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Brain tumors are common solid pediatric malignancies and the main reason for cancer-related death in the pediatric setting. Recently, evidence has revealed that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play a critical role in brain tumor development and progression. Therefore, in this review article, we describe the functions and molecular mechanisms of ncRNAs in multiple types of cancer, including medulloblastoma, pilocytic astrocytoma, ependymoma, atypical teratoid/rhabdoid tumor, glioblastoma, diffuse intrinsic pontine glioma, and craniopharyngioma. We also mention the limitations of using ncRNAs as therapeutic targets because of the nonspecificity of ncRNA targets and the delivery methods of ncRNAs. Due to the critical role of ncRNAs in brain oncogenesis, targeting aberrantly expressed ncRNAs might be an effective strategy to improve the outcomes of pediatric patients with brain tumors., Graphical abstract, In this review article, the authors describe the functions and molecular mechanisms of ncRNAs, such as miRNAs, lncRNAs, and circRNAs, in pediatric brain malignancies, including medulloblastoma, pilocytic astrocytoma, ependymoma, atypical teratoid/rhabdoid tumor, glioblastoma, diffuse intrinsic pontine glioma, and craniopharyngioma.

Among the many malignant neoplasms, glioblastoma (GBM) leads to one of the worst prognosis for patients and has an almost 100% recurrence rate. The only chemotherapeutic drug that is widely used for treating glioblastoma is temozolomide, a DNA alkylating agent. Its impact, however, is only minor; it increases patients survival just by 12 to 14 months. Multiple highly selective compounds that affect specific proteins and have performed well in other types of cancer have proved ineffective against glioblastoma. Hence, there is an urgent need for novel methods that could help achieve the long-awaited progress in glioblastoma treatment. One of the potentially promising approaches is the targeting of non-coding RNAs (ncRNAs). These molecules are characterized by extremely high multifunctionality and often act as integrators by coordinating multiple key signaling pathways within the cell. Thus, the impact on ncRNAs has the potential to lead to a broader and stronger impact on cells, as opposed to the more focused action of inhibitors targeting specific proteins. In this review, we summarize the functions of long noncoding RNAs, circular RNAs, as well as microRNAs, PIWI-interacting RNAs, small nuclear and small nucleolar RNAs. We provide a classification of these transcripts and describe their role in various signaling pathways and physiological processes. We also provide examples of oncogenic and tumor suppressor ncRNAs belonging to each of these classes in the context of their involvement in the pathogenesis of gliomas and glioblastomas. In conclusion, we considered the potential use of ncRNAs as diagnostic markers and therapeutic targets for the treatment of glioblastoma.

Circular RNAs (circRNAs) are a complicated class of non-coding RNAs that have a covalently closed loop structure and are very stable and cautious. Multiple biological processes of malignancy, including tumorigenesis, development, invasion, metastasis, apoptosis, and vascularization, are disrupted by an increased number of circRNAs. Recent research has showed that circRNAs, functioning as microRNA (miRNA) sponges or protein scaffolds, interacting with RNA-binding proteins (RBPs), and autophagy regulators, affect the transcription and splicing regulation. Many circRNAs have tissue-specific expression patterns and are heavily conserved. CircRNA levels in neurons are dynamically modulated. Growing evidence suggests that circRNAs are highly abundant in neural tissues, perhaps owing to the proliferation of particular genes that promote circularization, implying that circRNA dysregulation is linked to nervous system disorders including glioma. The most widespread and deadly primary malignant brain tumor is glioma. CircRNA has a close connection to glioma, according to reported research. Here, the current knowledge about the properties of circRNAs is introduced and the biological and molecular functions of circRNAs are described. Then, the clinical association of circRNAs with glioma/glioblastoma and their level of expression and their regulatory mechanisms in tumorigenesis are discussed. Moreover, the potential of circRNAs as diagnostic biomarkers and predictors of brain cancer risk and possible therapeutic targets in medicine is examined.

BackgroundHigh-grade glioma has a poor prognosis, and GSCs can have pivotal roles in glioma pathology. This study investigated GSC exosome-containing circRNA mechanisms affecting the malignant progression of glioma.MethodsIn this study, we identified differentially expressed circRNAs and constructed a circRNA-miRNA-mRNA regulatory network through circRNA sequencing/bioinformatics analysis. Then, we identified circRNAs that were upregulated in GSC23 cells and employed them as downstream targets in subsequent investigations. Such investigations included downstream target knockout to assess any influence on A172 cell proliferation, invasion, migration and apoptosis. In addition, in vivo investigations using tumor-bearing animals evaluated the in vivo influences of the selected targets.ResultsThis study identified circ-Serpine2/miR-124-3p/KIF20A as a regulatory pathway in glioma. Our in vitro analysis confirmed that circ-Serpine2 could upregulate KIF20A by sponging miR-124-3p, consequently promoting A172 cell proliferation, migration and invasion. Such a signaling channel could also inhibit glioma cell apoptosis. Additionally, our research indicated that circ-Serpine2 inhibited glioma apoptosis and promoted in vivo tumor progression.ConclusionCirc-Serpine2 exacerbated the malignant progression of glioma mediated by the miR-124-3p/KIF20A nexus, thus providing novel predictive/prognostic biomarkers and drug targets against glioma.

Osteoporosis is one bone disease characterized with skeletal impairment, bone strength reduced and fracture risk enhanced. The regulation processes of bone metabolism are associated with several factors such as mechanical stimulation, epigenetic regulation and hormones. However, the mechanism of osteoporosis remains unsatisfactory. Increasing high‐throughput RNA sequencing and circular RNAs (circRNAs) microarray studies indicated that circRNAs are differentially expressed in osteoporosis. Growing functional studies further pinpointed specific deregulated expressed circRNAs (e.g., circ_28313, circ_0016624, circ_0006393, circ_0076906 and circ_0048211) for their functions involved in bone metabolism, including bone marrow stromal cells (BMSCs) differentiation, proliferation and apoptosis. Moreover, CircRNAs (circ_0002060, Circ_0001275 and Circ_0001445) may be acted as diagnostic biomarkers for osteoporosis. This review discussed recent progresses in the circRNAs expression profiling analyses and their potential functions in regulating BMSCs differentiation, proliferation and apoptosis.

