Hepatocellular carcinoma (HCC), primarily caused by chronic hepatitis B virus (HBV) infection, remains a leading cause of liver cancer worldwide. Despite advances in antiviral therapies, persistent HBV replication, mediated by covalently closed circular DNA (cccDNA), contributes to poor prognoses and frequent recurrence of HCC. This study investigates for the first time the role of circular RNA circBRWD1 in HBV-related HCC, aiming to elucidate its function and regulatory mechanism in HBV replication and hepatocarcinogenesis. Results showed that circBRWD1 was significantly overexpressed in HBV-positive HCC tissues and cell lines compared to HBV-negative controls and promoted HBV replication by increasing cccDNA accumulation. Silencing circBRWD1 markedly reduced the levels of HBV DNA, HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and HBV core antigen (HBcAg), indicating its critical role in HBV replication. Functionally, circBRWD1 knockdown led to reduced cell proliferation, colony formation, and migration while increasing apoptosis in HCC cells. Mechanistic studies revealed that circBRWD1 acts as a sponge for miR-513a-5p, thereby upregulating TNPO1, a key player in promoting HCC malignancy. Rescue experiments confirmed that TNPO1 overexpression reversed the effects of circBRWD1 depletion, restoring cell proliferation, migration, and HBV replication. Additionally, circBRWD1 depletion significantly reduced tumor growth with reduced expression of TNPO1 and increased miR-513a-5p levels in a mouse xenograft model. Collectively, this study identifies circBRWD1 as a key oncogenic circRNA that facilitates HBV replication and HCC progression via the miR-513a-5p/TNPO1 axis. Targeting circBRWD1 may offer a novel therapeutic strategy for HBV-related HCC, potentially addressing the challenge of HBV persistence and improving patient outcomes.

Circular RNAs (circRNAs) are a large family of non-coding RNAs characterized by a single-stranded, covalently closed structure, predominantly synthesized through a back-splicing mechanism. While thousands of circRNAs have been identified, only a few have been functionally characterized. Although circRNAs are less abundant than other RNA types, they exhibit exceptional stability due to their covalently closed structure and demonstrate high cell and tissue specificity. CircRNAs play a critical role in maintaining cellular homeostasis by influencing gene transcription, translation, and post-translation processes, modulating the immune system, and interacting with mRNA, miRNA, and proteins. Abnormal circRNA expression has been associated with a wide range of human diseases and various infections. Due to their remarkable stability in body fluids and tissues, emerging research suggests that circRNAs could serve as diagnostic and therapeutic biomarkers for these diseases. This review focuses on the emerging role of circRNAs in various human diseases, exploring their biogenesis, molecular functions, and potential clinical applications as diagnostic and therapeutic biomarkers with current evidence, challenges, and future perspectives. The key theme highlights the significance of circRNAs in regulating gene expression, their involvement in diseases like cancer, neurodegenerative disorders, cardiovascular diseases, and diabetes, and their potential use in translational medicine for developing novel therapeutic strategies. We also discuss recent clinical trials involving circRNAs. Thus, this review is important for both basic researchers and clinical scientists, as it provides updated insights into the role of circRNAs in human diseases, aiding further exploration and advancements in the field.

Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.

Gastric cancer is the fifth most common malignancy and the fifth primary cause of death from cancer all over the world. Because of diagnosis of gastric cancer at advanced, incurable stages and limited response to treatment, the disease has an adverse prognosis and a low survival rate. Chemotherapy consisting of medications such as platinum and 5-Fluorouracil can be effective for patients with advanced stomach cancer. Nevertheless, drug resistance eventually leads to unsuccessful therapy and adverse outcomes for gastric cancer patients. Most therapy failures in gastric cancer patients undergoing chemotherapy are caused by the development of drug resistance. Several studies have shown that noncoding RNAs (ncRNAs) play important roles in the resistance of gastric cancer to chemotherapy drugs. The development of stomach cancer is greatly impacted by a number of ncRNAs, including microRNAs (e.g., miR-21, miR-27a), circular RNAs (e.g., CircPVT1), and long noncoding RNAs (e.g., HOTAIR). Because of their regulatory characteristics in certain genes implicated in the chemoresistant phenotype of gastric cancer, much evidence has demonstrated their function in the emergence and persistence of drug resistance. In the future, ncRNA-based treatment could represent a novel approach to treating drug resistance. Despite numerous studies on anticancer drug resistance mechanisms, it is still unclear how these mechanisms are regulated. In this review, we investigated the evolving function and molecular mechanisms of ncRNAs related to drug resistance, their function in controlling drug resistance in gastric cancer, and their potential to create targeted therapeutics for reducing drug resistance in gastric cancer.

