• Biomarker
• CircRNA
• Drug Resistance
• Hallmarks of Cancer
• Tumor Therapy

• Humans
• RNA, Circular/genetics
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/therapy
• Neoplasms/diagnosis
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Animals

• ARHGEF10L
• acute myeloid leukemia
• cell proliferation
• circFN1
• miR-1294

• Humans
• MicroRNAs/metabolism
• Leukemia, Myeloid, Acute/genetics
• HL-60 Cells
• Apoptosis/genetics
• Cell Proliferation/genetics
• Cell Line, Tumor
• Rho Guanine Nucleotide Exchange Factors/genetics

• Biotechnological drugs
• Gastric cancer
• RNA binding protein
• Translational template
• circRNA
• miRNA sponge

• Humans
• RNA, Circular/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/therapy
• Stomach Neoplasms/diagnosis
• Prognosis
• Carcinogenesis/genetics
• Cell Transformation, Neoplastic

• 22SXQT0001 Science and Technology Support Program of Nanchong
• 2023GC009 Scientific research foundation for advanced talents, Affiliated hospital of North Sichuan Medical College
• Q23047 Youth medical innovation research project of Sichuan province
• Science and Technology Support Program of Nanchong

• Apoptosis
• chemoresistance
• epithelial-mesenchymal transition
• gastrointestinal cancer
• personalized therapy

• Humans
• RNA, Untranslated/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Colorectal Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Biomarkers
• Epithelial-Mesenchymal Transition/genetics
• Apoptosis/genetics

• Cancer
• circRNA
• lncRNA
• miRNA
• ncRNA

• 202150063473 the Hengyang City Science and Technology Planning Project
• 202202044140 the Scientific Research Project of Hunan Provincial Health Commission
• 21B0438 the Scientific Research Project of Hunan Provincial Education Department

• Cancer
• MicroRNA-182
• Signaling pathways

• NLRP3
• Pyroptosis
• Stat5
• breast cancer
• miR-182

• Humans
• Female
• MicroRNAs/genetics
• MicroRNAs/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Pyroptosis
• STAT5 Transcription Factor/genetics
• STAT5 Transcription Factor/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Drug Resistance, Neoplasm

• Drug resistance
• Gastrointestinal cancers
• circRNAs

• Humans
• RNA, Circular/genetics
• RNA/genetics
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/genetics
• RNA, Untranslated
• Esophageal Neoplasms

• biogenesis
• circular RNA
• drug resistance
• gastric cancer
• therapeutic target

Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis, primarily caused by metastatic lesions. Improved understanding of GC metastasis at the molecular level yields meaningful insights into potential biomarkers and therapeutic targets. Covalently closed circular RNAs (circRNAs) have emerged as crucial regulators in diverse human cancers including GC. Furthermore, accumulating evidence has demonstrated that circRNAs exhibit the dysregulated patterns in GC and have emerged as crucial regulators in GC invasion and metastasis. However, systematic knowledge regarding the involvement of circRNAs in metastatic GC remains obscure. In this review, we outline the functional circRNAs related to GC metastasis and drug resistance and discuss their underlying mechanisms, providing a comprehensive delineation of circRNA functions on metastatic GC and shedding new light on future therapeutic interventions for GC metastases.

At present, there are still no effective diagnosis methods for gastric cancer (GC). Increasing evidences indicate that Extracellular Vesicle circular RNAs (EV circRNAs) play a crucial role in several diseases. However, their correlations with GC are not clarified. This study aims to investigate the expression profile of serum EV circRNAs in GC and evaluate its potential clinical value.

High-throughput RNA sequencing (RNA-seq) was used to assess circRNA expression profiles between 4 patients with GC and 4 healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed (DE) circRNAs. A circRNA-miRNA-mRNA network was constructed using bioinformatics tools. Reverse transcription-quantitative polymerase chain reaction (RT-q)PCR was used to validate the dysregulated circRNAs. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of circRNAs for GC.