Here we describe a new integrative approach for accurate annotation and quantification of circRNAs named Short Read circRNA Pipeline (SRCP). Our strategy involves two steps: annotation of validated circRNAs followed by a quantification step. We show that SRCP is more sensitive than other individual pipelines and allows for more comprehensive quantification of a larger number of differentially expressed circRNAs. To facilitate the use of SRCP, we generate a comprehensive collection of validated circRNAs in five different organisms, including humans. We then utilize our approach and identify a subset of circRNAs bound to the miRNA-effector protein AGO2 in human brain samples. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02497-7.

CircRNAs are a large class of endogenous single-stranded RNA that is different from other linear RNA, which are produced by back-splicing and fusion of either exons, introns, or both exon-intron into covalently closed loops. CircRNAs are found in almost all living organisms and have emerged as potentially important players effecting on all life activities. It was characterized by stable structure, resistant to RNA degradation, highly abundance and conservation and tissue-specific expression. Early circRNAs were ignored as a by-product of meaningless abnormally cut RNA and had little biological function. Currently, circRNAs have become a research hotspot due to its special characteristics. CircRNAs could function as miRNA sponges, interfere with splicing and bind to protein to regulate the expression of parental genes and so on. In recent years, an increasing number of studies have revealed that circRNAs are closely related to a series of physiological and pathological processes. Additionally, circRNAs play an important role in the occurrence and development of a variety of diseases, suggesting circRNAs may be as novel indicators or biomarkers for cancer and other diseases with which they are associated. In this article, we review the biogenesis, biological functions of circRNAs and recent advances in circRNAs research in human diseases. Results will provide new insights on the roles and new ideas of circRNAs for the diagnosis and treatment of diseases and possible directions and approach for future circRNA applications.

Malignant melanoma (MM) is a malignant tumor that originates from melanocytes and has a high mortality rate. Therefore, early diagnosis and treatment are very important for survival. So far, the exact molecular mechanism leading to the occurrence of melanoma, especially the molecular metastatic mechanism, remains largely unknown. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNA (circRNAs), have been investigated and found to play vital roles in regulating tumor occurrence and development, including melanoma. In this review, we summarize the progress of recent research on the effects of ncRNAs on melanoma and attempt to elucidate the role of ncRNAs as molecular markers or potential targets that will provide promising application perspectives on melanoma., Graphical abstract, Non-coding RNAs serve as oncogenes or tumor suppressors in the regulation of many biological processes of melanoma by activating or inhibiting tumor-associated signaling. Clarifying the relationship between non-coding RNAs and melanoma provides the potential impact and promise of non-coding RNAs in the diagnosis and treatment of melanoma.

Circular RNA (circRNAs) belong to the long non-coding RNA family, but unlike the linear RNA in circular RNA, the 3’ and 5’ end in the RNA molecule are joined together, forming their circular structure. Until recently, circRNAs have been believed to be a side product of splicing, but now it is known that they have a wide range of biological functions, from regulators of gene expression to regulators of other non-coding RNAs - microRNAs (miRNAs). CircRNAs have the potential of being therapeutic targets and biomarkers for diseases. There are little data and only several investigations about this type of RNAs in myocardial infarction in humans. This review summarizes the role of some new circRNA – miRNA interactions in the development of Myocardial Infarction.

Endometrial development is a complicated process involving numerous regulatory factors. Circular RNAs (circRNAs) have been known as a member of the naturally occurring non-coding RNA family, and are reportedly crucial for a variety of physiological processes. This study investigated the circRNA landscape of non-pregnant endometrium of dairy goats during estrus. Non-pregnant endometrial samples of goats at estrus day 5 (Ed5) and estrus day 15 (Ed15) were used to methodically analyze the circRNA landscape using strand-specific Ribo-Zero RNA-Seq. A total of 2 331 differentially expressed (P

Human breast milk (HBM) provides essential nutrients for newborn growth and development, and contains a variety of biologically active ingredients that can affect gastrointestinal tract and immune system development in breastfed infants. HBM also contains mRNAs, microRNAs and lncRNAs, most of which are encapsulated in milk-derived exosomes and exhibit various important infant development related biological functions. While previous studies have shown that exosomal circRNAs are involved in the intestinal epithelial cells’ proliferation and repair. However, the effect of HBM exosomal circRNAs on intestinal development is not clear. In this study, we identified 6756 circRNAs both in preterm colostrum (PC) and term colostrum (TC), of which 66 were upregulated, and 42 were downregulated (|fold change>2|, p < 0.05) in PC. Pathway analysis showed that the VEGF signalling pathway was involved, and network analysis revealed that the differentially expressed circRNAs bound various miRNAs. Further analyses showed that has_circRNA_405708 and has_circRNA_104707 were involved in the VEGF signalling pathway, and that they all bound various mirRNAs. Exosomes found in preterm colostrum (PC) and term colostrum (TC) promoted VEGF protein expression and induced the proliferation and migration of small intestinal epithelial cells (FHCs). Exosomal circRNAs found in human colostrum (HC) binding to related miRNAs may regulate VEGF signalling, and intestinal development.

Warburg effect reflects that tumor cells tend to generate energy by aerobic glycolysis rather than oxidative phosphorylation (OXPHOS), thus promoting the development of malignant tumors. As a kind of non-coding RNA, circular RNA (circRNA) is characterized by a closed ring structure and emerges as a regulator of cancer metabolism. Mounting studies revealed that circRNA can regulate the cancer metabolism process through affecting the expression of glycolysis relevant enzymes, transcription factors (TFs), and signaling pathways. In this review, we comprehensively analyzed and concluded the mechanism of circRNA regulating glycolysis, hoping to deepen the cognition of the cancer metabolic regulatory network and to reap huge fruits in targeted cancer treatment.

