• Cancer
• Cell growth
• Mutated in colorectal cancer (MCC)
• NF-kB
• WNT signaling

• Humans
• Carcinogenesis/metabolism
• Carcinogenesis/genetics
• Signal Transduction
• Wnt Signaling Pathway
• Animals
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology

• Crosstalk
• Frequency preference
• Out-of-equilibrium
• ceRNA
• miRNA

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Gene Expression Regulation
• Humans
• Gene Regulatory Networks
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Models, Genetic
• RNA, Competitive Endogenous

• Colorectal cancer
• MIR17HG
• Non-coding RNA
• miR-17-92a-1 cluster host gene
• miRNA

• Humans
• Cell Proliferation
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Disease Progression
• Gene Expression Regulation, Neoplastic
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Multigene Family
• RNA, Long Noncoding/genetics

• colorectal cancer
• diagnostic marker
• gene regulation
• miR-17-92 cluster
• prognostic marker
• signaling pathway

• Cancer stem cells
• Colon cancer
• Targeted therapy
• Theranostic
• miRNA

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Colonic Neoplasms/pathology
• Neoplastic Stem Cells/pathology
• Signal Transduction/genetics
• Gene Expression Regulation, Neoplastic
• Tumor Microenvironment

• Departmental grants Chettinad Academy of Research and Education
• 190963 Department of Science and Technology

• Cancer
• Metastasis colorectal cancer
• Oncogenes
• miRNAs

• Humans
• MicroRNAs/genetics
• Colonic Neoplasms/genetics
• Rectal Neoplasms
• Apoptosis
• Cell Cycle

• Brain region specificity
• Methamphetamine (METH)
• Methamphetamine-related psychiatric disorders
• Neurotoxicity
• Non-coding RNA (ncRNA)

• Humans
• Methamphetamine/toxicity
• Amphetamine
• MicroRNAs/metabolism
• Neurotoxicity Syndromes/genetics
• Behavior, Addictive

• 2021A1515110414 Natural Science Foundation of Guangdong Province
• 2021A1515010909 Natural Science Foundation of Guangdong Province
• 2021M701609 Postdoctoral Research Foundation of China
• B2022019 Medical Science and Technology Foundation of Guangdong Province
• 82271536 National Natural Science Foundation of China
• 82271930 National Natural Science Foundation of China

• E2F4
• miR17-5p
• nucleolar protein 14
• pancreatic cancer
• subcellular localization

• Humans
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Cell Line, Tumor
• Pancreatic Neoplasms/pathology
• MicroRNAs/genetics
• Cell Proliferation/genetics
• Gene Expression Regulation, Neoplastic
• E2F4 Transcription Factor/genetics
• E2F4 Transcription Factor/metabolism

• EMT
• biomarker
• gastrointestinal tumors
• metastasis
• miRNA
• nutraceuticals
• tumor cell migration
• tumor microenvironment

• PNC0000001 Ministero della Salute, Piano Nazionale Complementare "D3 4 Health - Digital Driven Diagnostics, prognostics and therapeutics for sustainable Health care.
• RM12117A7F986146 Progetto Ateneo Sapienza 2021
• E85F22000060006 Ministero dell'Università e della Ricerca, PRIN 2020

• Carcinogenesis
• Cell Plasticity
• Humans
• Inflammation
• Neoplasms/genetics
• Neoplasms/pathology
• Tumor Microenvironment/physiology

