MiR-29b-3p Increases Radiosensitivity in Stemness Cancer Cells via Modulating Oncogenes Axis.
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ABSTRACT:
SUBMITTER: Pan D
PROVIDER: S-EPMC8481616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHyaluronan (HA) metabolism by chondrocytes is important for cartilage development and homeostasis. However, information about the function of circular RNAs (circRNAs) in HA metabolism is limited. We therefore profiled the role of the novel HA-related circRNA circHYBID in the progression of osteoarthritis (OA).MethodsCircHYBID function in HA metabolism in chondrocytes was investigated using gain-of-function experiments, and circHYBID mechanism was confirmed via bioinformatics analysis and luciferase assays. The expression of circHYBID-hsa-miR-29b-3p-transforming growth factor (TGF)-β1 axis was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. CircHYBID, TGF-β1, and HA levels in cartilage samples were evaluated using qRT-PCR and pathological examination. Enzyme-linked immunosorbent assay was used to assess HA accumulation in chondrocyte supernatant.ResultsCircHYBID expression was significantly downregulated in damaged cartilage samples compared with that in the corresponding intact cartilage samples. CircHYBID expression was positively correlated with alcian blue score. Interleukin-1β stimulation in chondrocytes downregulated circHYBID expression and decreased HA accumulation. Gain-of-function experiments revealed that circHYBID overexpression in chondrocytes increased HA accumulation by regulating HA synthase 2 and HYBID expression. Further mechanism analysis showed that circHYBID upregulated TGF-β1 expression by sponging hsa-miR-29b-3p.ConclusionsOur results describe a novel HA-related circRNA that could promote HA synthesis and accumulation. The circHYBID-hsa-miR-29b-3p-TGF-β1 axis may play a powerful regulatory role in HA metabolism and OA progression. Thus, these findings will provide new perspectives for studies on OA pathogenesis, and circHYBID may serve as a potential target for OA therapy.
| S-EPMC8165762 | biostudies-literature
Project description:Radiotherapy is frequently applied for clinically localized prostate cancer while its efficacy could be significantly hindered by radioresistance. MicroRNAs (miRNAs) are important regulators in mediating cellular responses to ionizing radiation (IR), and strongly associate with radiosensitivity in many cancers. In this study, enhancement of radiosensitivity by miR-29b-3p was demonstrated in prostate cancer cell line LNCaP in vitro. Results showed that miR-29b-3p expression was significantly upregulated in response to IR from both X-rays and carbon ion irradiations. Knockdown of miR-29b-3p resulted in radioresistance while overexpression of miR-29b-3p led to increased radiosensitivity (showing reduced cell viability, suppressed cell proliferation and decreased colony formation). In addition, miR-29b-3p was found to directly target Wnt1-inducible-signaling protein 1 (WISP1). Inhibition of WISP1 facilitated the mitochondrial apoptosis pathway through suppressing Bcl-XL expression while activating caspase-3 and poly (ADP-ribose) polymerase (PARP). The results indicated that miR-29b-3p was a radiosensitizing miRNAs and could enhance radiosensitivity of LNCaP cells by targeting WISP1. These findings suggested a novel treatment to overcome radioresistance in prostate cancer patients, especially those with higher levels of the WISP1 expression.
| S-EPMC7532503 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide, and cancer stem cell is responsible for the poor clinical outcome of NSCLC. Previous reports indicated that long noncoding RNAs (lncRNAs) play important roles in maintaining cancer stemness, however, the underlying mechanisms remain unclear. This study investigates the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC.MethodsThe expression of ASAP1-IT1, microRNA-509-3p (miR-509-3p) and apoptosis-/stemness-related genes was analyzed by qRT-PCR in NSCLC tissues, cancer cells and spheres of cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection of respective plasmids. Sphere formation and colony formation were used to detect NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays were used to analyze the interaction between lncRNA and miRNA. The expression of expression of regulated genes of ASAP1-IT1/miR-509-3p axis was evaluated by qRT-PCR and Western blot. The NSCLC xenograft mouse model was used to validate the role of ASAP1-IT1 in NSCLC stemness and tumor growth in vivo.ResultsASAP1-IT1 was up-regulated in NSCLC tissues, cancer cells, and in spheres of A549-derived cancer stem cells. Downregulation of ASAP1-IT1 or overexpression of miR-509-3p significantly decreased cell colony formation and stem cell-like properties of A549-dereived stem cells with decreased expression of stem cell biomarkers SOX2, CD34, and CD133, and suppressing the expression of cell growth-related genes, Cyclin A1, Cyclin B1, and PCNA. Furthermore, knockdown of ASAP1-IT1 or overexpression of miR-509-3p repressed tumor growth in nude mice via reducing expression of tumorigenic genes. ASAP1-IT1 was found to interact with miR-509-3p. Moreover, overexpression of ASAP1-IT1 blocked the inhibition by miR-509-3p on stem cell-like properties and cell growth of A549-dereived stem cells both in vitro and in vivo. Finally, the level of YAP1 was regulated by ASAP1-IT1 and miR-509-3p.ConclusionsYAP1-involved ASAP1-IT1/miR-509-3p axis promoted NSCLC progression by regulating cancer cell stemness, and targeting this signaling pathway could be is a promising therapeutic strategy to overcome NSCLC stemness.