Background New noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of Parkinson's disease (PD) diagnosis are urgently needed. Circular RNAs (circRNAs) are stable noncoding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function. Objectives Τhe aims of this study were to identify differentially expressed circRNAs in blood mononuclear cells of patients with idiopathic PD and explore the competing endogenous RNA networks affected. Methods Eighty‐seven circRNAs were initially selected based on relatively high gene expression in the human brain. More than half of these were readily detectable in blood mononuclear cells using real‐time reverse transcription‐polymerase chain reaction. Comparative expression analysis was then performed in blood mononuclear cells from 60 control subjects and 60 idiopathic subjects with PD. Results Six circRNAs were significantly down‐regulated in patients with PD. The classifier that best distinguished PD consisted of four circRNAs with an area under the curve of 0.84. Cross‐linking immunoprecipitation‐sequencing data revealed that the RNA‐binding proteins bound by most of the deregulated circRNAs include the neurodegeneration‐associated FUS, TDP43, FMR1, and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs have the Gene Ontology categories “protein modification” and “transcription factor activity” mostly enriched. Conclusions This is the first study that identifies specific circRNAs that may serve as diagnostic biomarkers for PD. Because they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected. © 2021 Biomedical Research Foundation, Academy of Athens. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.

CircRNAs are now under hot discussion as novel promising bio-markers for patients with clear cell renal cell carcinoma. The purpose of our study is to identify several circRNAs related to the metastasis and progression of clear cell renal cell carcinoma, and to further investigate the mechanism of their influence on tumor progression. The transcriptome data of ccRCC and clinical characteristics used in this study were downloaded from the The Cancer Genome Atlas and Gene Expression Omnibus database. A total of 114 circRNAs were found to be related to tumor initiation, progression and metastasis after the intersection. In addition, 14 miRNAs and 201 eligible mRNAs were selected as targets gene, respectively. CeRNA network was constructed based on 8 circRNAs, 14 miRNAs, and 201 mRNAs. Besides, another 6 hub genes were identified via the PPI network. It should be noted that only TRIM2 was confirmed as an independent prognostic factor, which was simultaneously significantly related to both clinical stage and pathological grade in clinical cohorts. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis indicated the possible function of TRIM2 in ccRCC progression, such as ubiquitin mediated protein hydrolysis, cell adhesion molecules, Th17 cell differentiation signaling pathway and so on. Gene set enrichment analysis analysis revealed that TRIM2 may be involved in ubiquitin mediated proteolysis, apoptosis, autophagy and citrate cycle TCA cycle. Hub circ_RNAs expressions were validated in ccRCC tissues and cell lines. Our study revealed that the hsa_circ_0002286 / has-mir-222-5p / TRIM2 axis played a critical role in the progression of ccRCC. Specifically, it may inhibit the metastasis and progression of ccRCC, which could serve as a potential therapeutic target.

Accumulating evidence suggested that circular RNAs (circRNAs) play critical roles in the initiation and progression of malignant cancers. However, the roles of circRNAs in gastric cancer (GC) remain largely unknown. In the present study, we investigated the expression of circRNAs in 5 GC tissues with metastasis and 5 GC tissues without metastasis by microarray analysis. We focused on hsa_circ_0003506, which was spliced from CYFIP2 gene located at chr5:156786012–156788606 and finally formed a sense-overlapping circular transcript of 366 nt, and thus we named it circCYFIP2. circCYFIP2 was found to be significantly upregulated in GC tissues and cell lines. High expression of circCYFIP2 was associated with metastasis and poor prognosis of GC patients. Function assays revealed that overexpression or knockdown of circCYFIP2 significantly enhanced or reduced GC cell proliferation and invasion abilities. In mechanism, we found that circCYFIP2 might serve as a competing endogenous RNA (ceRNA) of microRNA-1205 (miR-1205) in GC progression. Besides, E2F1 was found to be a target of miR-1205. Collectively, our findings suggested that circCYFIP2 might serve as an oncogenic circRNA to promote GC progression via the miR-1205/E2F1 axis, which provided a potential therapeutic target for the treatment of GC., Graphical Abstract, Lin et al. found that circular RNA (circRNA) circCYFIP2 might serve as an oncogenic circRNA to promote gastric cancer (GC) progression via the miR-1205/E2F1 axis, which provided a potential therapeutic target for the treatment of GC.

BackgroundThe present study aimed to assess the perturbation in circular RNA (circRNA)/mRNA expression profiles and a circRNA-miRNA-mRNA coexpression network involved in the potential protective effect of diosgenin (DIO) on alveolar bone loss in rats subjected to ovariectomy (OVX).MethodsThe Wistar rats (female) manipulated with sham operation were classified as the SHAM group and the grouping of OVX rats administered with DIO, estradiol valerate or vehicle for 12 weeks was DIO group, EV group and OVX group respectively. Following treatments, the plasmatic levels of osteocalcin and tumor necrosis factor-alpha and the microstructure of alveolar bone were assayed. Based on microarray analyses, we identified differentially expressed (DE) circRNAs and mRNAs in alveolar bone of rats in both OVX and DIO group. The DE circRNAs and DE mRNAs involved in the bone metabolism pathway validated by RT-qPCR were considered key circRNAs/mRNAs. On the basis of these key circRNAs/mRNAs, we predicted the overlapping relative miRNAs of key circRNAs/mRNAs, and a circRNA-miRNA-mRNA network was built.ResultsDIO showed an anti-osteopenic effect on the rat alveolar bone loss induced by OVX. In total, we found 10 DE circRNAs (6 downregulated and 4 upregulated) and 614 DE mRNAs (314 downregulated and 300 upregulated) in samples of the DIO group compared with those of the OVX group. However, only one circRNA (rno_circRNA_016717) and seven mRNAs (Sfrp1,Csf1,Il1rl1,Nfatc4,Tnfrsf1a,Pik3c2g, andWnt9b) were validated by qRT-PCR and therefore considered key circRNA/mRNAs. According to these key circRNA/mRNAs and overlapping predicted miRNAs, a coexpression network was constructed. After network analysis, one circRNA-miRNA-mRNA axis (circRNA_016717/miR-501-5p/Sfrp1) was identified.ConclusionThe mechanism of DIO inhibiting alveolar bone loss after OVX is possibly relevant to the simultaneous inhibition of osteogenesis and osteoclastogenesis by mediating the expression of important molecules in the Wnt, PI3K, RANK/RANKL or osteoclastogenic cytokine pathways. The circRNA_016717/miR-501-5p/Sfrp1axis may play important roles in these processes.