Colorectal cancer (CRC) is becoming increasingly prevalent worldwide. Fluoropyrimidine drugs are the primary chemotherapy regimens in routine clinical practice of CRC. However, the survival rate of patients on fluoropyrimidine-based chemotherapy varies significantly among individuals. Biomarkers of fluoropyrimidine drugs'' efficacy are needed to implement personalized medicine. This review summarized fluoropyrimidine drug-related microRNA (miRNA) by affecting metabolic enzymes or showing the relevance of drug efficacy. We first outlined 42 miRNAs that may affect the metabolism of fluoropyrimidine drugs. Subsequently, we filtered another 41 miRNAs related to the efficacy of fluoropyrimidine drugs based on clinical trials. Bioinformatics analysis showed that most well-established miRNA biomarkers were significantly enriched in the cancer pathways instead of the fluoropyrimidine drug metabolism pathways. The result also suggests that the miRNAs screened from metastasis patients have a more critical role in cancer development than those from non-metastasis patients. There are five miRNAs shared between these two lists. The miR-21, miR-215, and miR-218 can suppress fluoropyrimidine drugs'' catabolism. The miR-326 and miR-328 can reduce the efflux of fluoropyrimidine drugs. These five miRNAs could jointly act by increasing intracellular levels of fluoropyrimidine drugs'' cytotoxic metabolites, leading to better chemotherapy responses. In conclusion, we demonstrated that the dynamic changes in the transcriptional regulation via miRNAs might play significant roles in the efficacy and toxicity of the fluoropyrimidine drug. The reported miRNA biomarkers would help evaluate the efficacy of fluoropyrimidine drug-based chemotherapy and improve the prognosis of colorectal cancer patients.

Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2^pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2^pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2^pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2^pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.

• Canadian Institutes of Health Research

The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.

• ceRNA
• circRNA
• colorectal cancer
• lncRNA
• miRNA
• noninvasive biomarkers
• sponging

• Animals
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy
• Gene Regulatory Networks
• Mammals/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Long Noncoding/genetics
• RNA, Messenger/genetics

• SOX4
• apoptosis
• colorectal cancer
• cylindromatosis
• drug tolerance
• microRNA-17
• proliferation

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Deubiquitinating Enzyme CYLD/biosynthesis
• Deubiquitinating Enzyme CYLD/genetics
• Down-Regulation
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics
• SOXC Transcription Factors/genetics
• SOXC Transcription Factors/metabolism
• Transcriptional Activation
• Mice

• JYTQN2020023 & JYTQN2020028 Scientific Research Fund of the Education Department of Liaoning Province

• cancer models
• cancer stem cells
• cell biology

• Adenoma/genetics
• Adenoma/mortality
• Adenoma/pathology
• Animals
• Apoptosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Disease Progression
• Female
• Humans
• Male
• Mice
• Survival Analysis
• bcl-X Protein/genetics

• 21139 Cancer Research UK
• KWF Kankerbestrijding (Dutch Cancer Society)
• Oncode Institute
• Cancer Research UK (CRUK)
• RJ was also funded by a Marie Sklodowska Curie Actions Individual Fellowship, 659666
• JPM was also funded by the Oncode Institute.

ATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients.

New treatments for gastric cancer could involve controlling the activity of a regulatory gene and associated signaling pathway. Over-activation of the Wnt signaling pathway, which regulates many cellular functions, occurs in around half of gastric cancers. Further, the activating transcription factor 3 gene (ATF3) is thought to influence tumorigenesis, although its role in gastric cancer is unclear. Guohua Xie and co-workers at Shanghai Jiao Tong University, China, explored the function of ATF3 in human gastric cancer tissues. Patients with low ATF3 expression had poorer prognosis and shorter life expectancy. The team discovered that reduced expression of ATF3 triggered the increased expression of two of its target genes, which then altered Wnt signaling. Reduced ATF3 expression also boosted the invasiveness of gastric cancer cells. Initial results suggest that overexpression of ATF3 could suppress gastric cancer progression.

• bioanalysis
• diagnosis
• enzymatic confining
• porous materials
• signal enhancement

• Wnt signaling
• cancer management
• colorectal cancer
• mcroRNA

As miRNAs show the capacity to be used as CRC biomarkers, we analysed experimentally validated data about frequently up-regulated miRNA clusters in CRC tissue. We identified 15 clusters that showed increased expression in CRC: miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224. Cluster positions in the genome are intronic or intergenic. Most clusters are regulated by several transcription factors, and by long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. The members of the selected clusters target 181 genes. Their functions and corresponding pathways were revealed with the use of Panther analysis. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research.