A total of 4692 circRNAs were detected in the serum EVs of healthy controls and patients with GC, most of which were novel (98%) and intergenic (52%). 7 circRNAs were upregulated and 4 circRNAs were downregulated (|log₂Fold Change| > 2, P < 0.05). GO and KEGG pathway enrichment analyses revealed that DE circRNAs were primarily involved in glutathione metabolism, protein folding, and drug metabolism-cytochrome P450. Of these, 3 circRNAs (Chr10q11, Chr1p11, and Chr7q11) were identified to be significantly overexpressed in patients with GC compared with healthy controls using RT-qPCR. The combination of 3 EV circRNAs and carcinoembryonic antigen (CEA) produced an area under the curve (AUC) of 0.866 (95%CI: 0.803-0.915) with a sensitivity and specificity of 80.4% and 81.8%, respectively. Additionally, the expression levels of 3 EV circRNAs were significantly correlated with tumor size, lymph node metastasis, and TNM stage. The circRNA-miRNA-mRNA network showed that the 3 identified circRNAs were predicted to interact with 13 miRNAs and 91 mRNAs.

Our results illustrate that the panel of EV circRNAs in serum are aberrantly expressed and may act as the suitable biomarkers for gastric cancer.

• National Natural Science Foundation of China

• Cisplatin
• Combination therapy
• Liver cancer
• Nanog siRNA

Cisplatin (DDP) is a well-known anticancer drug used for the treatment of numerous human cancers in solid organs, including bladder, breast, cervical, head and neck squamous cell, ovarian, among others. Its most important mode of action is the DNA-platinum adducts formation, inducing DNA damage response, silencing or activating several genes to induce apoptosis; these mechanisms result in genetics and epigenetics modifications. The ability of DDP to induce tumor cell death is often challenged by the presence of anti-apoptotic regulators, leading to chemoresistance, wherein many patients who have or will develop DDP-resistance. Cancer cells resist the apoptotic effect of chemotherapy, being a problem that severely restricts the successful results of treatment for many human cancers. In the last 30 years, researchers have discovered there are several types of RNAs, and among the most important are non-coding RNAs (ncRNAs), a class of RNAs that are not involved in protein production, but they are implicated in gene expression regulation, and representing the 98% of the human genome non-translated. Some ncRNAs of great interest are long ncRNAs, circular RNAs, and microRNAs (miRs). Accumulating studies reveal that aberrant miRs expression can affect the development of chemotherapy drug resistance, by modulating the expression of relevant target proteins. Thus, identifying molecular mechanisms underlying chemoresistance development is fundamental for setting strategies to improve the prognosis of patients with different types of cancer. Therefore, this review aimed to identify and summarize miRs that modulate chemoresistance in DDP-resistant in the top five deadliest cancer, both in vitro and in vivo human models.

• cancer
• cisplatin
• drug-resistance
• microRNA
• sensitivity

Although long non coding RNAs (lncRNAs) and circular RNAs (circRNAs) play important roles in the pathogenesis of diseases, endometriosis related lncRNAs and circRNAs are still rarely reported. This study focused on the potential molecular mechanism of endometriosis related competitive endogenous RNA (ceRNA) composed of lncRNAs and circRNAs. We performed high-throughout sequencing of six normal endometria, six eutopic endometria and six ectopic endometria for the first time to describe and analyze the expression profile of lncRNA, circRNA and mRNA. Our results showed that 140 lncRNAs, 107 circRNAs and 1,206 mRNAs were differentially expressed in the ectopic group, compared with the normal and eutopic groups. We established an lncRNA/circRNA-mRNA co-expression network using pearson correlation test. Meanwhile, the results of Gene set enrichment analysis analysis showed that the 569 up-regulated differentially expressed mRNA (DEmRNA) were mainly related to the epithelial-mesenchymal transition, regulation of immune system process and immune effector process. Subsequently, we established a DElncRNA-miRNA and DEcircRNA-miRNA network using the starbase database, identified the common miRNAs and constructed DElncRNA/DEcircRNA-miRNA pairs. miRDB, Targetscan, miRwalk and circRNA/lncRNA-mRNA pairs jointly determined the miRNA-mRNA portion of the circRNA/lncRNA-miRNA-mRNA co-expression network. RT-qPCR results of 15 control samples and 25 ectopic samples confirmed that circGLIS2, circFN1, LINC02381, IGFL2-AS1, CD84, LYPD1 and FAM163A were significantly overexpressed in ectopic tissues. In conclusion, this is the first study to illustrate ceRNA composed of differentially expressed circRNA, lncRNA and mRNA in endometriosis. We also found that lncRNA and circRNA exerted a pivotal function on the pathogenesis of endometriosis, which can provide new insights for further exploring the pathogenesis of endometriosis and identifying new targets.