Circular RNAs (circRNAs) are covalently linked RNAs that exhibit individual strand with a closed-loop framework compared with a conserving, steady and abundant linear counterpart. In recent years, as high-throughput sequencing advancement has been developing, functional circRNAs have been increasingly recognized, and more extensive analyses expounded their effect on different diseases. However, the study on the function of circRNAs in the immune system remains insufficient. This study discusses the basic principles of circRNAs regulation and the systems involved in physiology-related and pathology-related processes. The effect of circRNAs on immune regulation is elucidated. The ongoing development of circRNAs and basic immunology has multiplied their potential in treating diseases. Such perspective will summarize the status and effect of circRNAs on various immune cells in cancer, autoimmune diseases and infections. Moreover, this study will primarily expound the system of circRNAs in T lymphocytes, macrophages and other immune cells, which creates a novel perspective and lay a theoretical basis for treating diseases.

Bone cancer pain (BCP) is a common chronic pain that is caused by a primary or metastatic bone tumor. More detailed molecular mechanisms of BCP are warranted. In this study, we established a BCP rat model. The von Frey hair test, body weight, and hematoxylin and eosin staining were employed. We screened differentially expressed circRNAs (DECs) between the BCP group and sham group. The results revealed that 850 DECs were significantly up-regulated and 644 DECs were significantly down-regulated in the BCP group. Furthermore, we identified 1177 differentially expressed genes (DEGs) significantly up-regulated and 565 DEGs significantly down-regulated in the BCP group. Gene Ontology annotation of all 1742 DEGs revealed that biological regulation of metabolic processes, cellular processes, and binding were the top enriched terms. For Kyoto Encyclopedia of Genes and Genomes analysis, phagosome, HTLV-I infection, proteoglycans in cancer, and herpes simplex infection were significantly enriched in this study. In addition, we identified four selected circRNAs, chr6:72418120|72430205, chr20:7561057|7573740, chr18:69943105|69944476, and chr5:167516581|167558250, by quantitative real time PCR. chr6:72418120|72430205 (circStrn3) was selected for further study based on expression level and the circRNA–miRNA–mRNA network table. Western blot analysis suggested that knockdown of circStrn3 could effectively induce Walker 256 cell apoptosis. In summary, our study provided a more in-depth understanding of the molecular mechanisms of BCP.

Circular RNAs (circRNAs), one type of non-coding RNA, were initially misinterpreted as nonfunctional products of pre-mRNA mis-splicing. Currently, circRNAs have been proven to manipulate the functions of diverse molecules, including non-coding RNAs, mRNAs, DNAs and proteins, to regulate cell activities in physiology and pathology. Accumulating evidence indicates that circRNAs play critical roles in tumor genesis, development, and sensitivity to radiation and chemotherapy. Radiotherapy and chemotherapy are two primary types of intervention for most cancers, but their therapeutic efficacies are usually retarded by intrinsic and acquired resistance. Thus, it is urgent to develop new strategies to improve therapeutic responses. To achieve this, clarification of the underlying mechanisms affecting therapeutic responses in cancer is needed. This review summarizes recent progress and mechanisms of circRNAs in cancer resistance to radiation and chemotherapy, and it discusses the limitations of available knowledge and potential future directions.

Circular RNAs (circRNAs) are a class of noncoding RNAs broadly expressed in cells of various species. However, the molecular mechanisms that link circRNAs with progression of papillary thyroid carcinoma (PTC) are not well understood. In the present study, we attempted to provide a novel basis for targeted therapy for PTC from the aspect of the circRNA-microRNA (miRNA)-mRNA interaction. We investigated the expression of circRNAs in five paired PTC tissues and normal tissues by microarray analysis. The circRNA microarray assay followed by qRT-PCR was used to verify the differential expression of circFOXM1 (hsa_circ_0025033), which is located at chr12: 2966846-2983691 and derived from FOXM1. The spliced length of circFOXM1 is 3410 nt. The qRT-PCR analysis was to investigate the expression pattern of circFOXM1 in PTC tissues and cell lines. Then, the effects of circFOXM1 on tumor growth were assessed in PTC in vitro and in vivo. Furthermore, bioinformatics online programs predicted, and the luciferase reporter assay was used to validate the association of circFOXM1 and miR-1179 in PTC cells. In this study, circFOXM1 was observed to be upregulated in PTC tissues and cell lines. circFOXM1 downregulation inhibited tumor growth of PTC in vitro and in vivo. Bioinformatics analysis predicted that there is a circFOXM1/miR-1179/high-mobility group box 1 (HMGB1) axis in PTC. A dual luciferase reporter system validated the direct interaction of circFOXM1, miR-1179, and HMGB1. In summary, our study demonstrated that circFOXM1 modulates cancer progression through the miR-1179/HMGB1 pathway in PTC. Our findings indicate that circFOXM1 may serve as a promising therapeutic target for the treatment of PTC patients.