| S-EPMC8555224 | biostudies-literature
Project description:Our current research aimed to decipher the role and underlying mechanism with regard to miR-29b-3p involving in myocardial ischemia/reperfusion (I/R) injury. In the present study, cardiomyocyte H9c2 cell was used, and hypoxia/reoxygenation (H/R) model was established to mimic the myocardial I/R injury. The expressions of miR-29b-3p and pentraxin 3 (PTX3) were quantified deploying qRT-PCR and Western blot, respectively. The levels of LDH, TNF-α, IL-1β and IL-6 were detected to evaluate cardiomyocyte apoptosis and inflammatory response. Cardiomyocyte viability and apoptosis were examined employing CCK-8 assay and flow cytometry, respectively. Verification of the targeting relationship between miR-29b-3p and PTX3 was conducted using a dual-luciferase reporter gene assay. It was found that miR-29b-3p expression in H9c2 cells was up-regulated by H/R, and a remarkable down-regulation of PTX3 expression was demonstrated. MiR-29b-3p significantly promoted of release of inflammatory cytokines of H9c2 cells, and it also constrained the proliferation and promoted the apoptosis of H9c2 cells. Additionally, PTX3 was inhibited by miR-29b-3p at both mRNA and protein levels, and it was identified as a direct target of miR-29b-3p. PTX3 overexpression could reduce the inflammatory response, increase the viability of H9c2 cells, and inhibit apoptosis. Additionally, PTX3 counteracted the function of miR-29b-3p during the injury of H9c2 cells induced by H/R. In summary, miR-29b-3p was capable of aggravating the H/R injury of H9c2 cells by repressing the expression of PTX3.
| S-EPMC7817735 | biostudies-literature
Project description:Palbociclib, a CDK4/6 inhibitor, has been granted accelerated approval by US FDA for hormone receptor-positive HER2-negative metastatic breast cancer. To determine potential biomarkers of palbociclib sensitivity to assist in patient selection and clinical development, we investigated the effects of palbociclib in a panel of molecularly characterized breast cancer cell lines. We quantified palbociclib sensitivity and c-myc expression in 11 breast cancer cell lines, 124 breast cancer samples, and The Cancer Genome Atlas database. We found non-TNBC subtypes were more sensitive to palbociclib than TNBC. Activation of c-myc led to differential palbociclib sensitivities, and further inhibition of c-myc enhanced palbociclib sensitivity. Moreover, we identified for the first time a c-myc/miR-29b-3p/CDK6 axis in breast cancer that could be responsible for c-myc-induced palbociclib insensitivity, in which c-myc activation resulted in downregulation of miR-29b-3p, further activated CDK6 and inhibited cell-cycle arrest at G1 phase. Moreover, downregulated (inactived) c-myc-induced oncogenic addiction could increase palbociclib efficacy, using both Xenograft model and patient-derived tumor xenograft (PDTX) model. Our finding extends the concept of combined blockade of the CDK4/6 and c-myc signaling pathways to increase palbociclib sensitivity, making c-myc a promising biomarker for palbociclib sensitivity in breast cancer.
| S-EPMC7493901 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) have been reported to be important regulators of the development and progression of various carcinomas. However, the role of circRNA_100290 in gastric cancer (GC) is still unclear. This study aimed to investigate the role of circRNA_100290 in GC invasion and metastasis and the possible underlying mechanism.MethodsThe expression of circRNA_100290 in GC cells and tissues was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The role of circRNA_100290 in cell proliferation, migration, and invasion was evaluated in the AGS and HGC-27 cell lines in vitro. Bioinformatics tools, dual-luciferase reporter assays, Western blot assays and qRT-PCR were used to explore the pathways downstream of circRNA_100290. The mechanism underlying the regulation of circRNA_100290 expression was explored using RNA immunoprecipitation, qRT-PCR, and Western blot assays.ResultsThe expression of circRNA_100290 was significantly upregulated in GC cells and 102 GC tissues, and high circRNA_100290 expression in GC was closely related to Borrmann's type, lymph node metastasis and tumour-node-metastasis stage. In vitro, knockdown of circRNA_100290 in AGS and HGC-27 cells significantly inhibited cell proliferation, migration, and invasion. Mechanistically, a dual-luciferase reporter assay confirmed the direct interaction between circRNA_100290 and miR-29b-3p, which targets ITGA11, an oncogene that is closely related to epithelial-mesenchymal transition (EMT). In addition, EIF4A3, an RNA-binding protein (RBP), could inhibit the formation of circRNA_100290 by binding to the flanking sites of circRNA_100290. Low EIF4A3 expression in GC was related to a poor prognosis.ConclusionsElevated circRNA_100290 expression in GC promotes cell proliferation, invasion and EMT via the miR-29b-3p/ITGA11 axis and might be regulated by EIF4A3. CircRNA_100290 might be a promising biomarker and target for GC therapy.