Colorectal cancer (CRC) is one of the most common malignancies in Europe and North America. Early diagnosis is a key feature of efficient CRC treatment. As miRNAs can be used as CRC biomarkers, the aim of the present study was to analyse experimentally validated data on frequently up-regulated miRNA clusters in CRC tissue and investigate their members with respect to clinicopathological characteristics of patients. Based on available data, 15 up-regulated clusters, miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224, were selected. The positions of such clusters in the genome can be intronic or intergenic. Most clusters are regulated by several transcription factors, and miRNAs are also sponged by specific long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. Based on experimental evidence, 181 target genes of selected clusters were identified. Panther analysis was used to reveal the functions of the target genes and their corresponding pathways. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research.

• metastases
• miR-17/92a-1
• miR-183/96/182
• oncogenes
• survival
• tumour suppressors

• Colorectal cancer
• Wnt/β-catenin
• distant metastasis
• epithelial-mesenchymal transition (EMT)
• microRNA

• lung adenocarcinoma
• microRNA
• novel microRNA
• oncofetal

• FDN-143345 CIHR
• CRC #225404 Canada Research Chair Program
• #34876 Ontario Research Fund
• NSERC #203475 Natural Sciences Research Council
• CFI #203373, #30865 Canada Foundation for Innovation

MicroRNAs (miRNAs), a class of small non-coding RNAs represent potential biomarkers for colorectal cancer (CRC). The study hypothesized that miRNAs associated with liver metastases may also contribute to assessing treatment response when associated to plasma exosomes. In this study, we used two sets of biological samples, a collection of tumor tissues harvested from patients with CRC with and without liver metastases, and a collection of plasma from CRC patients with and without response to FOLFOX4/FOLFIRI regimens. We investigated 10 target miRNAs in the tissue of 28 CRC patients and identified miR-125b-5p, miR-17-5p, and miR-185-5p to be associated with liver metastasis. Further, we investigated the three miRNAs at the exosomal level in a plasma collection to test their association with chemotherapy response. Our data suggest that the elevated plasma levels of miR-17-5p and miR-185-5p could be predictive of treatment response. Overexpression of miR-17-5p and underexpression of miR-125b-5p and miR-185-5p in CRC tissue seem to be associated with metastatic potential. On the other hand, an increased expression of miR-125b-5p in plasma exosomes was potentially correlated with a more aggressive CRC phenotype.

• biomarkers
• chemotherapy response
• colorectal cancer
• exosomes
• liver metastases
• miR-125b-5p
• miR-17-5p
• miR-185-5p

The TNM staging remains the gold standard for determining the prognosis of patients with colorectal cancer (CRC), which is inadequate at identifying the subset of high-risk stage II and III patients that have a high potential of developing tumor recurrence and may experience death. Emerging evidence indicates that not only microRNAs (miRNAs) play important functional role in CRC development but may serve as important disease biomarkers. In this study we aimed to develop a miRNA-based classifier as a prognostic signature for improving the clinical outcome of patients with stage II/III CRC.

We performed a systematic and comprehensive discovery step to identify differentially expressed miRNAs in CRC. We subsequently determined the prognostic relevance of these miRNAs in stage II/III patients using qRT-PCR and developed a miRNA-based classifier for predicting disease-free survival (DFS) in a clinical cohort (n=186).

Based upon miRNA expression profiling studies, we identified a panel of 10 miRNAs which are consistently differentially expressed in CRC vs. normal tissues. By using cox proportional hazard models, we then developed 6-miRNA-classifier (miR-183, -20a, -21, -195, -139 and -20a) to predict prognosis in clinical cohort, that had significantly superior predictive performance compared to other clinicopathological factors, and could successfully identify high-risk stage II and III CRC patients with poor prognosis [hazard ratio (HR) =2.16; P=0.0048]. In a multivariate analysis, this miRNA-based classifier emerged as an independent prognostic signature for poor DFS.

