Circular RNAs regulate cancer-related signaling pathways and serve as potential diagnostic biomarkers for human cancers

(2021) 21:317 Garlapati et al. Cancer Cell Int https://doi.org/10.1186/s12935-021-02017-4 Cancer Cell International Open Access REVIEW Circular RNAs regulate cancer‑related signaling pathways and serve as potential diagnostic biomarkers for human cancers Pranavi Garlapati1†, Jinjie Ling2†, Paul J. Chiao1 and Jie Fu1* Abstract Circular RNAs (circRNAs) are RNAs that have an important role in various pathological processes, including cancer. After the usage of high-throughput RNA sequencing, many circRNAs were found to be differentially expressed in various cancer cell lines and regulate cell signaling pathways by modulating particular gene expressions. Understanding their role in these pathways and what cancers they are found in can set the stage for identifying diagnostic and prognostic biomarkers and therapeutic targets of cancer. This paper will discuss which circRNAs are found in different cancers and what mechanisms they use to upregulate or downregulate certain cellular components. Keywords: Circular RNA, Signaling pathways, Human cancer, Biomarkers, miRNA sponging Background Circular RNAs (circRNAs) are a novel class of endogenous covalently closed RNA molecules created by back splicing of exons from a single pre-mRNA. They are formed by joining the 3′ end of a downstream exon to the 5′ end of an upstream exon [1]. CircRNAs are found to be predominantly located in the cytoplasm and highly resistant to degradation due to their structure, where the linear ends are not accessible. The biogenesis of circRNAs is known to be highly regulated by intronic complementary sequences and splicing factors [2]. Sanger et al. in 1976, was the first to elucidate that single-stranded viroids are covalently closed circular RNA molecules in plants [3]. Initially, this noncoding RNA was thought to be a result of a post-transcriptional error, but in recent years, the advent of novel sequencing technologies advanced our understanding that CircRNAs represent a new type of alternative splicing of a pre-mRNA. *Correspondence: † Pranavi Garlapati and Jinjie Ling are Co-first authors 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Full list of author information is available at the end of the article Emerging evidence shows that this non-coding RNA has an important role in biological processes and disease development [4]. Studies have shown that circRNAs are dysregulated in various diseases such as neurodegenerative disease, cardiovascular disease, viral infection, and most important to this paper, cancer [5-8]. Over 30,000 circRNAs have been identified as of 2018, and the discovery of new ones continues to progress. There are 4 main types of circRNAs: intergenic circRNAs, exon–intron circRNAs, circRNA (ecircRNA), and circular intronic RNA (ciRNA), all of which can play key roles in regulating cellular functions [9, 10]. As more circRNAs continue to be found, it becomes increasingly important to define their function in cancer. The characteristics of a circ-RNA such as its stability, distribution, and specific expression in various cell or tissue types give rise to its functional role. In cancer, circRNAs have been shown to modulate cancer growth, metastasis, Tumor Node Metastasis (TNM) stage, and drug resistance [11-13]. Several circRNAs have been reported to increase cell proliferation in cancer cells. Examples include circ0005276 in prostate cancer cells through the activation of X-linked inhibitor of apoptosis protein (XIAP) and circVAPA in HCC cells through © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Garlapati et al. Cancer Cell Int (2021) 21:317 the activation of prosaposin (PSAP) [14, 15]. Certain circRNAs can also inhibit cancer cell proliferation like Circular RNA YAP1 in gastric cancer cells [16]. CircRNA also regulates the invasion and metastasis of cancer cells: examples of this are CircRIMS in gastric cancer cells and hsa_circ_0023404 in non-small cell lung cancer (NSCLC) [17, 18]. Another function of circRNA is controlling the cell cycle. circ-MDM2 in CRC regulates MDM2 leading to p53 suppression and defects in G 1-S progression [19]. Overall, circRNAs play a very important role in cancer. CircRNAs as biomarkers circRNA provides an important biomarker for cancer due to a few unique reasons. First, circRNAs are highly resistant to degradation by exonucleases and extremely stable because they do not have 5′ or 3′ prime ends and therefore have a high degree of tissue and disease specificity [20]. Second, circRNAs are found in all cancer cell tissues, solid tumors, peripheral blood, exosomes, and other body fluids such as saliva, plasma, and serum [21]. A recent study with over 1195 plasma samples showed that hsa_circ_0007750, and hsa_circ_0139897 levels were significantly higher in patients with hepatocellular carcinoma (HCC) than healthy controls as well as patients with other diseases such as hepatitis B or HBVrelated liver cirrhosis, indicating its specificity to cancer [22]. Because they are resistant to degradation and present in body fluids, circRNAs are the perfect candidate for noninvasive liquid biopsy and therefore have a high diagnostic potential. An example of this can be seen in a recent study where circ-KLDHC10 in serum samples was successfully used to distinguish patients with CRC from those without CRC [20]. In Lung adenocarcinoma, hsa_circ_0013958 was significantly upregulated and also correlated with lymphatic metastasis and tumor-nodemetastasis (TNM) stage, implicating it as an important biomarker for cancer [23]. Most important to this paper is that circRNAs are the optimal biomarkers for cancer because they regulate cancer signaling pathways. Many circRNAs to date have been shown to play important roles in cancer signaling pathways by upregulating or downregulating important downstream proteins in pathways such as Wnt/β-Catenin, PI3K/Akt, MAPK/ERK, etc. [25, 26]. (...truncated)