| S-EPMC8240270 | biostudies-literature
Project description:Radioresistant cervical cancer is likely to give rise to local recurrence, distant metastatic relapse, and decreased survival rates. Recent studies revealed microRNA mediated regulation of tumor aggressiveness and metastasis; however, whether specific microRNAs regulate tumor radioresistance and can be exploited as radiosensitizing agents remains unclear. Here, we find that miR-29b could promote radiosensitivity in radioresistant subpopulations of cervical cancer cells. Notably, therapeutic delivery of miR-29b mimics via R11-SSPEI nanoparticle, whose specificity has been proved by our previous studies, can sensitize the tumor to radiation in a xenograft model. Mechanistically, we reveal a novel function of miR-29b in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. Moreover, miR-29b inhibits DNA damage repair by targeting phosphate and tension homology deleted on chromsome ten (PTEN), and overexpression of PTEN could partially rescue miR-29b-mediated homologous recombination (HR)-DNA damage repair and increase radiosensitivity. These findings identify miR-29b as a radiosensitizing microRNA and reveal a new therapeutic strategy for radioresistant tumors.
| S-EPMC6554684 | biostudies-literature
Project description:BACKGROUND:The mechanism underlying breast cancer stem cell (BCSCs) characteristics remains to be fully elucidated. Accumulating evidence implies that long noncoding RNAs (lncRNAs) play a pivotal role in regulating BCSCs stemness. METHODS:LncRNA LUCAT1 expression was assessed in breast cancer tissues (n?=?151 cases) by in situ hybridization. Sphere-formation assay and colony formation assay were used to detect cell self-renewal and proliferation, respectively. RNA immunoprecipitation, RNA pull down and luciferase reporter assays were used to identify LUCAT1 and TCF7L2 as the direct target of miR-5582-3p. The activity of the Wnt/?-catenin pathway was analyzed by TOP/FOP-Flash reporter assays, western blot and immunohistochemistry (IHC). RESULTS:This study found LUCAT1 expression was related to tumor size (p?=?0.015), lymph node metastasis (p?=?0.002) and TNM staging (p?<?0.001). High LUCAT1 expression indicated a shorter overall survival (p?=?0.006) and disease-free survival (p?=?0.011). Furthermore, LUCAT1 was more expressed in BCSCs than in breast cancer cells (BCCs) by lncRNA microarray chips. LUCAT1 up-regulation promoted proliferation of BCCs, while LUCAT1 down-regulation inhibited self-renewal of BCSCs. MiR-5582-3p was directly bound to LUCAT1 and TCF7L2 and negatively regulated their expression. LUCAT1 affected Wnt/?-catenin pathway. CONCLUSIONS:LUCAT1 might be a significant biomarker to evaluate prognosis in breast cancer. LUCAT1 increased stem-like properties of BCCs and stemness of BCSCs by competitively binding miR-5582-3p with TCF7L2 and enhancing the Wnt/?-catenin pathway. The LUCAT1/miR-5582-3p/TCF7L2 axis provides insights for regulatory mechanism of stemness, and new strategies for clinical practice.
| S-EPMC6626338 | biostudies-literature
Project description:BACKGROUND:Accumulating evidence demonstrates the essential role of long non-coding RNA (lncRNA) in various types of cancers, including pancreatic cancer. However, the functions and regulation mechanism of lncRNA PMSB8-AS1 in pancreatic cancer are largely unclear. METHODS:Quantitative reverse transcription PCR (qRT-PCR) is used to examine the expression of PMSB8-AS1 in PC tissues and PC cell lines. The effect of PMSB8-AS1 on the proliferation of PC cells was detected using CCK8 assay, colony assay, and flow cytometry. The effect of PMSB8-AS1 on the migration and invasion of pancreatic cancer cells was detected using a wound-healing assay and transwell migration assay. Bioinformatic analysis, double luciferase reporting assay, western blot, and rescue experiments were used to detect the regulatory relationship between PMSB8-AS1, miR-382-3p, STAT1, and PD-L1. RESULTS:PMSB8-AS1 expression was upregulated in PC tissues and cell lines and positively associated with the worst survival in patients with PC. The in vitro and in vivo assays demonstrated that overexpression of PMSB8-AS1 significantly promoted pancreatic cancer cell proliferation, migration, and invasion, whereas knockdown of PMSB8-AS1 suppressed cell proliferation, migration, invasion, and EMT, and decreased apoptosis of PC cells. Besides, PMSB8-AS1 directly bound to miR-382-3p downregulated its expression. Besides, PMSB8-AS1 reversed the effect of miR-382-3p on the growth and metastasis of PC cells, which might be targeted on STAT1. Furthermore, STAT1 is the transcriptional factor that activates the expression of PD-L1. CONCLUSION:lncRNA PMSB8-AS1 promotes pancreatic cancer progression via STAT1 by sponging miR-382-3p involving regulation PD-L1.
| S-EPMC7487636 | biostudies-literature
Project description:Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3' untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p-ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.
| S-EPMC8526743 | biostudies-literature