Circular RNA (circRNA) is a novel class of noncoding RNAs, and the roles of circRNAs in the development of cardiac hypertrophy remain to be explored. Here, we investigate the potential roles of circRNAs in cardiac hypertrophy. By circRNA sequencing in left ventricular specimens collected from 8-week-old mice with isoproterenol hydrochloride-induced cardiac hypertrophy, we found 401 out of 3323 total circRNAs were dysregulated in the hypertrophic hearts compared with the controls. Of these, 303 circRNAs were upregulated and 98 were downregulated. Moreover, the GO and KEGG analyses revealed that the majority of parental gene of differentially expressed circRNAs were not only related to biological process such as metabolic process and response to stimulus, but also related to pathway such as circulatory system and cardiovascular diseases. On the other hand, total 1974 miRNAs were predicted to binding to these differentially expressed circRNAs, and the possible target mRNAs of those miRNAs were also predicted and analyzed in terms of functional annotation. Finally, we identified that ANF and miR-23a are downstream targets of circRNA wwp1, suggesting that circRNA wwp1 exerts inhibitory roles of cardiac hypertrophy via down-regulation of ANF and miR-23a, which underlying the potential mechanisms whereby circRNA regulates cardiac hypertrophy.

The tumour microenvironment (TME) constitutes the area surrounding the tumour during its development and has been demonstrated to play roles in cancer-related diseases through crosstalk with tumour cells. Circular RNAs (circRNAs) are a subpopulation of endogenous noncoding RNAs (ncRNAs) that are ubiquitously expressed in eukaryotes and have multiple biological functions in the regulation of cancer onset and progression. An increasing number of studies have shown that circRNAs participate in the multifaceted biological regulation of the TME. However, details on the mechanisms involved have remained elusive until now. In this review, we analyse the effects of circRNAs on the TME from various perspectives, including immune surveillance, angiogenesis, hypoxia, matrix remodelling, exo-circRNAs and chemoradiation resistance. Currently, the enormous potential for circRNA use in targeted therapy and as noninvasive biomarkers have drawn our attention. We emphasize the prospect of targeting circRNAs as an essential strategy to regulate TME, overcome cancer resistance and improve therapeutic outcomes.

The tumour suppressor p53 and its paralogues, p63 and p73, are essential to maintain cellular homoeostasis and the integrity of the cell’s genetic material, thus meriting the title of ‘guardians of the genome’. The p53 family members are transcription factors and fulfill their activities by controlling the expression of protein-coding and non-coding genes. Here, we review how the latter group transcended from the ‘dark matter’ of the transcriptome, providing unexpected and intriguing anti-cancer therapeutic strategies.

Circular RNAs (circRNAs) are a class of single-stranded covalently closed non-coding RNAs without a 5′ cap structure or 3′ terminal poly (A) tail, which are expressed in a variety of tissues and cells with conserved, stable and specific characteristics. Glioblastoma (GBM) is the most aggressive and lethal tumor in the central nervous system, characterized by high recurrence and mortality rates. The specific expression of circRNAs in GBM has demonstrated their potential to become new biomarkers for the development of GBM. The specific expression of circRNAs in GBM has shown their potential as new biomarkers for GBM cell proliferation, apoptosis, migration and invasion, which provides new ideas for GBM treatment. In this paper, we will review the biological properties and functions of circRNAs and their biological roles and clinical applications in GBM.

Simple Summary Variation exists in muscle-related traits, such as muscle growth and meat quality, between obese and lean pigs. In this study, the transcriptome profiles of skeletal muscle between Beijing Blackand Yorkshire pigs were characterized to explore the molecular mechanism underlying skeletal muscle-relatedtraits. Gene Ontology (GO) and KEGG pathway enrichment analyses showed that differentially expressed mRNAs, lncRNAs, and circRNAs involved in skeletal muscle development and fatty acid metabolism played a key role in the determination of muscle-related traits between different pig breeds. These results provide candidate genes responsible for muscle phenotypic variation and are valuable for pig breeding. Abstract RNA-Seq technology is widely used to analyze global changes in the transcriptome and investigate the influence on relevant phenotypic traits. Beijing Black pigs show differences in growth rate and meat quality compared to western pig breeds. However, the molecular mechanisms responsible for such phenotypic differences remain unknown. In this study, longissimus dorsi muscles from Beijing Black and Yorkshire pigs were used to construct RNA libraries and perform RNA-seq. Significantly different expressions were observed in 1051 mRNAs, 322 lncRNAs, and 82 circRNAs. GO and KEGG pathway annotation showed that differentially expressed mRNAs participated in skeletal muscle development and fatty acid metabolism, which determined the muscle-related traits. To explore the regulatory role of lncRNAs, the cis and trans-target genes were predicted and these lncRNAswere involved in the biological processes related to skeletal muscle development and fatty acid metabolismvia their target genes. CircRNAs play a ceRNA role by binding to miRNAs. Therefore, the potential miRNAs of differentially expressed circRNAs were predicted and interaction networks among circRNAs, miRNAs, and key regulatory mRNAs were constructed to illustrate the function of circRNAs underlying skeletal muscle development and fatty acid metabolism. This study provides new clues for elucidating muscle phenotypic variation in pigs.