Our miRNA-based classifier is a reliable predictive tool for determining prognosis in patents with stage II/III CRC, and might be able to identify high-risk patients that are candidates for more targeted personalized clinical management and surveillance.

• MicroRNA (miRNA)
• biomarker
• colorectal cancer (CRC)
• prognosis

MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.

• biomarker(s)
• cancer stem cell genes (CSCs)
• colorectal cancer (CRC)
• miRNA-17-92a cluster
• miRNA-23b-27b-24 cluster
• microRNAs (miRNAs)
• tumor heterogeneity

• Circulatory miRNAs
• Colorectal cancer
• Drug resistance
• miRNA
• miRNA dysregulation

• cell migration
• epithelial–mesenchymal transition
• metastasis
• miRNA
• oncomiR
• tumor invasiveness
• tumor suppressor miR

• Cancer
• Meta-analysis
• Radioresistance
• Systematic review
• miRNAs

• biomarkers
• colorectal cancer
• diabetes mellitus
• glucose
• insulin
• microRNA

• MicroRNAs
• bioengineered non-coding RNA agent
• biogenesis
• cancer
• chemo-sensitization
• delivery systems
• oncomirs

• Cancer-associated fibroblasts
• Colorectal cancer
• Exosomes
• miR-17-5p

• Adult
• Aged
• Animals
• Cancer-Associated Fibroblasts/physiology
• Cell Line, Tumor
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/pathology
• Core Binding Factor Alpha 3 Subunit/physiology
• Exosomes/physiology
• Feedback, Physiological
• Female
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• MicroRNAs/physiology
• Middle Aged
• Phenotype
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc/physiology
• Signal Transduction
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/physiology
• Tumor Microenvironment

Purpose: Dysregulation of microRNAs (miRNAs) contributes to tumor progression via the regulation of the expression of specific oncogenes and tumor suppressor genes. One such example, miR-27b-3p, has reportedly been involved in tumor progression in many types of cancer. The aim of the present study was to delve into the role and the underlying mechanism of miR-27b-3p in colorectal cancer (CRC) cells. Methods: In the present study, we detected the expression level of miR-27b-3p by RT-PCR. The effect of miR-27b-3p overexpression on cell proliferation in CRC cells was evaluated by cell counting and Edu assays. Transwell migration and invasion assays were used to examine the effects of cell migration and invasion. Bioinformatics, luciferase reporter assay and western blot assay were performed to identify the target of miR-27b-3p. Results: Here, we have demonstrated that although miR-27b-3p can affect cell morphology, it has no observable effect on the proliferation of CRC cells. However, it significantly promotes the migration and invasion of CRC cells. We discovered that HOXA10 was a newly identified target of miR-27b-3p in CRC cells, as confirmed by bioinformatics, western blots and dual luciferase reporter assay. Furthermore, the overexpression of miR-27b-3p or the suppression of HOXA10 can activate the integrin β1 signaling pathway. In conclusion, our results reveal a new function of miR-27b-3p that demonstrates its ability to promote CRC cell migration and invasion by targeting the HOXA10/integrin β1 cell signal axis. Conclusion: This may provide a mechanism to explain why miR-27b-3p promotes CRC cell migration and invasion.

