Oncogenic Functions and Clinical Significance of Circular RNAs in Colorectal Cancer.
TL;DR: In this paper, the authors presented circular RNAs (circRNAs) with their unique features as potential prognostic and diagnostic biomarkers in colorectal cancer and highlighted the mechanism of action and the role of circRNAs with oncogenic functions in the CRC as well as the association between their expression and clinicopathological characteristics of CRC patients.
Abstract: Colorectal cancer (CRC) is ranked as the second most commonly diagnosed disease in females and the third in males worldwide. Therefore, the finding of new more reliable biomarkers for early diagnosis, for prediction of metastasis, and resistance to conventional therapies is an important challenge in overcoming the disease. The current review presents circular RNAs (circRNAs) with their unique features as potential prognostic and diagnostic biomarkers in CRC. The review highlights the mechanism of action and the role of circRNAs with oncogenic functions in the CRC as well as the association between their expression and clinicopathological characteristics of CRC patients. The comprehension of the role of oncogenic circRNAs in CRC pathogenesis is growing rapidly and the next step is using them as suitable new drug targets in the personalized treatment of CRC patients.
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TL;DR: This review summarizes the biological and carcinogenic functions of circRNAs and their related PI3K/AKT, MAPK, Notch, JAK/STAT, Hippo/YAP, WNT/β-catenin, and VEGF signaling pathways in CRC.
Abstract: Colorectal cancer (CRC) is the leading malignant tumor in terms of morbidity and mortality worldwide, and its pathogenesis involves multiple factors, including environment, lifestyle, and genetics. Continuing evidence suggests that circular RNAs (circRNAs), as a novel non-coding RNA, constitute an important genetic variable in the pathogenesis of CRC. These circRNAs with covalently closed-loop structures exist objectively in organisms. They not only have the biological functions of regulating the expression of target genes, changing the activity of proteins, and translating proteins, but also play a key role in the proliferation, invasion, migration, and apoptosis of tumor cells. CRC is one of the most common cancers in which circRNAs are involved in tumorigenesis, metastasis, and drug resistance, and circRNAs have been demonstrated to function through crosstalk with multiple signaling pathways. Therefore, this review summarizes the biological and carcinogenic functions of circRNAs and their related PI3K/AKT, MAPK, Notch, JAK/STAT, Hippo/YAP, WNT/β-catenin, and VEGF signaling pathways in CRC. We further explore the clinical value of circRNAs and important signaling proteins in the diagnosis, prognosis, and treatment of CRC.
6 citations
TL;DR: In this article , the authors described the ubiquitinome of colorectal cancer cells and identified abnormal ubiquitination(s) potentially affecting the patient survival, thereby offering new probable opportunities for clinical treatment.
Abstract: Abstract Background According to the Global Cancer Statistics in 2020, the incidence and mortality of colorectal cancer (CRC) rank third and second among all tumors. The disturbance of ubiquitination plays an important role in the initiation and development of CRC, but the ubiquitinome of CRC cells and the survival-relevant ubiquitination are poorly understood. Methods The ubiquitinome of CRC patients (n = 6) was characterized using our own data sets of proteomic and ubiquitin-proteomic examinations. Then, the probable survival-relevant ubiquitination was searched based on the analyses of data sets from public databases. Results For the ubiquitinomic examination, we identified 1690 quantifiable sites and 870 quantifiable proteins. We found that the highly-ubiquitinated proteins (n ≥ 10) were specifically involved in the biological processes such as G-protein coupling, glycoprotein coupling, and antigen presentation. Also, we depicted five motif sequences frequently recognized by ubiquitin. Subsequently, we revealed that the ubiquitination content of 1172 proteins were up-regulated and 1700 proteins were down-regulated in CRC cells versus normal adjacent cells. We demonstrated that the differentially ubiquitinated proteins were relevant to the pathways including metabolism, immune regulation, and telomere maintenance. Then, integrated with the proteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 98), we revealed that the increased ubiquitination of FOCAD at Lys583 and Lys587 was potentially associated with patient survival. Finally, we depicted the mutation map of FOCAD and elucidated its potential functions on RNA localization and translation in CRC. Conclusions The findings of this study described the ubiquitinome of CRC cells and identified abnormal ubiquitination(s) potentially affecting the patient survival, thereby offering new probable opportunities for clinical treatment.
2 citations
TL;DR: The importance of exosomes as biomarkers in the diagnosis of CRC, as well as their use in the treatment of CRC metastasis, chemoresistance, and recrudescence are discussed.
Abstract: Colorectal cancer (CRC) is a common cancer that is one of the leading causes of cancer-related deaths around the world. The creation of new biomarkers for this disease is an important public health strategy for lowering the disease's mortality rate. According to new research, exosomes may be important sources of biomarkers in CRC. Exosomes are nanometer-sized membrane vesicles (30-200 nm) secreted by normal and cancer cells that transport RNA and proteins between cells and are thought to help with intercellular communication. Exosomes have been linked to CRC initiation and progression, and some differentially expressed RNAs and proteins in exosomes have been identified as potential cancer detection candidates. As a result, studying the relationship between exosomes and CRC may aid in the development of new biomarkers for the disease. This article discusses the importance of exosomes as biomarkers in the diagnosis of CRC, as well as their use in the treatment of CRC metastasis, chemoresistance, and recrudescence. We discuss the benefits and drawbacks of using exosomes as tumour markers, as well as the benefits and drawbacks of using exosomes as tumour markers.
27 Apr 2023
TL;DR: In this article , the authors present some common methods and biomarkers for early detection and diagnosis of colorectal cancer, they hope this review will encourage the adoption of screening programs and the clinical use of these potential molecules as biomarkers.
Abstract: Colorectal cancer (CRC) is one of the most common digestive diseases worldwide. It has steadily ascended to the top three cancers in terms of incidence and mortality. The primary cause is the inability to diagnose it at an early stage. Therefore, early detection and diagnosis are essential for colorectal cancer prevention. Although there are now various methods for CRC early detection, in addition to recent developments in surgical and multimodal therapy, the poor prognosis and late detection of CRC still remain significant. Thus, it is important to investigate novel technologies and biomarkers to improve the sensitization and specification of CRC diagnosis. Here, we present some common methods and biomarkers for early detection and diagnosis of CRC, we hope this review will encourage the adoption of screening programs and the clinical use of these potential molecules as biomarkers for CRC early detection and prognosis.
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TL;DR: This study serves as the first functional analysis of a naturally expressed circular RNA, ciRS-7, which contains more than 70 selectively conserved miRNA target sites, and is highly and widely associated with Argonaute proteins in a miR-7-dependent manner.
Abstract: 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.
5,885 citations
TL;DR: It is proposed that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer.
5,334 citations
TL;DR: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
Abstract: PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The imp...
3,738 citations
TL;DR: High-throughput sequencing of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease showed that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
Abstract: Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
3,310 citations
TL;DR: Evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences is provided and it is demonstrated that circularization and splicing compete against each other.
2,225 citations