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Myocardial infarction, a coronary heart disease, is a serious hazard to human health. Cardiomyocyte oxidative stress and apoptosis have been considered as the main causes of myocardial infarction. Here, we aimed to investigate the role of miR-615-3p in oxidative stress and apoptosis of human cardiomyocytes. Reverse transcription-quantitative polymerase chain reaction was performed to determine miR-615-3p or MEF2A expression in human cardiomyocytes. Apoptosis and viability of human cardiomyocytes were assessed by flow cytometry analysis and CCK-8 assay. In addition, the contents of malondialdehyde, reactive oxygen species, and superoxide dismutase were detected by corresponding commercial kits. The binding of miR-615-3p and MEF2A in human cardiomyocytes was examined by luciferase reporterassay. Hypoxia/reoxygenation treatment downregulated the expression level ofmiR-615-3p in human cardiomyocytes. Overexpressing miR-615-3p increased human cardiomyocyte viability and decreased human cardiomyocyte apoptosis. Moreover, miR- 615-3p mimics suppressed oxidative stress in hypoxia/reoxygenation-stimulated human cardiomyocytes. MEF2A was confirmed as a target gene of miR-615-3p and was highly expressed in hypoxia/reoxygenation-stimulated human cardiomyocytes, and its upregu-lation partially reversed the influence of miR-615-3p mimics on oxidative stress and apop-tosis of human cardiomyocytes. Moreover, miR-615-3p inactivated the P13K/Akt pathway by inhibiting MEF2A. Overexpression of miR-615-3p protects human cardiomyocytes from oxida-tive stress injury by targeting MEF2A via the PI3K/Akt signaling.

Drug resistance restrains the effect of drug therapy in non-small cell lung cancer (NSCLC). However, the mechanism of the acquisition of drug resistance remains largely unknown. This study aims to investigate the effect of exosomal lncRNA H19 on erlotinib resistance in NSCLC and the underlying mechanism. HCC827 and A549 cells were continuously grafted into erlotinib-containing culture medium to establish erlotinib-resistant cell lines. The expression of H19 and miR-615-3p was detected by qRT-PCR. The protein levels of MMP2, MMP9, CD9, CD63 and ATG7 were measured by Western blot. Cell viability and proliferation were determined by Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, respectively. Migration and invasion were assessed by transwell assay. Xenograft tumor models were used to investigate the effect of H19 on erlotinib resistance in vivo. Online software and dual-luciferase reporter assay were used to predicate the downstream targets and confirm the targeted relationships. H19 was upregulated in erlotinib-resistant cells, and knockdown of H19 inhibited cell proliferation, migration and invasion in erlotinib-resistant cells. Extracellular H19 can be packaged into exosomes. Exosomes containing H19 induced erlotinib resistance of sensitive cells, while knockdown of H19 abolished this effect. miR-615-3p was a target of H19 and can bind to ATG7. Exosomal H19 affected erlotinib resistance of erlotinib-resistant NSCLC cells via targeting miR-615-3p to regulate ATG7 expression. In addition, the serum exosomal H19 was upregulated in patients with erlotinib resistance. Furthermore, downregulated H19 decreased the resistance of tumor cells to erlotinib in vivo. Our study demonstrated that exosomal H19 facilitated erlotinib resistance in NSCLC via miR-615-3p/ATG7 axis, which might provide a potential target for the diagnosis and treatment of NSCLC.

Background Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear. Methods Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays. Results Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine. Conclusion Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC.

Background Increasing evidence indicates that epithelial-mesenchymal transition (EMT) can be regulated by microRNAs (miRNAs). miR-615-3p was shown to be involved in tumor development. However, the role of miR-615-3p in the metastasis of breast cancer remains largely unknown. Methods The expression of miR-615-3p in breast cancer cells and tissues was assessed by qRT-PCR and situ hybridization assays. Effects of miR-615-3p on tumor metastasis were evaluated with experiments in vitro and mouse model. EMT markers were detected by western blot and immunofluorescence assays. Molecular mechanism of miR-615-3p in the regulation of breast cancer cell metastasis was analyzed by Western Blot, Co-immunoprecipitation, and Luciferase assay. Results In the present study, we found that miR-615-3p was significantly elevated in breast cancer cells and tissues, especially in those with metastasis. In breast cancer cell lines, stable overexpression of miR-615-3p was sufficient to promote cell motility in vitro, and pulmonary metastasis in vivo, accompanied by the reduced expression of epithelial markers and the increased levels of mesenchymal markers. Further studies revealed that the reintroduction of miR-615-3p increased the downstream signaling of TGF-β, the type I receptor (TGFBRI) by targeting the 3′-untranslated regions (3′-UTR) of PICK1. PICK1 inhibits the binding of DICER1 to Smad2/3 and the processing of pre-miR-615-3p to mature miR-615-3p in breast cancer cells, thus exerting a negative feedback loop. Conclusions Our data highlight an important role of miR-615-3p in the molecular etiology of breast cancer, and implicate the potential application of miR-615-3p in cancer therapy.

