Circular RNA Calm4 Regulates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cells Pyroptosis via the Circ-Calm4/miR-124-3p/PDCD6 Axis.
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ABSTRACT:
SUBMITTER: Jiang Y
PROVIDER: S-EPMC8057524 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abnormal circular RNA (circRNA) expression correlates with human traits such as many kinds of cancers. Though circRNAs have links to cancer, they have less characterization in metastatic castration-resistant prostate cancer (PCa), which is main reason for PCa mortality. Therefore, high-throughput sequencing was used for selected circRNA profiles. The result showed that circ-TRPS1 was upregulated significantly in high-grade PCa tissues or cell lines. High circ-TRPS1 expression correlated to aggressive PCa phenotypes. Knockdown of circ-TRPS1 suppressed PCa proliferation and metastasis through targeting miR-124-3p/EZH2 axis-mediated stemness in PCa, which was validated by luciferase reporter assays. EZH2 overexpression or miR-124-3p inhibition reversed the inhibition of circ-TRPS1 silencing in PCa cell migration and proliferation by recovering stemness. In summary, data demonstrated that circ-TRPS1 suppressed PCa progression through functioning similar to a miR-124-3p sponge to enhance EZH2 expression and cancer stem-like cell differentiation. Thus, circ-TRPS1 might be a candidate target for PCa treatment.
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Project description:BackgroundDrug-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer.MethodsCirc-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo.ResultsCirc-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. Circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p.ConclusionCirc-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.
| S-EPMC8290203 | biostudies-literature
Project description:BACKGROUND:Circular RNAs (circRNAs) represent a subclass of regulatory RNAs that have been shown to have significant regulatory roles in cancer progression. However, the biological functions of circRNAs in bladder cancer (BCa) are largely unknown. METHODS:Cell invasion models were established, and invasion-related circRNAs were detected by qPCR. Using above method, circ-ZKSCAN1 was picked out for further study. Circ-ZKSCAN1 expression and survival analyses were performed through qPCR. The survival curves were generated by the Kaplan-Meier method, and the log-rank test was used to assess the significance. Cell proliferation, migration and invasion were examined to investigate the function of circ-ZKSCAN1. Tumorigenesis in nude mice was assessed to determine the effect of circ-ZKSCAN1 in bladder cancer. Biotin-coupled probe pull-down assays, FISH and luciferase reporter assays were conducted to confirm the relationship between circ-ZKSCAN1 and microRNA. RNA-seq revealed different molecular changes in downstream genes. RESULTS:Here, we found that circ-ZKSCAN1 was downregulated in BCa tissues and cell lines. Circ-ZKSCAN1 levels were associated with survival, tumor grade, pathological T stage and tumor recurrence. Overexpressed circ-ZKSCAN1 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo. Mechanistically, we demonstrated that circ-ZKSCAN1 upregulated p21 expression by sponging miR-1178-3p, which suppressed the aggressive biological behaviors in bladder cancer. CONCLUSIONS:These results reveal that Circ-ZKSCAN1 acts as a tumor suppressor via a novel circ-ZKSCAN1/miR-1178-3p/p21 axis, which have the important role in the proliferation, migration and invasion ablitities of BCa cells and provide a novel perspective on circRNAs in BCa progression.
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Project description:BACKGROUND:Radiation resistance poses a major clinical challenge in treatment of nasopharyngeal carcinoma (NPC). Studies have shown that the abnormal expression of microRNAs (miRNAs) is associated with radiosensitivity, however, the mechanisms have not been fully elucidated. The aim of this study, therefore, was to investigate whether ectopic expression of miR-124 is correlated with radiosensitivity in NPC. METHODS:In this study, the expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). Cell radiosensitivity was determined by colony formation assay. Target prediction algorithms and luciferase assay were used to confirm the target of miR-124. Tumor xenograft model was performed to understand the functions of miR-124 in vivo. RESULTS:We found that miR-124 was down-regulated in both NPC specimens and NPC cell lines. Ectopic expression of miR-124 increased radiosensitivity of NPC cells. In vivo assays extended the significance of these results, showing that miR-124 overexpression decreased cell resistance to radiation treatment in tumor xenografts. Furthermore, we identified PDCD6 as a novel direct target of miR-124. Functional studies showed that knockdown PDCD6 enhanced cell radosensitivity to irradiation, and PDCD6 could rescue the effect caused by overexpression of miR-124, indicating that PDCD6 is a functional target of miR-124. CONCLUSIONS:MiR-124 enhances cell radiosensitivity by targeting PDCD6, miR-124/PDCD6 axis may facilitate the development of novel targeted therapies for NPC.