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

Litter size is a crucial quantitative trait in animals, closely linked to follicular development. Circular RNA (circRNA), a type of single-stranded closed-loop endogenous RNA with stable expression, plays pivotal roles in various biological processes, yet its function in goat follicular development remains unclear. In this study, we collected large (follicle diameter > 3 mm) and small (1 mm < follicle diameter < 3 mm) follicles from black goats in the Chuanzhong region for circRNA sequencing, with the aim of elucidating the functional circRNAs that influence follicle development in goats. Differential analysis revealed that 17 circRNAs were upregulated in large follicles, and 28 circRNAs were upregulated in small follicles. Functional enrichment analysis revealed significant enrichment of pathways related to reproduction, including cellular response to follicle-stimulating hormone stimulus, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and the Notch signaling pathway. Based on the ceRNA mechanism, 45 differentially expressed circRNAs were found to target and bind a total of 418 miRNAs, and an intercalation network including miR-324-3p (circRNA2497, circRNA5650), miR-202-5p (circRNA3333, circRNA5501), and miR-493-3p (circRNA4995, circRNA5508) was constructed. In addition, conservation analysis revealed that 2,239 circRNAs were conserved between goats and humans. Prediction of translation potential revealed that 154 circRNAs may potentially utilize both N6-methyladenosine (m6A) and internal ribosome entry site (IRES) translation mechanisms. Furthermore, the differential expression and circularization cleavage sites of five circRNAs were validated through RT-qPCR and DNA sequencing. Our study constructed a circRNA map in goat follicle development, offering a theoretical foundation for enhancing goat reproductive performance.

The interactions among circRNAs, the PI3K/AKT pathway, and their downstream effectors are intricately linked to their functional roles in tumorigenesis. Furthermore, the circRNAs/PI3K/AKT axis has been significantly implicated in the context of digestive system tumors. This axis is frequently abnormally activated in digestive cancers, including gastric cancer, colorectal cancer, pancreatic cancer, and others. Moreover, the overactivation of the circRNAs/PI3K/AKT axis promotes tumor cell proliferation, suppresses apoptosis, enhances invasive and metastatic capabilities, and contributes to drug resistance. In this regard, gaining crucial insights into the complex interaction between circRNAs and the PI3K/AKT pathway holds great potential for elucidating disease mechanisms, identifying diagnostic biomarkers, and designing targeted therapeutic interventions.

The metabolism of cancer has been an interesting hallmark and metabolic reprogramming, especially the change from oxidative phosphorylation in mitochondria to glucose metabolism known as glycolysis occurs in cancer. The molecular profile of glycolysis, related molecular pathways and enzymes involved in this mechanism such as hexokinase have been fully understood. The glycolysis inhibition can significantly decrease tumorigenesis. On the other hand, circRNAs are new emerging non-coding RNA (ncRNA) molecules with potential biological functions and aberrant expression in cancer cells which have received high attention in recent years. CircRNAs have a unique covalently closed loop structure which makes them highly stable and reliable biomarkers in cancer. CircRNAs are regulators of molecular mechanisms including glycolysis. The enzymes involved in the glycolysis mechanism such as hexokinase are regulated by circRNAs to modulate tumor progression. Induction of glycolysis by circRNAs can significantly increase proliferation rate of cancer cells given access to energy and enhance metastasis. CircRNAs regulating glycolysis can influence drug resistance in cancers because of theirimpact on malignancy of tumor cells upon glycolysis induction. TRIM44, CDCA3, SKA2 and ROCK1 are among the downstream targets of circRNAs in regulating glycolysis in cancer. Additionally, microRNAs are key regulators of glycolysis mechanism in cancer cells and can affect related molecular pathways and enzymes. CircRNAs sponge miRNAs to regulate glycolysis as a main upstream mediator. Moreover, nanoparticles have been emerged as new tools in tumorigenesis suppression and in addition to drug and gene delivery, then mediate cancer immunotherapy and can be used for vaccine development. The nanoparticles can delivery circRNAs in cancer therapy and they are promising candidates in regulation of glycolysis, its suppression and inhibition of related pathways such as HIF-1α. The stimuli-responsive nanoparticles and ligand-functionalized ones have been developed for selective targeting of glycolysis and cancer cells, and mediating carcinogenesis inhibition.

