Intriguing circles: Conflicts and controversies in circular RNA research

Abstract

Circular RNAs (circRNAs) are covalently closed RNA circles without a 5 0 cap or 3 0 tail. Since the landmark discovery of ciRS-7/CDR1as functioning as a miR-7 sponge in 2013, circRNAs have become a hot topic in RNA research. CircRNAs have been found to play active roles in cancer, cardiovascular diseases, neurological disorders, and many other diseases. They can function as microRNA (miRNA) sponges, protein scaffolds, and even translation templates. However, as circRNA research expands, many divergent views have emerged. For example, are most circRNAs competent in serving as miRNA sponges? What kinds of circRNAs are most likely to sponge miRNAs? Apart from sponging miRNAs, what could the functions of most circRNAs be? What are the features of circRNAs that are translatable? Many researchers have claimed that circRNAs are abundant, stable, conserved, and specific molecules, which hold great potential in serving as biomarkers. However, circRNA abundance is variable and some circRNAs are abundant while others are not. In addition, their stability and conservation may vary under different circumstances. Furthermore, it is unclear whether circRNA biogenesis is more likely to be regulated by RNA binding proteins or transcription factors. All of these are open questions that remain to be answered by researchers in this field. Discussing and investigating these questions will advance the understanding of this class of novel molecules and may propel inspiring new ideas for future studies.

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

“…circRNA is characterized by the covalently closed loop structure without 5′‐end cup and 3′‐end ploy‐A tail. It is widely expressed in eukaryotic cells and possesses important gene regulatory potential, which makes it involved in tumorigenesis and aggressiveness . Recent studies have shown that circRNA functions through different actions, including serving as ‘miRNA sponge’, regulation of transcription and splicing, interacting with RNA‐binding protein, and even translating polypeptide .…”

“…It is widely expressed in eukaryotic cells and possesses important gene regulatory potential, which makes it involved in tumorigenesis and aggressiveness. 15 Recent studies have shown that circRNA functions through different actions, including serving as 'miRNA sponge', regulation of transcription and splicing, interacting with RNA-binding protein, and even translating polypeptide. 16 The most extensively studied is circRNA as a competing endogenous RNA (ceRNA) to effectively sponge miRNA, for example, circ-HIPK3/miR-7 in colorectal cancer, 17 circ-EPSTI1/miR-942 in ovarian cancer, 18 circ-ANKS1B/ miR-148/152 in breast cancer 19 and circ-AMOTL1L/miR-193a-5p in prostate cancer.…”

<p>Circular RNA hsa_circ_0068033 Acts as a Diagnostic Biomarker and Suppresses the Progression of Breast Cancer Through Sponging miR-659</p>

“…CircRNA, a class of enclosed non-coding RNA molecules generated by RNA splicing, function as an miRNA sponge and regulate gene transcription and alternative splicing. 4,5,8,13,18,19 Recent studies have confirmed that circRNA is involved in the regulation of gene expression by various means, thereby indirectly participating in the occurrence and development of various solid cancers. 6,[9][10][11]13,14,16,17 However, the biological functions of circRNA in BC are scarcely reported.…”

Circular RNA hsa_circ_0068033 inhibits proliferation and invasion of breast cancer cells through sponging miR-659

“…CircRNA, a class of enclosed non-coding RNA molecules generated by RNA splicing, function as an miRNA sponge and regulate gene transcription and alternative splicing [18,19,8,13,4,5]. Recent studies have confirmed that circRNA is involved in the regulation of gene expression by various means, thereby indirectly participating in the occurrence and development of various solid cancers [13,11,10,6,17,9,16,14].…”