• HOXA10
• colorectal cancer
• invasion
• miR-27b-3p
• migration

Osteoarthritis (OA) is a degenerative disease characterized by cartilage destruction. Previous research has demonstrated that long non-coding RNAs serve a role in OA progression. The current study aimed to determine the function and mechanism of taurine upregulated gene (TUG) 1 in OA. The results of reverse transcription quantitative PCR revealed that TUG1 was elevated in OA cartilage tissues and interleukin (IL)-1β-induced chondrocytes. Cell Counting kit-8 and flow cytometry analysis revealed that TUG1 knockdown promoted cell viability and inhibited cell apoptosis. Furthermore, matrix metalloprotein (MMP) 13, collagen II and aggrecan expression was determined by western blotting, of which the results demonstrated that TUG1 knockdown significantly decreased MMP13 expression and increased collagen II and aggrecan expression in IL-1β-stimulated chondrocytes, indicating that extracellular matrix (ECM) damage was inhibited. Additionally, using bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation assays, TUG1 was revealed to upregulate fucosyltransferase (FUT) 1 by targeting miR-17-5p. Furthermore, miR-17-5p was downregulated and FUT1 upregulated in OA cartilage tissues and IL-1β-induced chondrocytes. TUG1 overexpression reversed the aforementioned effects on cell viability, cell apoptosis and ECM degradation mediated by miR-17-5p in IL-1β-activated chondrocytes. Additionally, the effects of FUT1 knockdown on cell viability, apoptosis and ECM degradation mediated by FUT1 knockdown were reversed by miR-17-5p inhibition. In conclusion, TUG1 knockdown inhibited OA progression by downregulating FUT1 via miR-17-5p.

• extracellular matrix
• fucosyltransferase 1
• microRNA-17-5p
• osteoarthritis
• taurine upregulated gene 1

Palliative systemic therapy is currently standard of care for patients with extensive metastatic colorectal cancer (mCRC). A biomarker predicting chemotherapy benefit which prevents toxicity from ineffective treatment is urgently needed. Therefore, a previously developed tissue‐derived microRNA profile to predict clinical benefit from chemotherapy was evaluated in tissue biopsies and serum from patients with mCRC.

Samples were prospectively collected from patients (N = 132) who were treated with capecitabine or 5‐FU/LV with oxaliplatin ± bevacizumab. Response evaluation was performed according to RECIST 1.1 after three or four cycles, respectively. Baseline tissue and serum miRNAs expression levels of miR‐17‐5p, miR‐20a‐5p, miR‐30a‐5p, miR‐92a‐3p, miR‐92b‐3p, and miR‐98‐5p were quantified with RT‐qPCR and droplet digital PCR, respectively. Combined predictive performance of selected variables was tested using logistic regression analysis.

From 132 patients, 81 fresh frozen tissue biopsies from metastases and 93 serum samples were available. Based on expression levels of miRNAs in tissue, progressive disease could be predicted with an AUC of 0.85 (95% CI:0.72‐0.91) and response could be predicted with an AUC of 0.70 (95% CI:0.56‐0.80). This did not outperform clinical parameters alone (respectively P = .14 and P = .27). Expression levels of miR‐92a‐3p and miR‐98‐5p in serum significantly improved the predictive value of clinical parameters for response to chemotherapy (AUC 0.74, 95% CI:0.64‐0.84, P = .003) in this cohort.

The additive predictive value to clinical parameters of the tissue‐derived six miRNA profile for clinical benefit could not be validated in patients with mCRC treated with first‐line systemic therapy. Although miR‐92a‐3p and miR‐98‐5p serum levels improved the predictive value of clinical parameters, it remained insufficient for clinical decision‐making.

• chemotherapy
• colorectal cancer
• metastases
• miRNA
• response prediction
• serum

Colorectal cancer (CRC) is a common malignant tumor with a poor prognosis. However, its pathogenesis has not been fully elucidated, accounting for poor overall survival. Circular RNA (circRNA) is a class of noncoding RNAs discovered many years ago. Only recently have they been re-evaluated for their important roles in the regulation of gene expression. Studies have confirmed that circRNAs have important biological functions in a variety of malignant tumors. This study aimed to characterize one circRNA derived from the MBOAT2 gene and termed it circMBOAT2, which has been reported to promote prostate cancer progression. CircMBOAT2 is highly expressed in both CRC tissues and serum samples, and has a correlation with tumor stage. The receiver-operating characteristic curves suggested that circMBOAT2 acted as a novel diagnostic tumor marker in CRC. Univariate and multivariate analyses showed that the levels of circMBOAT2 in tissues were independent prognostic markers of CRC. Further functional studies revealed that circMBOAT2 served as a microRNA (miRNA) sponge of miR-519d-3p and promoted the proliferation, migration, and invasion of CRC cells. Also, circMBOAT2 regulated cell proliferation and migration by competitively binding to miR-519d-3p and targeting troponin-associated protein (TROAP) in CRC cells. These results suggested that circMBOAT2 might be a novel potential biomarker of CRC.

