Abstract
Simple SummaryCircular RNAs (circRNAs) are a relatively new and unexplored RNA type, implicated in several aspects of cell life, in normal and pathological states. This review aims to discuss the roles of circRNAs in colorectal cancer (CRC) initiation, progression, and therapy resistance, as well as their potential clinical value as CRC biomarkers. CRC is characterized by an elevated mortality rate, poor prognosis of high-grade tumors, high metastatic potential, and resistance to conventional therapies. Therefore, there is an urgent need for identification of novel molecules involved in colorectal carcinogenesis. Prompted by several studies examining circRNA involvement in CRC, in this review we seek to summarize the existing knowledge on circRNA expression in CRC and their implication in cellular pathways and molecular mechanisms underlying colorectal carcinogenesis. Lastly, we discuss the limitations and future perspectives highlighting the missing pieces of the puzzle and aspects of the circRNA research field that should be further investigated.Colorectal cancer (CRC) is the third most fatal type of malignancy, worldwide. Despite the advances accomplished in the elucidation of its molecular base and the existing CRC biomarkers introduced in the clinical practice, additional research is required. Circular RNAs (circRNAs) constitute a new RNA type, formed by back-splicing of primary transcripts. They have been discovered during the 1970s but were characterized as by-products of aberrant splicing. However, the modern high-throughput approaches uncovered their widespread expression; therefore, several questions were raised regarding their potential biological roles. During the last years, great progress has been achieved in the elucidation of their functions: circRNAs can act as microRNA sponges, transcription regulators, and interfere with splicing, as well. Furthermore, they are heavily involved in various human pathological states, including cancer, and could serve as diagnostic and prognostic biomarkers in several diseases. Particularly in CRC, aberrant expression of circRNAs has been observed. More specifically, these molecules either inhibit or promote colorectal carcinogenesis by regulating different molecules and signaling pathways. The present review discusses the characteristics and functions of circRNA, prior to analyzing the multifaceted role of these molecules in CRC and their potential value as biomarkers and therapeutic targets.
Highlights
Colorectal cancer (CRC) is one of the most well-studied types of human malignancies, due to its high occurrence and mortality rate worldwide
This review aims to shed light on the current knowledge regarding the implication of circRNAs in the development of CRC, including proliferation, invasion, metastasis, and treatment resistance, and to present circRNAs which could ideally act as biomarkers and/or therapeutic targets
Bachmayr-Heyda et al have identified 11 upregulated and 28 downregulated circRNAs in CRC, through differential gene expression analysis of normal colon mucosa and paired cancerous tissues [42]. Their RNA-seq data showed that the ratio of circRNAs to their respective linear transcripts is often decreased in CRC samples and cell lines, compared to non-cancerous ones
Summary
Colorectal cancer (CRC) is one of the most well-studied types of human malignancies, due to its high occurrence and mortality rate worldwide. CircRNAs present the following four particular features: firstly, they form a circular structure, without terminal structures, via a head-to-tail back-splice, and show increased stability and resistance to exonuclease decay, compared to the linear RNA molecules [6] Their length varies from hundreds to thousands of nucleotides [7] and they have a wide expression pattern [8]. In 2000, six hallmarks of cancer, which the progressive conversion of normal cells into malignant ones was attributed to, were proposed These hallmarks could be categorized as self-sufficiency in growth signals, evasion of antigrowth signals, resistance to cell death, limitless replication potential, sustained angiogenesis, tissue invasion, and metastasis [18]. This review aims to shed light on the current knowledge regarding the implication of circRNAs in the development of CRC, including proliferation, invasion, metastasis, and treatment resistance, and to present circRNAs which could ideally act as biomarkers and/or therapeutic targets
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