing with miR-579, although the authors shown that the colocalization between cPWWP2A and miR-579 in pericytes by the RNA-FISH assays. I think the authors need add the biotin-coupled microRNA capture assay and RNA pull-dwon assay to further verify whether cPWWP2A can enrich miR-579 in pericytes.

In summary, the study by Liu et al. (2019) demonstrated the competing endogenous effects of cPWWP2A and miR-579 that contribute to the promotion of DR progression through up-regulation of the Angiopoietin 1/Occluding/SIRT1 proteins, thereby forming a novel regulatory axis “cPWWP2A-miR-579-Angiopoietin 1/Occluding/SIRT1” in DR. This study may provide new insight into the potential use the cPWWP2A-miR-579 as new treatment strategies for DR. Although the quick development of high-throughput RNA deep sequencing, along with bioinformatics predictor tools, will enable a faster discovery of the pathway interactions of CircRNAs (Zhong et al. 2018), the roles and functions of numerous CircRNAs are still largely unclear. Thus, the identification and validation of novel functional CircRNAs in vivo and in vitro are urgently needed currently. Generally, CircRNAs could play a crucial role in modulation of both oncogenic and suppressive pathways by competing with miRNAs. Interestingly, CircRNAs may become novel diagnostic biomarkers and therapeutic targets for DM. Once the molecular mechanisms and functions of CircRNAs are clarified, they will bring more surprises and breakthroughs for the treatment of human diseases.

Author contributions

Conception and design: CL Ou, and QJ Yan. Writing, review, and/or revision of the manuscript: QJ Yan, XY He, and GY Kuang. Administrative, technical, or material support: J Yan, XY He, GY Kuang, and CL Ou.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no competing financial interest.