Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart\'s limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.

Ovarian cancer (OC) is one of the most common malignant tumors in women. Circular RNAs (circRNAs) can potentially regulate the development of OC. Therefore, this study investigated the role of circASXL1 in OC progression. Cell functions were assessed by MTT, colony formation, wound healing, and transwell assays. RIP and dual luciferase reporter assays confirmed the relationship between miR-320d and circASXL1 or RACGAP1. MeRIP was utilized to detect m6A levels. Xenograft tumor was established for in vivo experiments. CircASXL1 and RACGAP1 levels were increased in OC tissues and cells, whereas miR-320d expression was decreased. Upregulation of circASXL1 was associated with poor prognosis in OC patients. CircASXL1 silencing suppressed OC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, METTL3/IGF2BP1-mediated m6A modification maintained circASXL1 stability and upregulated its expression. CircASXL1 was a ceRNA that sequestrated miR-320d from RACGAP1, leading to increased RACGAP1 expression. CircASXL1 promoted OC cell proliferation, migration and invasion via the miR-320d/RACGAP1 axis. Therefore, m6A-modified circASXL1 acts as an oncogene in OC by targeting miR-320d and activating RACGAP1/PI3K/Akt pathway, which provides novel promising biomarkers for OC diagnosis.

UNASSIGNED: Non-small cell lung carcinoma (NSCLC) is a primary prevalent type of cancer in people worldwide. Cisplatin (DDP) has been widely used to treat NSCLC; however, its curative effect was restrained under hypoxia. In this study, the effects of hypoxia treatment on DDP resistance and NSCLC progression and underneath mechanism were revealed.
UNASSIGNED: The expression of circular RNA ASXL1 (circASXL1) and microRNA-206 (miR-206) in NSCLC tissues, cells and hypoxia-mediated NSCLC cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of proliferation, metastasis and apoptosis-related proteins, drug resistance-related protein and hypoxia-inducible factor-1alpha (HIF-1α) protein was detected by Western blot. The effects of circASXL1 knockdown on hypoxia-induced DDP resistance and NSCLC progression were revealed by cell counting kit-8 proliferation (CCK-8), cell colony formation, transwell and flow apoptosis assays. RNA immunoprecipitation (RIP) assay was performed to determine whether circASXL1 could form silence-inducing complexes with miRNA. The associated relationship between circASXL1 and miR-206 was predicted by circBank online database, and identified by RNA pull-down and dual-luciferase reporter assays. The effects between circASXL1 knockdown and miR-206 downregulation on tumor growth in vivo were investigated by in vivo tumor formation assay.
UNASSIGNED: CircASXL1 expression was dramatically upregulated, whereas miR-206 was significantly down-regulated in NSCLC tissues, cells and hypoxia-mediated NSCLC cells as compared to control groups. CircASXL1 knockdown reversed hypoxia-mediated promotion effects on DDP resistance, cell proliferation, migration, and invasion, and inhibition impact on cell apoptosis, whereas these effects were restored by miR-206 inhibitor. Additionally, circASXL1 was found to form silence-inducing complexes with miRNA and act as a sponge of miR-206. CircASXL1 silencing downregulated HIF-1α expression by controlling miR-206 expression. Furthermore, circASXL1 silencing repressed tumor growth in vivo by sponging miR-206.
UNASSIGNED: CircASXL1 knockdown inhibited DDP resistance, cell proliferation, migration and invasion, whereas induced cell apoptosis under hypoxia by associating with miR-206 in NSCLC. This study provides a new sight in treating NSCLC with DDP under hypoxia.

BACKGROUND: Colorectal cancer (CRC) is a common aggressive tumor that poses a heavy burden to human health. An increasing number of studies have reported that circular RNA (circRNA) is involved in the progression of CRC. In this study, the special profiles of circASXL1 (circ_0001136) in CRC progression were revealed.
METHODS: The expression of circASXL1, microRNA-1205 (miR-1205), and glutamate ionotropic receptor kainate type subunit 3 (GRIK3) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression was determined by Western blot or immunohistochemistry. Cell colony-forming ability was investigated by colony formation assay. Cell cycle and apoptosis were demonstrated using cell-cycle and cell-apoptosis analysis assays, respectively. Cell migration and invasion were detected by wound-healing and transwell migration and invasion assays, respectively. The binding sites between miR-1205 and circASXL1 or GRIK3 were predicted by circBank or miRDB online database, and identified by dual-luciferase reporter assay. The impact of circASXL1 on tumor formation in vivo was investigated by in vivo tumor formation assay.
RESULTS: CircASXL1 and GRIK3 expression were apparently upregulated, and miR-1205 expression was downregulated in CRC tissues and cells relative to control groups. CircASXL1 knockdown inhibited cell colony-forming ability, migration and invasion, whereas induced cell arrest at G0/G1 phase and cell apoptosis in CRC cells; however, these effects were attenuated by miR-1205 inhibitor. Additionally, circASXL1 acted as a sponge for miR-1205, and miR-1205 was associated with GRIK3. Furthermore, circASXL1 silencing hindered tumor formation by upregulating miR-1205 and downregulating GRIK3 expression.
CONCLUSIONS: CircASXL1 acted an oncogenic role in CRC malignant progression via inducing GRIK3 through sponging miR-1205. Our findings provide a theoretical basis for studying circASXL1-directed therapy for CRC.

Circular RNAs (circRNAs) as a family of non-coding RNAs are increasingly recognized regarding their biogenesis, regulatory roles in gene expression and clinic significance in developmental diseases and cancers. In this study, we aim to identify circRNAs that may be associated with clinicopathological characteristics of patients with bladder cancer. The circRNAs databases CircBase and circ2 Traits were used to seek circRNAs reported to bladder cancer. The expression levels of the circRNA of interest in paired samples of tumor tissue and adjacent normal mucosa from 61 patients with bladder cancer were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and statistically analyzed. Database search shows that circASXL1 (circBase ID: hsa_circ_0001136) transcribed from the ASXL1 gene locus is among the circRNAs with altered expressions in bladder cancer. Results showed that the expression level of circASXL1 was significantly higher in bladder cancer tissues compared to that in adjacent noncancerous tissues (P<0.001). To be noticed, chi-square tests support that the expression of circASXL1 significantly correlates with tumor grade (P=0.025), tumor stage (P=0.019), lymph node invasion (P=0.011) and distant metastasis (P=0.032). The area under ROC curve (AUC) is 0.770 for circASXL1 in predicting tumor invasion (T2-T4 tumors). Kaplan-Meier survival analysis indicates that tumors of high circASXL1 expression are associated with shorter overall survival compared to tumors of low circASXL1 expression. Further, multivariate analysis reveals that circASXL1 is an independent prognostic factor for overall survival for patients with bladder cancer. Expression of circASXL1 in bladder tumor correlates with TNM classification and may independently predict overall survival for patients with bladder cancer.