Circular RNAs (circRNAs) are associated with cisplatin resistance in gastric cancer (GC). This study aims to explore the role of circRNA AKT serine/threonine kinase 3 (circ_AKT3) in the resistance of GC to cisplatin.

42 sensitive and 23 resistant GC patients were recruited for tissue collection. The cisplatin-resistant GC cells MKN-7/DDP and HGC-27/DDP were used for in vitro study. circ_AKT3, microRNA-206 (miR-206) and protein tyrosine phosphatase non-receptor type 14 (PTPN14) levels were detected via quantitative reverse transcription real-time PCR (qPCR) and Western blot. Cisplatin resistance was assessed by detecting P-glycoprotein (P-gp) level, half maximal inhibitory concentration (IC₅₀) of cisplatin and cell apoptosis. The target relationship between miR-206 and circ_AKT3 or PTPN14 was analyzed via dual-luciferase reporter and RNA pull-down assays. The role of circ_AKT3 in vivo was assessed using xenograft model.

circ_AKT3 level was increased, but miR-206 was declined in cisplatin-resistant GC tissues and cells. circ_AKT3 knockdown or miR-206 overexpression decreased the level of P-gp and IC₅₀ of cisplatin and increased apoptosis of MKN-7/DDP and HGC-27/DDP cells. Additionally, circ_AKT3 targeted miR-206, and regulated cisplatin resistance by interacting with miR-206. PTPN14 was regulated by circ_AKT3 through miR-206 as a bridge. Also, circ_AKT3 knockdown decreased xenograft tumor growth.

circ_AKT3 knockdown suppressed cisplatin resistance using miR-206/PTPN14 axis in cisplatin-resistant GC cells.

Background: Chemoresistance is a major barrier to the treatment of human cancers. Circular RNAs (circRNAs) are implicated in drug resistance in cancers, including gastric cancer (GC). In this study, we aimed to explore the functions of circRNA Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (circARVCF) in cisplatin (DDP) resistance in GC.

Methods: The expression of circARVCF, microRNA-1205 (miR-1205) and fibroblast growth factor receptor 1 (FGFR1) was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot assay or immunohistochemistry (IHC) assay. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were performed to evaluate DDP resistance and cell colony formation ability. Transwell assay was conducted to assess cell migration and invasion. Flow cytometry analysis was done to analyze cell apoptosis. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were manipulated to analyze the relationships of circARVCF, miR-1205 and FGFR1. Murine xenograft model was constructed to explore DDP resistance in vivo.

Results: CircARVCF level was increased in DDP-resistant GC tissues and cells. CircARVCF silencing inhibited DDP resistance, colony formation and metastasis and induced apoptosis in DDP-resistant GC cells. CircARVCF directly interacted with miR-1205 and miR-1205 inhibition reversed circARVCF silencing-mediated effect on DDP resistance in DDP-resistant GC cells. FGFR1 served as the target gene of miR-1205. MiR-1205 overexpression restrained the resistance of DDP-resistant GC cells to DDP, but FGFR1 elevation abated the effect. In addition, circARVCF knockdown repressed DDP resistance in vivo.

Conclusion: CircARVCF enhanced DDP resistance in GC by elevating FGFR1 through sponging miR-1205.