The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes "(IRS-4 or IRS4)", or the combination of these terms with the word "(cancer)" or "(human)", for searches. Terms related to specific tumor pathologies ("breast", "ovary", "colon", "lung", "lymphoma", etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.

Evidence indicates that circular RNAs (circRNAs) may play an important role in regulating gene expression by binding to miRNAs through miRNA response elements. circRNAs are formed by back-splicing and have a covalently closed structure. The biogenesis of circRNAs also appears to be regulated by certain cell-specific and/or gene-specific mechanisms, and thus some circRNAs are tissue specific and tumor-expression specific. Furthermore, the high stability and tissue specificity of circRNAs may be of value for early diagnosis, survival prediction and precision medicine. This review summarizes current knowledge regarding the classification and functions of circRNAs and the role of circRNAs in regulating the PI3K/AKT and/or MEK/ERK signaling pathways in digestive tract malignancy tumors.

Circular RNAs (circRNAs) are endogenous covalently closed non-coding RNAs produced by reverse splicing of linear RNA. These molecules are highly expressed in mammalian cells and show cell/tissue-specific expression patterns. They are also significantly dysregulated in various cancers and function as oncogenes or tumor suppressors. Emerging evidence reveals that circRNAs contribute to cancer progression via modulating different cell signaling pathways. Nevertheless, the functional significance of circRNAs in cell signaling pathways regulation is still largely elusive. Considering this, shedding light on the multi-pathway effects of circRNAs may improve our understanding of targeted cancer therapy. Here, we discuss how circRNAs regulate the major cell signaling pathways in human cancers.

We adopted a systematic search in PubMed using the following MeSH terms: circRNAs, non-coding RNAs, lncRNAs, exosomal circRNAs, cancer, and cell signaling.

We discussed different roles of circRNAs during tumorigenesis in which circRNAs affect tumor development through activating or inactivating certain cell signaling pathways via molecular interactions using various signaling pathways. We also discussed how crosstalk between circRNAs and lncRNAs modulate tumorigenesis and provides a resource for the identification of cancer therapeutic targets.

We here elucidated how circRNAs can modulate different cell signaling pathways and play roles in cancer. This can broaden our horizons toward introducing promising prognostic, diagnostic, and therapeutic targets.

Gastric cancer (GC) is one of the leading malignancies of the digestive system. Circular RNAs (circRNAs) are well-established to play critical regulatory roles in GC development. The current study sought to explore the effects and regulatory mechanism of circ_0001013 in the course of GC.

First, differential circRNAs and related mechanisms in GC were predicted by microarray analysis. Circ_0001013, microRNA (miR)-136, and TWSG1 expression patterns were subsequently detected in GC clinical samples and cells using RT-qPCR. The relationship among circ_0001013, miR-136, and TWSG1 was further assessed by dual-luciferase reporter assay, biotin-coupled probe pull-down assay, and biotin-coupled miRNA capture. Based on gain- and loss-of-function assays, GC cell proliferation, migration, invasion, and the cell cycle and apoptosis were also measured by 5-ethynyl-2'-deoxyuridine (EdU) assay, scratch test, Transwell assay, and flow cytometry, respectively. Moreover, the effect of circ_0001013 on tumor growth was detected by tumor xenografting in nude mice.

Circ_0001013 was predicted to be up-regulated in GC by microarray profiling, which was confirmed by RT-qPCR detection in GC tissues and cells. miR-136 was poorly expressed, and TWSG1 was highly expressed in GC tissues. Mechanistically, circ_0001013 bound to miR-136, which negatively targeted TWSG1 in the GC cells. Silencing circ_0001013 or TWSG1 or over-expressing miR-136 led to decreased GC cell proliferation, migration, invasion, and cell cycle arrest and enhanced apoptosis. Furthermore, silencing circ_0001013 resulted in diminished TWSG1 expression and inhibited transplanted tumor growth in the nude mice.

Collectively, our findings indicated that circ_0001013 increased TWSG1 expression by binding to miR-136, thereby exerting oncogenic effects in GC.