Wandong cattle are an autochthonous Chinese breed used extensively for beef production. The breed tolerates extreme weather conditions and raw feed and is resistant to tick-borne diseases. However, the genetic basis of testis development and sperm production as well as breeding management is not well established in local cattle. Therefore, improving the reproductive efficiency of bulls via genetic selection is crucial as a single bull can breed thousands of cows through artificial insemination (AI). Testis development and spermatogenesis are regulated by hundreds of genes and transcriptomes. However, circular RNAs (circRNAs) are the key players in many biological developmental processes that have not been methodically described and compared between immature and mature stages in Bovine testes. In this study, we performed total RNA-seq and comprehensively analyzed the circRNA expression profiling of the testis samples of six bulls at 3 years and 3 months of developmental age. In total, 17,013 circRNAs were identified, of which 681 circRNAs (p-adjust < 0.05) were differentially expressed (DE). Among these DE circRNAs, 579 were upregulated and 103 were downregulated in calf and bull testes. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the identified target genes were classified into three broad functional categories, including biological process, cellular component, and molecular function, and were enriched in the lysine degradation, cell cycle, and cell adhesion molecule pathways. The binding interactions between DE circRNAs and microRNAs (miRNAs) were subsequently constructed using bioinformatics approaches. The source genes ATM, CCNA1, GSK3B, KMT2C, KMT2E, NSD2, SUCLG2, QKI, HOMER1, and SNAP91 were found to be actively associated with bull sexual maturity and spermatogenesis. In addition, a real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed a strong correlation with the sequencing data. Moreover, the developed model of Bovine testes in the current study provides a suitable framework for understanding the mechanism of circRNAs in the development of testes and spermatogenesis.

Background Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. Methods High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502–5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. Results CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502–5p and interacting with IGF2BP2. Conclusion Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

Swine hepatitis E (SHE) is a new type of zoonotic infectious disease caused by swine hepatitis E virus (SHEV). Open reading frame 3 (ORF3) is a key regulatory and virulent protein of SHEV. Circular RNAs (circRNAs) are a special kind of non-coding RNA molecule, which has a closed ring structure. In this study, to identify the circRNA profile in host cells affected by SHEV ORF3, adenovirus ADV4-ORF3 mediated the overexpression of ORF3 in HepG2 cells, whole genome sequencing was used to investigate the differentially expressed circRNAs, GO and KEGG were performed to enrichment analyze of differentially expressed circRNA-hosting gene, and Targetscan and miRanda softwares were used to analyze the interaction between circRNA and miRNA. The results showed adenovirus successfully mediated the overexpression of ORF3 in HepG2 cells, 1,105 up-regulation circRNAs and 1,556 down-regulation circRNAs were identified in ADV4-ORF3 infection group compared with the control. GO function enrichment analysis of differentially expressed circRNAs-hosting genes classified three main categories (cellular component, biological process and molecular function). KEGG pathway enrichment analysis scatter plot showed the pathway term of top20. The circRNAs with top10 number of BS sites for qRT-PCR validation were selected to confirmed, the results indicated that the up-regulated hsa_circ_0001423 and hsa_circ_0006404, and down-regulated of hsa_circ_0004833 and hsa_circ_0007444 were consistent with the sequencing data. Our findings first preliminarily found that ORF3 protein may affect triglyceride activation (GO:0006642) and riboflavin metabolism (ko00740) in HepG2 cells, which provides a scientific basis for further elucidating the effect of ORF3 on host lipid metabolism and the mechanism of SHEV infection.

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization, however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology.

Cancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

Circular RNAs (circRNAs) are regulatory molecules that participate in the occurrence, development and progression of tumors. To obtain a complete blueprint of cervical carcinogenesis, we analyzed the temporal transcriptomic landscapes of mRNAs and circRNAs. Microarrays were performed to identify the circRNA and mRNA expression profiles of cervical squamous cell carcinoma (CSCC) and high-grade squamous intraepithelial lesion (HSIL) patients compared with normal controls (NC). Short time-series expression miner (STEM) was utilized to characterize the time-course expression patterns of circRNAs and mRNAs from NC to HSIL and CSCC. A total of 3 circRNA profiles and 3 mRNA profiles with continuous upregulated patterns were identified and selected for further analysis. Furthermore, functional annotation showed that the mRNAs were associated with DNA repair and cell division. The protein-protein interaction (PPI) network analysis revealed that the ten highest-degree genes were considered to be hub genes. Subsequently, a competing endogenous RNA (ceRNA) network analysis and real-time PCR validation indicated that hsa_circ_0001955/hsa-miR-6719-3p/CDK1, hsa_circ_0001955/hsa-miR-1277-5p/NEDD4L and hsa_circ_0003954/hsa-miR-15a-3p/SYCP2 were highly correlated with cervical carcinogenesis. Silencing of hsa_circ_0003954 inhibited SiHa cell proliferation and perturb the cell cycle in vitro. This study provides insight into the molecular events regulating cervical carcinogenesis, identifies functional circRNAs in CSCC, and improves the understanding of the pathogenesis and molecular biomarkers of CSCC and HSIL.

Glioma is the most common malignant primary brain tumour in adults. Despite improvements in neurosurgery and radiotherapy, the prognosis of glioma patients remains poor. One of the main limitations is that there are no proper clinical therapeutic targets for glioma. Therefore, it is crucial to find one or more effective targets. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of genes. Abnormal expression of STAT3 is involved in the process of cell proliferation, migration, invasion, immunosuppression, angiogenesis, dryness maintenance, and resistance to radiotherapy and chemotherapy in glioma. Therefore, STAT3 has been considered an ideal therapeutic target in glioma. Noncoding RNAs (ncRNAs) are a group of genes with limited or no protein-coding capacity that can regulate gene expression at the epigenetic, transcriptional and posttranscriptional level. In this review, we summarized the ncRNAs that are correlated with the ectopic expression of STAT3 in glioma.