• DDP
• FGFR1
• GC
• circARVCF
• miR-1205
• resistance

The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally. Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes, their clinical success is limited by drug resistance, treatment failure and recurrence of metastatic disease. Therefore, there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies. Circular RNAs (circRNAs) exhibit a covalently closed structure, high stability and biological conservation, and their expression is associated with the occurrence and development of gastrointestinal tumors. Moreover, circRNAs may significantly influence drug resistance of gastrointestinal cancers. In this article, we review the role of circRNAs in the occurrence and development of gastrointestinal cancer, their association with drug resistance, and potential application for early diagnosis, treatment and prognosis in gastrointestinal malignancies. Furthermore, we summarize characteristics of circRNA, including mechanism of formation and biological effects via mRNA sponging, chromatin replication, gene regulation, translational modification, signal transduction, and damage repair. Finally, we discuss whether circRNA-related noninvasive testing may be clinically provided in the future. This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.

• Gastrointestinal cancer
• Circular RNA
• Drug resistance
• Genomics
• Targeted therapy
• Molecular mechanics

• gastrointestinal cancers
• non-coding RNAs
• response to chemotherapy

Circular RNAs (circRNAs) are a novel class of noncoding RNA molecules with a unique closed continuous loop structure. CircRNAs are abundant in eukaryotic cells, have unique stability and tissue specificity, and can play a biological regulatory role at various levels, such as transcriptional and posttranscriptional levels. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and chemotherapy. Chemotherapy is a primary type of intervention for most cancers, but its therapeutic efficacy is usually retarded by intrinsic and acquired resistance. CircRNAs regulate tumor chemoresistance through various molecular mechanisms, such as affecting apoptosis, promoting drug transportation, promoting DNA repair, promoting epithelial-mesenchymal transformation, regulating the characteristics of tumor stem cells, and affecting autophagy. This review summarizes the recent progress and mechanisms of circRNAs in cancer cell resistance to chemotherapy.

• Circular RNAs
• Competing endogenous RNA
• Chemoresistance
• Digestive system neoplasms

• BIRC5
• Chemoresistance
• LINC00511
• Lung adenocarcinoma
• miR-182

• A549 Cells
• Adenocarcinoma of Lung/drug therapy
• Adenocarcinoma of Lung/genetics
• Animals
• Cell Line, Tumor
• Cisplatin/administration & dosage
• Cisplatin/pharmacology
• Down-Regulation
• Drug Resistance, Neoplasm/drug effects
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Male
• Mice
• MicroRNAs/genetics
• RNA, Long Noncoding/antagonists & inhibitors
• RNA, Long Noncoding/genetics
• RNA, Small Interfering/administration & dosage
• RNA, Small Interfering/pharmacology
• Survivin/genetics
• Up-Regulation/drug effects
• Xenograft Model Antitumor Assays

Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified.

Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient.

Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson’s R = −0.42, p < 2.2e⁻¹⁶). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11–3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways.

Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.

• DNA methylation
• Foxf2
• gastric cancer
• miRNA
• prognosis

• cancer
• circular RNA
• cisplatin resistance
• gene
• non-coding RNA

Gastric cancer (GC) is one of the most common malignant tumors. The mechanism of how GC develops is vague, and therapies are inefficient. The function of microRNAs (miRNAs) in tumorigenesis has attracted the attention from many scientists. During the development of GC, miRNAs function in the regulation of different phenotypes, such as proliferation, apoptosis, invasion and metastasis, drug sensitivity and resistance, and stem-cell-like properties. MiRNAs were evaluated for use in diagnostic and prognostic predictions and exhibited considerable accuracy. Although many problems exist for the application of therapy, current studies showed the antitumor effects of miRNAs. This paper reviews recent advances in miRNA mechanisms in the development of GC and the potential use of miRNAs in the diagnosis and treatment of GC.