| S-EPMC6966029 | biostudies-literature
Project description:Recent evidence revealed an inhibitory effect of circ-ITCH on the progression of papillary thyroid cancer via affecting the circ-ITCH/miR-22-3p/CBL axis. Rs4911154, an SNP located in circ-ITHC, was previously reported to be significantly associated with an increased risk of hepatocellular carcinoma. Ultrasound testing was used to evaluate the doubling time of thyroid nodules. 202 patients diagnosed with thyroid nodule disorders were divided into three groups according to their genotypes at rs4911154. We found that the A allele was correlated with a shortening doubling time of thyroid nodules. Moreover, the A allele contributed to reduced expression of circ-ITCH/CBL and increased expression of miR-22-3p. Besides, decreased tissue apoptosis was linked to the A allele. Luciferase assays indicated that miR-22-3p could effectively suppress the luciferase activities of CBL and circ-ITCH. Furthermore, manual up-regulation of miR-22-3p effectively suppressed the expression of CBL, while CBL siRNA apparently abolished circ-ITCH induced CBL upregulation, reduced proliferation and increased apoptosis of K1 and TPC-1 cells. A signaling pathway of circ-ITCH/miR-22-3p/CBL axis was established to explain the effect of SNP of circ-ITCH in thyroid tumor malignancy. Compared with the G allele, the A allele in rs4911154 contributed to the malignancy of thyroid nodules with decreased doubling time and down-regulated CBL expression.
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Project description:Pulmonary artery smooth muscle cells (PASMCs) undergo proliferation by the mammalian target of rapamycin (mTOR) signaling pathway under hypoxia. Hypoxia induces expression of a specific set of microRNAs (miRNAs) in a variety of cell types. We integrated genomic analyses of both small non-coding RNA and coding transcripts using next-generation sequencing (NGS)-based RNA sequencing with the molecular mechanism of the mTOR signaling pathway in hypoxic PASMCs. These analyses revealed hypoxia-induced miR-92b-3p as a potent regulator of the mTOR signaling pathway. We demonstrated that miR-92b-3p directly targets the 3'-UTR of a negative regulator in the mTOR signaling pathway, TSC1. mTOR signaling and consequent cell proliferation were promoted by enforced expression of miR-92b-3p but inhibited by knocking down endogenous miR-92b-3p. Furthermore, inhibition of miR-92b-3p attenuated hypoxia-induced proliferation of vascular smooth muscle cells (VSMCs). Therefore, this study elucidates a novel role of miR-92b-3p as a hypoxamir in the regulation of the mTOR signaling pathway and the pathological VSMC proliferative response under hypoxia. These findings will help us better understand the miRNA-mediated molecular mechanism of the proliferative response of hypoxic VSMCs through the mTOR signaling pathway.
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Project description:Clear cell renal cell carcinoma (ccRCC) is one of the most common urogenital tumors with high mortality. Circular RNA (circRNA), as an emerging endogenous RNA, has been proved to play a crucial role in the clear cell renal cell carcinoma (ccRCC) progression. In this study, we obtained circAFAP1 upregulated in ccRCC by high-sequencing and verified by qRT-PCR in several renal cancer cell lines. In situ hybridization (ISH) assays and Kaplan-Meier plot showed a higher level of circAFAP1 was linked to shorter overall survival. Moreover, CCK8, colony formation, and EdU experiments showed circAFAP1 promoted ccRCC growth while tube formation displayed circAFAP1 contributed to ccRCC angiogenesis. We predicted the downstream miR-374b-3p and VEGFA by bioinformatic analysis and validated further by qRT-PCR, RNA pull-down, RIP, and dual-luciferase. Downregulation miR-374b-3p or overexpression VEGFA could restore proliferation, vascular formation after circAFAP1 silencing. Consistently with the results in vitro, silencing circAFAP1 suppressed ccRCC growth in vivo. In conclusion, the circAFAP1/miR-374b-3p/VEGFA axis played a critical role in the progression and development of ccRCC which might be novel biological marks and therapeutical targets.