BackgroundPlasmodiophora brassicae is a soil-borne pathogen that attacks the roots of cruciferous plants, causing clubroot disease. CircRNAs are non-coding RNAs widely exist in plant and animal species which can acting as “microRNA (miRNA) sponges” and “competing endogenous RNAs (ceRNAs)”. Knowledge of circRNAs has been updated continuously and rapidly. However, the information about circRNAs in the regulation of clubroot-disease resistance is limited in Brassica rapa. ResultsHere, the Chinese cabbage (BJN 222) containing clubroot resistance gene (CRa) resistant to the Pb4 was susceptible to the PbE of P. brassicae. To investigate the mechanism of cicRNAs responsible for clubroot-disease resistance in Brassica rapa, the circRNA-seq was performed roots of BJN 222 at 0 d, 8 d, and 23 d after inoculated with Pb4 and PbE. A total of 1636 circRNAs were detected distributed on 10 chromosomes. Furthermore, total 231 differentially expressed circRNAs between groups were screened. Parental genes of circRNAs functions analysis results indicated that the expression of circRNAs was affected not only by inoculation time but also by the pathogenicity of P. brassicae. However, the “Phenylalanine, tyrosine, and tryptophan biosynthesis” pathway was significant enriched between the two pathotypes at different inoculation times. All the expression of target genes annotated with “receptor-like protein kinase,” “zinc finger protein,” “LRR-repeat protein,” and “hormone-related” identified from the circRNA-miRNA-mRNA network were analyzed. 5 target genes were consistent with the expression pattern of novel_circ_000495 at 8 dpi, but only Bra026508 was significantly up-regulated. ConclusionThe up-regulated novel_circ_000495 might suppressed the expression of miR5656-y, leading to the up-regulation of Bra026508. Our results provided new insights to clubroot resistance mechanisms of B.rapa and laid a foundation for further research on the function of circRNAs responsible for the pathogen infection.

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, the overall survival of HCC patients remains poor. Main Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with covalently closed structures and tissue- or organ-specific expression patterns in eukaryotes. They are highly stable and have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates and interacting with RNA-binding protein. Recent advances have indicated that circRNAs present abnormal expression in HCC tissues and that their dysregulation contributes to HCC initiation and progression. Furthermore, researchers have revealed that some circRNAs might serve as diagnostic biomarkers or drug targets in clinical settings. In this review, we systematically evaluate the characteristics, biogenesis, mechanisms and functions of circRNAs in HCC and further discuss the current shortcomings and potential directions of prospective studies on liver cancer-related circRNAs. Conclusion CircRNAs are a novel class of ncRNAs that play a significant role in HCC initiation and progression, but their internal mechanisms and clinical applications need further investigation.

Ling Lu,1,&ast; Shikun Fang,2,&ast; Yue Zhang,2 Longtao Jin,1 Wenrong Xu,2 Zhaofeng Liang2 1Child Healthcare Department, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China; 2Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaofeng LiangJiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People’s Republic of ChinaEmail liangzhaofeng@ujs.edu.cnAbstract: Gastric cancer (GC) is a common malignant tumor affecting human health, with occult onset and poor prognosis. Exosomes are extracellular vesicles secreted by almost all cells, which can reflect the state of source cells or tissues. It is reported that exosomes are involved in almost all processes of GC. Exosomes provided a window to understand changes in cell or tissue states by carrying active components such as circular RNAs (circRNAs). CircRNAs are a naturally occurring class of endogenous noncoding RNAs and abnormal expression during the occurrence and development of GC. Exosomal circRNAs are those circRNAs stably existing in exosomes and having high clinical values as novel potential diagnosis and prognosis biomarkers of GC, which have the characteristics of abnormal expression, tissue specificity and development stage specificity. Herein, we briefly summarize the functions and roles and the current research progress of exosomes and exosomal circRNAs in GC with a focus on the potential application for GC progression, diagnosis and prognosis. We also prospected the clinical application of exosomes and exosomal circRNAs in the future.Keywords: gastric cancer, exosomes, circRNAs, function

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. AD is characterized by the production and aggregation of beta-amyloid (Aβ) peptides, hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs), and subsequent neuroinflammation, synaptic dysfunction, autophagy and oxidative stress. Non-coding RNAs (ncRNAs) can be used as potential therapeutic targets and biomarkers due to their vital regulatory roles in multiple biological processes involved in disease development. The involvement of ncRNAs in the pathogenesis of AD has been increasingly recognized. Here, we review the ncRNAs implicated in AD and elaborate on their main regulatory pathways, which might have contributions for discovering novel therapeutic targets and drugs for AD.

With the rapid development of sequencing technologies, the characteristics and functions of circular RNAs (circRNAs) in different tissues, and their underlying pathophysiological mechanisms, have been identified. circRNAs are significantly enriched in the brain and are continually expressed from the embryonic stage to the adult stage in rats. Previous studies have reported that certain circRNAs are differentially expressed in glioma and regulate a number of biological processes, such as cell proliferation, metastasis and oncogenesis of glioma. Furthermore, certain circRNAs have been associated with tumor size, World Health Organization tumor grade and poor prognosis in patients with glioma. It has been hypothesized that circRNAs may be involved in the onset and progression of glioma through transcriptional regulation, protein translation and binding to microRNAs. These properties and functions suggest the potential of circRNAs as prognostic biomarkers and therapeutic targets for glioma. For the present review, published studies were examined from PubMed, Embase, Cochrane Central and the reference lists of the retrieved articles. The aim of the present review was to summarize the progress of circRNA research in glioma, discuss the potential diagnostic and prognostic values, and the roles of circRNAs in glioma, and provide a novel theoretical basis and research concepts for the prediction, diagnosis and treatment of glioma.

Ferroptosis is a newly identified form of regulated cell death that is associated with iron metabolism and oxidative stress. As a physiological mechanism, ferroptosis selectively removes cancer cells by regulating the expression of vital chemical molecules. Current findings on regulation of ferroptosis have largely focused on the function of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), in mediating ferroptotic cell death, while the sponging effect of circular RNAs (circRNAs) has not been widely studied. In this review, we discuss the molecular regulation of ferroptosis and highlight the value of circRNAs in controlling ferroptosis and carcinogenesis. Herein, we deliberate future role of this emerging form of regulated cell death in cancer therapeutics and predict the progression and prognosis of oncogenesis in future clinical therapy. publishedVersion