• Circular RNA
• cancer
• chemoresistance
• drug resistance

• 81702435 National Natural Science Foundation of China
• 82073133 National Natural Science Foundation of China
• BK20170264 Natural Science Foundation of Jiangsu Province
• BK20191154 Natural Science Foundation of Jiangsu Province
• WSW-050 Six Talent Peaks Project in Jiangsu Province

Gastric cancer (GC) is a prevalent malignancy, leading to a high incidence of cancer-associated death. Cisplatin (DDP)-based chemotherapy is the principal therapy for clinical GC treatment, but DDP resistance is a severe clinical challenge and the mechanism remains poorly understood. Circular RNAs (circRNAs) have been identified to play crucial roles in modulating the chemoresistance of gastric cancer cells.

To explore the effect of circVAPA on chemotherapy resistance during GC progression.

The effect of circVAPA on GC progression and chemotherapy resistance was analyzed by MTT assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry analysis in GC cells and DDP resistant GC cell lines, and tumorigenicity analysis in nude mice in vivo. The mechanism was investigated by luciferase reporter assay, quantitative real-time PCR, and Western blot analysis.

CircVAPA expression was up-regulated in clinical GC tissues compared with normal samples. CircVAPA depletion inhibited proliferation, migration, and invasion and increased apoptosis of GC cells. The expression of circVAPA, STAT3, and STAT3 downstream genes was elevated in DDP resistant SGC7901/DDP cell lines. CircVAPA knockdown attenuated the DDP resistance of GC cells. Mechanically, circVAPA was able to sponge miR-125b-5p, and miR-125b-5p could target STAT3 in the GC cells. MiR-125b-5p inhibitor reversed circVAPA depletion-enhanced inhibitory effect of DDP on GC cells, and STAT3 knockdown blocked circVAPA overexpression-induced proliferation of DDP-treated SGC7901/DDP cells. The depletion of STAT3 and miR-125b-5p inhibitor reversed circVAPA depletion-induced GC cell apoptosis. Functionally, circVAPA contributed to the tumor growth of SGC7901/DDP cells in vivo.

CircVAPA promotes chemotherapy resistance and malignant progression in GC by miR-125b-5p/STAT3 signaling. Our findings present novel insights into the mechanism by which circVAPA regulates chemotherapy resistance of GC cells. CircVAPA and miR-125b-5p may be considered as the potential targets for GC therapy.

• Gastric cancer
• Progression
• Chemoresistance
• CircVAPA
• miR-125b-5p
• STAT3

• Animals
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Mice
• Mice, Nude
• MicroRNAs/genetics
• RNA, Circular
• STAT3 Transcription Factor
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics

Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with decreased functionality. However, recent advances in high-throughput genomic technology have allowed circRNAs to be characterized in detail and revealed their role in controlling various biological and molecular processes, the most essential being gene regulation. Because of the structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA biology. Compared to the linear RNA, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming a covalently closed loop structure missing 3′ poly-(A) tail or 5′ cap, rendering them immune to exonuclease-mediated degradation. Emerging research has identified multifaceted roles of circRNAs as miRNA and RNA binding protein (RBP) sponges and transcription, translation, and splicing event regulators. CircRNAs have been involved in many human illnesses, including cancer and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, due to their aberrant expression in different pathological conditions. The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular mechanisms of circRNAs and their use as potential therapeutic targets in different human malignancies.

• RNA binding protein
• circRNA
• drug resistance
• miRNA sponges
• signaling pathways
• tumor

Gastric cancer (GC) is one of the most common cancers in the world. Due to the lack of specific symptoms, more than 80% of patients are diagnosed as the advanced stage with a high mortality rate, so the early diagnosis of GC is incredibly essential. Circular RNAs (CircRNAs) are a kind of endogenous non-coding RNA with stable structure, the long half-life, and tumor specificity. It can be used as a diagnostic marker for tumors.

Using circRNA sequencing technology screened three pairs of GC and adjacent tissues, and circRNAs with significant expression differences were screened out. The circular structure and characteristics of circPTPN22 were determined by RT-qPCR, agarose gel electrophoresis, Sanger sequencing, RNase R, and actinomycin D assays. Cell Counting Kit‐8, colony formation, Transwell, Wound healing, tumor formation in mice and western blotting assays were used to detect the effects of circPTPN22 on the proliferation, invasion, migration, tumor growth of GC cells in vitro and protein expression.