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Project description:Irreversible pulmonary hypertension (PH) mainly results from vascular remodeling, in which the aberrant growth of pulmonary arterial smooth muscle cells (PASMCs) plays a significant role. Our previous work suggested that KLF5 and HIF1α are closely associated with the pathogenesis of hypoxic PH as they intervene in the growth of PASMCs. MicroRNAs (miRNAs) have been demonstrated to be involved in the control of cell proliferation and apoptosis. In the present study, we detected the expression of six miRNAs connected with KLF5 in hypoxia-exposed rat PH models and PASMCs and then further investigated the role of miR-320-3p in the abnormal proliferation of hypoxic PASMCs and in the progression and treatment outcomes of hypoxia-induced PH. The results indicated that miR-320-3p was downregulated in hypoxia-exposed rat PH models, hypoxia-induced PASMCs and chronic thromboembolic pulmonary hypertension (CTEPH) patients. Moreover, miR-320-3p directly regulated the expression of KLF5 and HIF1α. miR-320-3p mimics inhibited proliferation and migration and promoted apoptosis in hypoxic PASMCs. KLF5 and HIF1α reversed the above effects of miR-320-3p. In conclusion, miR-320-3p plays a certain role in the progression of hypoxic PH via KLF5 and HIF1α and might be a potent therapeutic tool for PH.
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Project description:Transient receptor potential canonical (TRPC) proteins play important roles in chronically hypoxic pulmonary hypertension (CHPH). Previous results indicated that sildenafil inhibited TRPC1 and TRPC6 expression in rat distal pulmonary arteries (PAs). However, the underlying mechanisms remain unknown. We undertook this study to investigate the downstream signaling of sildenafil's regulation on TRPC1 and TRPC6 expression in pulmonary arterial smooth muscle cells (PASMCs). Hypoxia-exposed rats (10% O2 for 21 d) and rat distal PASMCs (4% O2 for 60 h) were taken as models to mimic CHPH. Real-time PCR, Western blotting, and Fura-2-based fluorescent microscopy were performed for mRNA, protein, and Ca(2+) measurements, respectively. The cellular cyclic guanosine monophosphate (cGMP) analogue 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate sodium salt (CPT-cGMP) (100 ?M) inhibited TRPC1 and TRPC6 expression, store-operated Ca(2+) entry (SOCE), and the proliferation and migration of PASMCs exposed to prolonged hypoxia. The inhibition of CPT-cGMP on TRPC1 and TRPC6 expression in PASMCs was relieved by either the inhibition or knockdown of cGMP-dependent protein kinase (PKG) and peroxisome proliferator-activated receptor ? (PPAR?) expression. Under hypoxic conditions, CPT-cGMP increased PPAR? expression. This increase was abolished by the PKG antagonists Rp8 or KT5823. PPAR? agonist GW1929 significantly decreased TRPC1 and TRPC6 expression in PASMCs. Moreover, hypoxia exposure decreased, whereas sildenafil treatment increased, PKG and PPAR? expression in PASMCs ex vivo, and in rat distal PAs in vivo. The suppressive effects of sildenafil on TRPC1 and TRPC6 in rat distal PAs and on the hemodynamic parameters of CHPH were inhibited by treatment with the PPAR? antagonist T0070907. We conclude that sildenafil inhibits TRPC1 and TRPC6 expression in PASMCs via cGMP-PKG-PPAR?-dependent signaling during CHPH.
| S-EPMC3824028 | biostudies-literature
Project description:Hypoxia is a critical factor in the malignant progression of glioma, especially for the highly-invasive mesenchymal (MES) subtype. But the detailed mechanisms in hypoxia-induced glioma MES transition remain elusive. Pseudogenes, once considered to be non-functional relics of evolution, are emerging as a critical factor in human tumorigenesis and progression. Here, we investigated the clinical significance, biological function, and mechanisms of protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) in hypoxia-induced glioma MES transition. In this study, we found that PDIA3P1 expression was closely related to tumor degree, transcriptome subtype, and prognosis in glioma patients. Enrichment analysis found that high PDIA3P1 expression was associated with epithelial-mesenchymal transition, extracellular matrix (ECM) disassembly, and angiogenesis. In vitro study revealed that overexpression of PDIA3P1 enhanced the migration and invasion capacity of glioma cells, while knockdown of PDIA3P1 induced the opposite effect. Further studies revealed that PDIA3P1 functions as a ceRNA, sponging miR-124-3p to modulate RELA expression and activate the downstream NF-κB pathway, thus promoting the MES transition of glioma cells. In addition, Hypoxia Inducible Factor 1 was confirmed to directly bind to the PDIA3P1 promotor region and activate its transcription. In conclusion, PDIA3P1 is a crucial link between hypoxia and glioma MES transition through the PDIA3P1-miR-124-3p-RELA axis, which may serve as a prognostic indicator and potential therapeutic target for glioma treatment.
| S-EPMC7054337 | biostudies-literature