Background In mammals, the ovary is the essential system of female reproduction for the onset of puberty, and the abnormal puberty has negative outcomes on health. CircRNA is a non-coding RNA produced by non-canonical alternative splicing (AS). Several studies have reported that circRNA is involved in the gene regulation and plays an important role in some human diseases. However, the contribution of circRNA has received little known within the onset of puberty in ovary. Results Here, the profiles of ovarian circRNAs across pre-, in- and post-pubertal stages were established by RNA-sEq. In total, 972 circRNAs were identified, including 631 stage-specific circRNAs and 8 tissue-specific circRNAs. The biological functions of parental genes of circRNAs were enriched in steroid biosynthesis, autophagy-animal, MAPK signaling pathway, progesterone-mediated oocyte maturation and ras signaling pathway. Moreover, 5 circRNAs derived from 4 puberty-related genes (ESR1, JAK2, NF1 and ARNT) were found in this study. The A3SS events were the most alternative splicing, but IR events were likely to be arose in post-pubertal ovaries. Besides, the circRNA-miRNA-gene networks were explored for 10 differentially expressed circRNAs. Furthermore, the head-to-tail exon as well as the expressions of 10 circRNAs were validated by the divergent RT-qPCR and sanger sequencing. Conclusions In summary, the profiles of ovarian circRNAs were provided during pubertal transition in gilts, and these results provided useful information for the investigation on the onset of puberty at the ovarian-circRNAs-level in mammals.

The uterine endometrium, which lines the mammalian uterus, is essential for embryo implantation. This lining undergoes significant changes during sexual and menstrual cycles. The endometrium is also associated with hormone-related diseases such as endometriosis and endometrial cancer. Circular RNAs (circRNAs) play a role in various biological processes. Recent studies have determined that circRNAs function in both normal and pathological endometrial environments. Here, we review high-throughput studies pertaining to circRNAs as well as individual circRNAs active in the endometrium, in order to explore the myriad functions of circRNAs in the endometrium and mechanisms underlying these functions, from panoramic and individual perspectives. Owing to their abundant expression, stability, and small size, circRNAs have displayed potential usefulness as diagnostic markers and treatment targets for endometrial-related diseases. Therefore, the specific role of circRNAs in the endometrium warrants systematic investigation in the future.

Background Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. Methods In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. Results circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. Conclusions FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.

Background Cryptosporidium is an important zoonotic pathogen responsible for severe enteric diseases in humans and animals. However, the molecular mechanisms underlying host and Cryptosporidium interactions are still not clear. Methods To study the roles of circRNAs in host cells during Cryptosporidium infection, the expression profiles of circRNAs in HCT-8 cells infected with C. parvum were investigated using a microarray assay, and the regulatory role of a significantly upregulated circRNA, ciRS-7, was investigated during C. parvum infection. Results C. parvum infection caused notable alterations in the expression profiles of circRNAs in HCT-8 cells, and a total of 178 (including 128 up- and 50 downregulated) circRNAs were significantly differentially expressed following C. parvum infection. Among them, ciRS-7 was significantly upregulated and regulated the NF-κB signaling pathway by sponging miR-1270 during C. parvum infection. Furthermore, the ciRS-7/miR-1270/relA axis markedly affected the propagation of C. parvum in HCT-8 cells. Conclusions Our results revealed that ciRS-7 would promote C. parvum propagation by regulating the miR-1270/relA axis and affecting the NF-κB pathway. To the best of our knowledge, this is the first study to investigate the role of circRNA during Cryptosporidium infection, and the findings provide a novel view for implementing control strategies against Cryptosporidium infection. Graphical Abstract

Depression is the second most common disease burden worldwide that threatens human health; however, mechanisms underlying the development of depression remain unclear. A family of non-coding RNAs, circular RNAs (circRNAs), has been shown to play a critical role in the development of depression by competitively binding to certain microRNAs (miRNA) and regulating the expression of target genes. Behavioral symptoms of depression may be ameliorated by knockdown or overexpression of depression-associated circRNAs. In this review, we summarized important functions of circRNAs and analyzed the most recent findings regarding the expression and biological function of circRNAs in depression. We discussed novel circRNA-based strategies to illuminate potential therapeutic targets that may aid in the development of new treatments for depression.

Vasculogenic mimicry (VM) is a vascular formation mechanism used by aggressive tumor cells. VM provides an alternative pathway for adequate blood perfusion and challenges the traditional angiogenesis mechanism that depends only on endothelial cells (ECs), as VM-forming tumor cells express a mixed endothelial/tumor phenotype. VM is closely correlated with tumor invasion, migration, and progression. Hence, anticancer therapeutic strategies targeting VM biogenesis are essential. It is widely acknowledged that the VM formation mechanism involves multiple pathways. The purpose of this review is to describe the potential molecular mechanisms related to different pathways and discuss the involvement of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in VM formation. Moreover, we discuss the significance of VM in clinical practice and present new anticancer therapeutic strategies that target VM.

Circular RNAs (circRNAs) are becoming new therapeutic drug targets. However, their profiles under astilbin treatment have not been reported yet. In this study, we analysed the global reprogramming of circRNA transcriptome and a regulatory network of circRNAs with their targeted genes under astilbin treatment in pulmonary fibrosis. A total of 145 circRNAs were differentially expressed in the astilbin‐treated group compared with the bleomycin‐treated group using RNA sequencing. In the bleomycin‐ and astilbin‐treated groups, 29 coexpressed circRNAs were found. The maximum number of circRNAs was distributed on chromosome two, and their length varieties were mainly within 1000 bp. Four differentially expressed circRNAs (circRNA‐662, 949, 394 and 986) were tested to validate the RNA sequencing data, and their targeted microRNAs and genes were analysed by qRT‐PCR, Western blot, Pearson correlation coefficient, a dual‐luciferase reporter system and anti‐AGO2 RNA immunoprecipitation. The results showed that circRNA‐662 and 949 can act as “miR‐29b sponges” targeting Gli2 and STAT3 to exert their functions. Our work suggests that the transcriptome complexity at the circRNA level under astilbin treatment. These circRNAs may be potential molecular targets for drug action.