CircPTPN22 is up-regulated and positively correlated with metastasis in GC tissues, cells, and plasma. RT-qPCR results showed that circPTPN22 had good diagnostic efficacy and could be used to predict the prognosis of GC patients. In vitro and vivo experiments showed that the downregulation of circPTPN22 could inhibit cell proliferation, migration, and invasion through the epithelial-mesenchymal transformation (EMT) pathway. CircPTPN22 may regulate GC progression through the competitive binding of miRNAs.

CircPTPN22 can be used as a potential diagnostic and prognostic marker for GC and can inhibit cell proliferation and metastasis through the competitive binding of miRNA to inhibit the EMT pathway.

• Biomarker
• Diagnosis and prognosis
• Epithelial-mesenchymal transformation
• Gastric cancer
• circPTPN22

• circular RNA
• clinical application
• gastric cancer
• oncogenic or tumor-suppressive role
• regulatory molecular mechanisms

• Humans
• Stomach Neoplasms/genetics
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/metabolism
• RNA, Circular/genetics
• RNA, Circular/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Prognosis
• Gene Expression Regulation, Neoplastic

• 81772641, 81902510 The National Natural Science Foundation of China

Gastric cancer is a prevalent primary stomach tumor. Cisplatin is frequently used to treat gastric cancer. However, the resistance of cisplatin in gastric cancer often occurs, which brings a heavy burden to gastric cancer treatment.

In this study, we revealed a novel underlying mechanism about cisplatin-resistant effect in gastric cancer. A Cell Counting Kit-8 (CCK-8) cell viability assay and a xenograft model were performed to evaluate the function of circRNA in the cisplatin resistance of gastric cancer.

Compared with control groups, we observed that circ_0110805 was highly expressed, the mRNA and protein expression levels of ENDOPDI were dramatically upregulated, and the expression of miR-299-3p was significantly downregulated in gastric cancer cells, cisplatin-resistant gastric cancer tissues or cells. Functionally, circ_0110805 knockdown improved cisplatin sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in AGS/DDP and HGC-27/DDP cells, which was reversed by miR-299-3p inhibitor. Additionally, ENDOPDI overexpression hindered the effects of miR-299-3p on cisplatin sensitivity and gastric cancer progression. Circ_0110805 knockdown enhanced cisplatin sensitivity in vivo. Mechanistically, circ_0110805 acted as a sponge of miR-299-3p and its targeted ENDOPDI.

We showed that circ_0110805 knockdown increased the sensitivity of gastric cancer to cisplatin, which also repressed gastric cancer progression by sponging miR-299-3p to downregulate ENDOPDI expression. It might provide a new insight for future studying cisplatin-resistant gastric cancer.

• ENDOPDI
• circ_0110805
• cisplatin
• gastric cancer
• miR-299-3p
• sensitivity

Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) and can modulate gene expression by binding to miRNAs; further, circRNAs have been shown to participate in several pathological processes. However, the expression and biological function of circCUL2 in gastric cancer (GC) remains largely unknown.

circRNA microarrays and quantitative real-time PCR (qRT-PCR) were used to identify differentially expressed circRNAs in GC tissues and cell lines. circCUL2 knockdown and overexpression were performed to indicate the functional role of circCUL2 in vitro and in vivo. The expression and regulation of circCUL2, miR-142-3p and ROCK2 were evaluated using fluorescence in situ hybridization (FISH), dual-luciferase assays, RNA pull-down assays, RNA immunoprecipitation (RIP) and rescue experiments. Furthermore, the regulation of cisplatin sensitivity and autophagy by circCUL2/miR-142-3p/ROCK2 was demonstrated by cellular apoptosis assays, western blot, immunofluorescence and transmission electron microscopy analyses.