Pancreatic cancer is a malignancy of rising incidence, especially in developed countries due to causes such as sedentary lifestyles, tobacco smoking and ultraprocessed high fat and high sugar diets, amongst others. It is in fact the 7th cause of cancer-related deaths worldwide, and, in the following years, it is expected to climb upwards to 2nd position, after lung cancer. This is because it may have an asymptomatic course, and when it becomes evident it is in advanced stages, accompanied by metastasis generally. For this reason, survival rates are so low and, even in the few successful cases there is a high possibility of recurrence. Identifying new molecular biomarkers is arising as a highly useful tool for pancreatic cancer clinical management, although much research and work remain to be done in this field. Thus, the present study aims to analyze a series of molecules (IRS-4, Rb1, Ki-67 y COX-2) as candidates for prognosis and survival by immunohistochemistry techniques. Additionally, a 60-month longitudinal surveillance program was conducted, associated with diverse clinical parameters. Kaplan-Meier curves estimating the time of survival according to tumoral expression of those molecules denoted a low cumulative survival rate. Importantly, we observed that high levels of IRS-4 were significantly associated with a bad prognosis of the disease, increasing 160 times the mortality risk. In this way, our research showed a relevant value of these biomarkers in pancreatic cancer patients' survival, opening a pathway for future research areas designed to inhibit these components.

Nocardia rubra cell-wall skeleton (Nr-CWS) is reported as an external immunotherapeutic enhancer with the advantage of antitumor effect on human cancers. However, the immune regulatory role of Nr-CWS is not fully illustrated. We studied mouse CD4+ T lymphocytes isolated from mice spleen were induced by Nr-CWS and observed that the differentiation of Th1 CD4+ T cells and the cytokines of IL-2, TNF-α, IFN-γ were all enhanced by Nr-CWS. Furthermore, RNA sequencing was conducted to investigate the different mRNA profiling induced by Nr-CWS. We observed that paired box 8 (PAX8) was significantly up-regulated in Nr-CWS-treated Th1 cells compared to control. As a transcription factor, chromatin immunoprecipitation sequencing was carried out to study the genome-wide distribution of PAX8. Interestingly, we found that the binding domain of PAX8 was elevated by Nr-CWS, and the target genes associated with these binding sites showed a positive correlation between their transcription and PAX8 binding strength. Finally, we determined that Nr-CWS could enhance the activity of the PI3 K/Akt signaling pathway. Akt agonist could mimic the effect of Nr-CWS for PAX8 up-regulation, while Akt inhibitor compromised the expression of PAX8. Taken together, we determined a novel role of Nr-CWS in boosting the activity of Th1 maturation via the PI3 K/Akt/PAX8 axis.

Circular RNAs (circRNAs), covalently closed noncoding RNAs, are widely expressed in eukaryotes and viruses. They can function by regulating target gene expression, linear RNA transcription and protein generation. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays key roles in many biological and cellular processes, such as cell proliferation, growth, invasion, migration, and angiogenesis. It also plays a pivotal role in cancer progression. Emerging data suggest that the circRNA/PI3K/AKT axis modulates the expression of cancer-associated genes and thus regulates tumor progression. Aberrant regulation of the expression of circRNAs in the circRNA/PI3K/AKT axis is significantly associated with clinicopathological characteristics and plays an important role in the regulation of biological functions. In this review, we summarized the expression and biological functions of PI3K-AKT-related circRNAs in vitro and in vivo and assessed their associations with clinicopathological characteristics. We also further discussed the important role of circRNAs in the diagnosis, prognostication, and treatment of cancers.

Yiqi-Huoxue granule (YQHX), consisting of four kinds of traditional Chinese medicine, is an empirical prescription for the treatment of coronary heart disease. It is known to promote angiogenesis, but the mechanism is unknown.

This article investigates the possible mechanism of YQHX inducing angiogenesis in the ischemic myocardium.

EAhy.926 cells were treated with YQHX hypoxic cardiomyocyte-conditioned medium (YHMCM) and the levels of VEGF, CD34, and phosphorylation of PI3K/Akt were detected by western blotting. Also, the effects on endothelial tube formation and migration were observed. The level of miR-126 was detected by qRT-PCR.

YQHX promoted tube formation and migration of EAhy.926 cells and upregulated VEGF, CD34, and the phosphorylation of PI3K/AKT via regulating miR-126 levels. However, these effects were inhibited by a miR-126 inhibitor.

In summary, YQHX improves angiogenesis by regulating the miR-126/PI3K/Akt signaling pathway, which indicates that YQHX could be a promising therapeutic strategy for ischemic myocardium.