Mounting evidence indicates that long non-coding RNAs influence the progression of cervical cancer, but the precise function of LINC01503 in the pathogenesis of the disease remains unknown. Here, we found higher levels of LINC01503 in cervical cancer tissues. High LINC01503 expression was associated with enhanced progression of cervical cancer as indicated by advanced FIGO stage, increased metastasis of tumor cells to lymph nodes, and invasion into deeper cervical tissues. LINC01503 inhibition markedly suppressed the invasion and proliferative ability of tumor cells. Mechanistically, LINC01503 was demonstrated to negatively modulate the expression of miR-615-3p in cervical cancer. CCND1 was found to be a target of miR-615-3p. Rescue experiments indicated that LINC01503 inhibition suppressed the invasion and proliferative ability of the tumor cells, a phenomenon that was reversed following miR-615-3p inhibition or CCND1 overexpression. Collectively, these data indicate that LINC01503 enhances the progression of cervical cancer cells via interaction with miR-615-3p/CCND1 axis.

Background Ovarian cancer (OC) is a malignancy among female globally. Circular RNAs (circRNAs) are a family of circular endogenous RNAs generated from selective splicing, which take part in many traits. Former investigation suggested that circ-TFRC was abnormally expressed in breast cancer (BC). Further, the role of circ-TFRC to the progress of OC remains unclear. So, the aim of this study was to reveal the regulatory mechanism of circ-TFRC. Methods Our team made the luciferase reporter assay to validate circ-TFRC downstream target. Transwell migration assay, 5-ethynyl-20-deoxyuridine, and cell counting kit-8 were applied to investigate both proliferation and migration. In vivo tumorigenesis and metastasis assays were performed to investigate the circ-TFRC role in OC. Results The outputs elucidated that circ-TFRC expression incremented in OC cells and tissues. circ-TFRC downregulation inhibited OC cell proliferation as well as migration in in vivo and in vitro experiments. The luciferase results validated that miR-615-3p and IGF2 were circ-TFRC downstream targets. IGF2 overexpression or miR-615-3p inhibition reversed OC cell migration after circ-TFRC silencing. Also, IGF2 overexpression reversed OC cell migration and proliferation post miR-615-3p upregulation. Conclusion Results demonstrate that circ-TFRC downregulation inhibits OC progression and metastasis via IGF2 expression regulation and miR-615-3psponging.

Background Osteosarcoma (OS) is the most common primary malignant bone neoplasm. Growing researches have highlighted the tumor promoting role of miR-615-3p in various cancers. Notwithstanding, the biological function and underlying mechanisms of miR-615-3p in OS development still unclear. Methods Quantitative Real-Time PCR analysis (qRT-PCR) and RNA fluorescence in situ hybridization (FISH) staining were performed to measure miR-615-3p expression in OS. CCK-8 assay, colony formation assay and EdU assay were applied to analyze the OS cell proliferation activity. Cell metastasis abilities were evaluated using Transwell assays. Analysis of apoptosis was performed based on flow cytometric detection. The potential mechanisms of miR-615-3p in OS progression were investigated through RNA immunoprecipitation (RIP) assays, dual-luciferase reporter assays, qRT-PCR and western blotting. In vivo experiments, mouse xenograft model was carried out to assess the tumorigenicity of miR-615-3p. Results This study demonstrated a significant upregulation of miR-615-3p in OS. In addition, miR-615-3p knockdown suppressed OS proliferation, invasion, metastasis and EMT. Mechanistically, miR-615-3p regulated sestrin 2 (SESN2) expression negatively by targeting its 3’UTR. Moreover, silencing SESN2 facilitated OS progression and activated mTOR pathway. Noteworthy, the anticancer functions of miR-615-3p knockdown were partially recovered by SESN2 silencing. Taken together, the miR-615-3p/SESN2/mTOR pathway is critical for regulating OS progression. Conclusion Our results revealed that miR-615-3p modulated mTOR signaling, thus influencing the progression of OS. For OS treatment, molecular strategies that target the miR-615-3p/SESN2/mTOR pathway is promising.