The level of circCUL2, which is stable and cytoplasmically localized, was significantly reduced in GC tissues and cells. Overexpressed circCUL2 inhibited malignant transformation in vitro and tumorigenicity in vivo. In the AGS and SGC-7901 cell lines, circCUL2 sponged miR-142-3p to regulate ROCK2, thus modulating tumor progression. Furthermore, in the AGS/DDP and SGC-7901/DDP cell lines, circCUL2 regulated cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation.

circCUL2 may function as a tumor suppressor and regulator of cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation, which could be a key mechanism and therapeutic target for GC.

Supplementary information accompanies this paper at 10.1186/s12943-020-01270-x.

• Autophagy
• Cisplatin resistance
• Gastric cancer
• ROCK2
• circCUL2
• miR-142-3p

• biomarkers
• cancer
• circRNAs
• diagnostics
• therapeutics

• EMT
• apoptosis regulation
• breast cancer
• chemoresistance
• circRNAs
• colorectal cancer
• epithelial-mesenchymal transition
• gastric cancer
• lung cancer
• prostate cancer
• radioresistance

• CircPRRX1
• Doxorubicin
• Exosome
• Gastric cancer
• MiR-3064-5p
• PTPN14

• Cell Line, Tumor
• Doxorubicin/pharmacology
• Drug Resistance, Neoplasm/genetics
• Exosomes/genetics
• Exosomes/metabolism
• Exosomes/pathology
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Protein Tyrosine Phosphatases, Non-Receptor/metabolism
• Real-Time Polymerase Chain Reaction
• Signal Transduction/genetics
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology

• Cancer
• Circular RNA
• Drug
• Resistance

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor
• Disease Management
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• RNA, Circular/genetics

• National Natural Science Foundation of China
• Key Research and Development plan (Social development) of science and technology department of Jiangsu Province
• the Medical Innovation Team Foundation of the Jiangsu Provincial Enhancement Health Project
• Project 789 of Excellent Talent Training Program of The Second Affiliated Hospital of Nanjing Medical University

Targeted treatment, which can specifically kill tumour cells without affecting normal cells, is a new approach for tumour therapy. However, tumour cells tend to acquire resistance to targeted drugs during treatment. Circular RNAs (circRNAs) are single-stranded RNA molecules with unique structures and important functions. With the development of RNA sequencing technology, circRNAs have been found to be widespread in tumour-resistant cells and to play important regulatory roles. In this review, we present the latest advances in circRNA research and summarize the various mechanisms underlying their regulation. Moreover, we review the role of circRNAs in the chemotherapeutic resistance of tumours and explore the clinical value of circRNA regulation in treating tumour resistance.

• Circular RNAs (CircRNAs)
• Functions
• Self-circularize
• Targeted treatment
• Tumor resistance

• ciRS-7
• circHIPK3
• circNF1
• circPVT1
• circ_0000096
• gastric carcinogenesis
• gastrointestinal tumors
• sponge circRNA

• CAPES/Biologia Computacional: No. 3381/2013/CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• CNPq/Productivity: 304413/2015-1 Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Edital No.51/2013/Biologia Computacional; Proc. No. 88887.313819/2019-00/CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

• circular RNA
• digestive system
• cancer
• biomarker
• therapeutic targets

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Carcinogenesis/genetics
• Digestive System Neoplasms/diagnosis
• Digestive System Neoplasms/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• RNA, Circular/analysis
• RNA, Circular/metabolism

Circular RNA downstream neighbor of SON (circDONSON) has been revealed to promote gastric cancer (GC) growth and invasion, while the role and molecular mechanism underlying circDONSON in GC cisplatin (DDP) resistance remain unclear.

Levels of circDONSON, microRNA (miR)-802, and B lymphoma Mo-MLV insertion region 1 (BMI1) mRNA were detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 assay, colony formation assay and flow cytometry, respectively. Protein levels of BMI1, Cyclin D1, p27, Caspase-3 Cleavage and Caspase-9 Cleavage were determined by western blot. The interaction between miR-802 and circDONSON or BMI1 was confirmed by dual-luciferase reporter assay. In vivo experiments were conducted via the murine xenograft model.