Colorectal cancer (CRC) is the third leading cause of cancer death in the world, and its incidence is rising in developing countries. Treatment with 5-Fluorouracil (5-FU) is known to improve survival in CRC patients. Most anti-cancer therapies trigger apoptosis induction to eliminate malignant cells. However, de-regulated apoptotic signaling allows cancer cells to escape this signaling, leading to therapeutic resistance. Treatment resistance is a major challenge in the development of effective therapies. The microRNAs (miRNAs) play important roles in CRC treatment resistance and CRC progression and apoptosis. This review discusses the role of miRNAs in contributing to the promotion or inhibition of apoptosis in CRC and the role of miRNAs in modulating treatment resistance in CRC cells.

• apoptosis
• colorectal cancer
• microRNA
• resistance

• Apoptosis
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Drug Resistance, Neoplasm
• Fluorouracil/therapeutic use
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Neoplasm/genetics
• RNA, Neoplasm/metabolism
• Signal Transduction

• Inflammation
• colorectal cancer
• inflammatory cytokine
• intestine
• lncRNA
• miRNA
• non-coding RNA
• tumorigenesis

• Adenocarcinoma/pathology
• Adenoma/pathology
• Animals
• Carcinogenesis/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Disease Progression
• Gene Expression Regulation, Neoplastic/physiology
• Humans
• Mice
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology

• Colorectal cancer (CRC)
• invasion
• microRNA-497-5p (miR-497-5p)
• proliferation
• protein tyrosine phosphatase non-receptor type 3 (PTPN3)

• carcinogenesis
• colorectal cancer (CRC)
• invasion
• proliferation
• ubiquitous mitochondrial creatine kinase (uMtCK)

• Scientific Research and Technology Development Program of Guangxi

• cancer stem cells
• colorectal cancer
• miRNAs
• regulatory mechanisms

Purpose: There is mounting evidence to indicate that microRNA-17 (miR-17) is expressed and functionally involved in human cancers. However, the molecular mechanism underlying the role of miR-17 in colorectal cancer (CRC) remains largely unclear. This study aims to reveal the biological function of miR-17 in colorectal cancer.

Materials and methods: The expression of miR-17 in CRC cells and tissues was examined using qRT-PCR. Cell proliferation and migration assays were performed after transfection with an miR-17 mimic and inhibitors. The potential gene targets of miR-17 were predicted by bioinformatics analysis and further validated by PCR, Western blot and dual luciferase reporter assays.

Results: The expression of miR-17 was significantly upregulated in CRC cell lines and tissues and may imply poor prognosis. miR-17 upregulation promoted cell invasion and migration in CRC cell lines in vitro, while downregulation of miR-17 inhibited tumor progression. SIK1 was identified as a potential direct target of miR-17 by dual luciferase reporter assay, and its downregulation in CRC may suggest poor prognosis.

Conclusions: Our study indicated that upregulated miR-17 may promote the progression of CRC and may exert its function as a tumor suppressor miRNA by targeting SIK1.

• SIK1
• colorectal cancer
• prognosis
• tumor biomarker

In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo.

The potential clinical relevance of miR-338-5p and its target gene was analysed on benign colorectal polyps and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis.

PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumour staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumours. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumours. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration and invasion induced by miR-338-5p.

MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients.

NCKU Hospital, Taiwan, Ministry of Science and Technology, Taiwan.

• Autophagy and colorectal cancer
• PIK3C3
• miR-338-5p

• 3' Untranslated Regions
• Animals
• Autophagy/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Class I Phosphatidylinositol 3-Kinases/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• MicroRNAs/genetics
• Neoplasm Metastasis
• Neoplasm Staging
• RNA Interference
• Signal Transduction
• Xenograft Model Antitumor Assays