Background Osteoarthritis (OA) is a widespread chronic joint disorder characterized by progressive cartilage degeneration, leading to substantial impairment in quality of life for millions of individuals globally. Cellular senescence has been increasingly recognized as a central contributor to OA pathogenesis, with senescent chondrocytes exhibiting a senescence-associated secretory phenotype that promotes tissue destruction. Long non-coding RNAs (lncRNAs) are known to play essential roles in maintaining cartilage homeostasis; however, their regulatory functions in OA remain poorly defined. This study aimed to elucidate the expression patterns, biological roles, and molecular mechanisms of lncRNA HOXC-AS3 in chondrocyte physiology and OA development. Results HOXC-AS3 expression was markedly reduced in OA-affected cartilage tissues and in human chondrocytes exposed to IL-1β. Functional analyses revealed that HOXC-AS3 knockdown suppressed chondrocyte proliferation, accelerated cellular senescence, and disrupted extracellular matrix homeostasis, whereas its overexpression ameliorated IL-1β-induced chondrocyte dysfunction. Mechanistically, HOXC-AS3 operates through two distinct pathways: acting as a competing endogenous RNA by directly sequestering miR-615-3p, and physically interacting with ribosome-binding protein 1 (RRBP1). Both pathways converge to regulate the expression of citron rho-interacting serine/threonine kinase (CIT), a critical modulator of the cell cycle. Notably, CIT knockdown mimicked the phenotypic effects of HOXC-AS3 deficiency, while HOXC-AS3 overexpression preserved chondrocyte function by sustaining CIT expression under inflammatory stress. Conclusions This study establishes lncRNA HOXC-AS3 as a key regulator of chondrocyte homeostasis that mitigates OA progression via dual mechanisms—miR-615-3p sponging and RRBP1 interaction—both of which maintain CIT expression. These findings advance the understanding of the molecular networks underlying OA pathogenesis and underscore HOXC-AS3 and its downstream signaling axis as promising therapeutic targets for OA intervention.

Background Mesenchymal stem cells (MSCs) are critical for dental tissue regeneration, yet their differentiation potential is tightly regulated by microRNAs (miRNAs). This study aimed to investigate the role of miR-615-3p in regulating odontogenic differentiation in stem cells from the apical papilla (SCAPs), offering insights into potential applications for enhancing dental tissue regeneration and repair. Methods Quantitative PCR (qPCR), Western blot analysis, alkaline phosphatase (ALP) activity assay, and Alizarin Red staining (ARS) were performed to assess odontogenic differentiation following miR-615-3p modulation in SCAPs. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels, membrane potential, and respiratory activity. In vivo, SCAPs with miR-615-3p modulation were transplanted into rabbit extraction sockets to examine dentin-like tissue formation. Results miR-615-3p was significantly downregulated in SCAPs compared to umbilical cord mesenchymal stem cells (WJCMSCs) and further decreased during mineralization induction, suggesting its negative regulatory role in odontogenic differentiation. Inhibition of miR-615-3p enhanced ALP activity, mineralization, and odontogenic marker expression both in vitro and in vivo. Proteomic analysis revealed that miR-615-3p inhibition improved mitochondrial function by reducing ROS levels and increasing mitochondrial function. Further Competing Endogenous RNA Sequencing(ceRNA-seq) analysis identified PVT1 as a downstream target of miR-615-3p. PVT1 overexpression promoted odontogenic differentiation and mitochondrial homeostasis, while its knockdown impaired these processes. Collectively, the miR-615-3p/PVT1 axis emerged as a critical regulator of dentinogenesis through mitochondrial modulation. Conclusions Inhibiting miR-615-3p fosters dentinogenesis through PVT1-mediated mitochondrial regulation in SCAPs. These findings highlight the miR-615-3p/PVT1 axis as a promising target for enhancing dentin tissue engineering applications.

Background: Polymorphisms of long noncoding RNAs are lately documented as hazardous factors for the development of numerous tumors. Furthermore, the evaluation of noncoding RNAs has emerged as a novel detector of breast cancer patients. We aimed to genotype the HOXA transcript at the distal tip (HOTTIP) rs1859168 and assess its relationship with the levels of the serum HOTTIP and its target miR-615-3p in patients with breast cancer (BC). Methods: One hundred and fifty-one patients with BC, 139 patients with fibroadenoma (FA), and 143 healthy participants were incorporated into the current study. The genotyping of rs1859168 and the measurements of the HOTTIP and miR-615-3p levels were assessed using quantitative real-time PCR. Results: We revealed a significant association between each of the CC genotypes, C allele, dominant and recessive models, and the increased risk of BC (p = 0.013, p < 0.001, p < 0.001, and p < 0.001, respectively) relative to the healthy controls. Similarly, the CC genotype, C allele, and recessive model were observed to be related to the increased incidence of BC with respect to FA (p < 0.001 for all). A significant upregulation of HOTTIP and a marked decrease of miR-615-3p were verified in patients with BC compared to each of the healthy individuals, patients with FA, and the non-BC group (healthy subjects + FA) (p < 0.001 for all). A significant negative correlation was demonstrated between the expression of HOTTIP and miR-615-3p in the serum of patients with BC. The HOTTIP expression was upregulated, while that of miR-615-3p was downregulated in patients with BC who carried the CC genotype with respect to those who carried the AA or AC genotypes (p < 0.05 for all). Conclusions: The genetic variants of rs1859168 are linked to an increased susceptibility to BC. Moreover, HOTTIP and miR-615-3p may be used as novel indicators and targets for the treatment of patients with BC.