CircDONSON was elevated in GC tissues and cell lines, especially in DDP-resistant GC tissues and cells. Knockdown of circDONSON sensitized GC cells to DDP by inhibiting cell viability and promoting cell apoptosis in vitro. Further mechanism-related investigations suggested that circDONSON functioned as “sponge” by competing for miR-802 binding to modulate its target BMI1. Silencing miR-802 reversed the inhibition of DDP-resistance in GC cells induced by circDONSON down-regulation. Besides, miR-802 alleviated DDP resistance in GC cells by targeting BMI1. Functionally, circDONSON knockdown enhanced the cytotoxicity of DDP in GC in vivo.

Our findings demonstrated circDONSON promoted cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis, shedding light on the development of a novel therapeutic strategy to overcome chemoresistance in gastric cancer patients.

• BMI1
• Cisplatin resistance
• Gastric cancer
• circDONSON
• miR-802

• cancer therapy
• chemoresistance
• cisplatin
• epithelial–mesenchymal transition (EMT)
• signal transduction

• Antineoplastic Agents/pharmacology
• Cell Differentiation
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition/drug effects
• Forkhead Box Protein O1/metabolism
• Humans
• MicroRNAs/metabolism
• NF-kappa B/metabolism
• Neoplasms/drug therapy
• Phosphatidylinositol 3-Kinases/metabolism
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism

• Animals
• Apoptosis/drug effects
• Cell Line, Tumor
• Cisplatin/pharmacology
• Disease-Free Survival
• Drug Resistance, Neoplasm/genetics
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• In Situ Hybridization, Fluorescence
• Infections/metabolism
• Lentivirus/genetics
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism
• RNA, Circular/metabolism
• Signal Transduction
• Stomach Neoplasms/drug therapy

Circular RNAs (circRNAs) have been demonstrated to act as key regulators in the chemoresistance of human cancers, including breast cancer (BC). Here, we aimed to explore the role of circ‐RNF111 in paclitaxel (PTX) resistance of BC.

Quantitative real‐time polymerase chain reaction (qRT‐PCR) was employed to determine the expression of circ‐RNF111, microRNA‐140‐5p (miR‐140‐5p) and E2F transcription factor 3 (E2F3) mRNA. The half maximal inhibitory concentration (IC₅₀) of PTX, cell viability, colony formation and cell invasion were assessed by cell counting kit‐8 (CCK‐8) assay, colony formation assay and transwell assay, respectively. Glucose consumption and lactate production were determined by specific kits. A murine xenograft model was established to investigate the role of circ‐RNF111 in PTX resistance of BC in vivo. Dual‐luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the relationship between miR‐140‐5p and circ‐RNF111 or E2F3. Western blot assay was conducted to examine the protein level of E2F3.

Circ‐RNF111 was upregulated in PTX‐resistant BC tissues and cells. Circ‐RNF111 knockdown restrained IC₅₀ of PTX, cell viability, colony numbers, cell invasion and glycolysis in PTX‐resistant BC cells in vitro and enhanced PTX sensitivity in vivo. MiR‐140‐5p was a target of circ‐RNF111 and miR‐140‐5p expression was negatively correlated with circ‐RNF111 expression in BC tissues. The effect of circ‐RNF111 knockdown on PTX resistance was rescued by miR‐140‐5p deletion. Additionally, miR‐140‐5p could interact with E2F3 and negatively regulate E2F3 expression. Moreover, miR‐140‐5p suppressed IC₅₀ of PTX, cell viability, colony numbers, cell invasion and glycolysis by targeting E2F3.

Circ‐RNF111 improved PTX resistance of BC by upregulating E2F3 via sponging miR‐140‐5p.

• Breast cancer
• E2F3
• PTX
• circ-RNF111
• miR-140-5p

• Circular RNA
• Drug resistance
• Gastric cancer
• Long non-coding RNA
• MicroRNA

• Animals
• Biomarkers, Tumor/genetics
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• RNA, Long Noncoding/genetics
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology