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Circular RNA ITCH (circ-ITCH) is implicated in papillary thyroid carcinoma (PTC) development. Nevertheless, the more detailed molecular mechanism remains uncovered. The transcriptional level of circ-ITCH was tested via quantitative real-time PCR. Transwell assay was introduced to assess the migrative and invasive abilities of cells. RNA interference technology was employed to reduce the level of circ-ITCH as well as JAZF1 in PTC cells. Western blot assay was utilized to reveal the content of JAZF1 and proteins related to epithelial–mesenchymal transformation (EMT) progression. Circ-ITCH was downregulated in PTC tissues as well as cells. Overexpression of circ-ITCH suppressed EMT, migration, invasion, facilitated apoptosis in PTC cells, while silencing circ-ITCH exhibited reversed effects. Additionally, miR-106a-5p was the target of circ-ITCH and negatively regulated through circ-ITCH. MiR-106a-5p mimic partly eliminated the influences of overexpressed circ-ITCH in PTC cells. Moreover, JAZF1 could interact with miR-106a-5p, then it was regulated via circ-ITCH. Silencing JAZF1 partially counteracted the role of circ-ITCH in PTC cells progress. This study uncovered that circ-ITCH suppressed the development of PTC cells at least partly by mediating miR-106a-5p/JAZF1 network. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) are promising biomarkers and therapeutic targets for acute kidney injury (AKI). In this study, we investigated the mechanism by which circRNA itchy E3 ubiquitin protein ligase (circ-ITCH) regulates sepsis-induced AKI. Methods: A sepsis-induced AKI mouse model was created using LPS induction and circ-ITCH overexpression. Circ-ITCH levels were confirmed via RT-qPCR. Kidney tissue changes were examined through various stains and TUNEL. Enzyme-linked immunosorbent assay (ELISA) gauged oxidative stress and inflammation. Mitochondrial features were studied with electron microscopy. RT-qPCR and western blotting assessed mitochondrial function parameters. Using starBase, binding sites between circ-ITCH and miR-214-3p, as well as miR-214-3p and ABCA1, were predicted. Regulatory connections were proven by dual-luciferase assay, RT-qPCR, and western blotting. Results: Circ-ITCH expression was downregulated in LPS-induced sepsis mice. Overexpression of circ-ITCH ameliorates indicators of renal function (serum creatinine [SCr], blood urea nitrogen [BUN], neutrophil gelatinase-associated lipocalin [NGAL], and kidney injury molecule-1 [Kim-1]), reduces renal cell apoptosis, mitigates oxidative stress markers (reactive oxygen species [ROS] and malondialdehyde [MDA]), and diminishes inflammatory markers (interleukin [IL]-1ß, IL-6, and tumor necrosis factor [TNF-a]). Moreover, circ-ITCH overexpression alleviated mitochondrial damage and dysfunction. Furthermore, circ-ITCH acts as a sponge for miR-214-3p, thereby upregulating ABCA1 expression. In addition, the miR-214-3p inhibitor repressed oxidative stress, inflammation, and mitochondrial dysfunction, which was reversed by circ-ITCH knockdown. Further cellular analysis in HK-2 cells supported these findings, highlighting the protective role of circ-ITCH against sepsis-induced AKI, particularly through the miR-214-3p/ABCA1 axis. Conclusion: The novel circ-ITCH/miR-214-3p/ABCA1 pathway plays an essential role in the regulation of oxidative stress and mitochondrial dysfunction in sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

Background: Diabetic foot ulcer (DFU) remains a serious chronic diabetic complication that can lead to disability. CircRNA‐itchy E3 ubiquitin protein ligase (circ‐ITCH) was observed to be down‐regulated in diabetic retinopathy and diabetic nephropathy, and overexpression of circ‐ITCH could inhibit the processes of these diseases. However, the detailed physiological and pathological functions of circ‐ITCH in wound healing of DFU remain undetermined. Methods: Exosomes derived from bone marrow stromal cells (BMSCs) were isolated and identified. Cell viability and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by cell counting kit‐8 (CCK‐8) and tube formation assays, respectively. The interplays of circ‐ITCH, TATA‐Box‐binding protein associated factor 15 (TAF15) and nuclear factor erythroid 2‐related factor 2 (Nrf2) mRNA were analysed by RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) combined immunofluorescent staining and RNA pull‐down assays. qRT‐PCR, western blot or immunohistochemistry (IHC) were used to measure the expression of circ‐ITCH, TAF15, Nrf2, vascular endothelial growth factor (VEGFR) and ferroptosis‐related makers. The mice DFU model was established to verify the in vitro results. Results: Circ‐ITCH was down‐regulated in in vitro and in vivo models of DFU. Deferoxamine (DFO), an iron chelating agent, improved the viability and angiogenic ability of high glucose (HG)‐treated HUVECs. Overexpression of circ‐ITCH or co‐cultured with exosomal circ‐ITCH from BMSCs could alleviate HG‐induced ferroptosis and improve the angiogenesis ability of HUVECs. Circ‐ITCH in HUVECs recruited TAF15 protein to stabilize Nrf2 mRNA, thus activating the Nrf2 signalling pathway and suppressing ferroptosis. Exosomal circ‐ITCH from BMSCs also accelerated the wound healing process by inhibiting ferroptosis in the DFU mice in a time‐dependent manner. Conclusion: Exosomal circ‐ITCH from BMSCs inhibited ferroptosis and improved the angiogenesis of HUVECs through activation of the Nrf2 signalling pathway by recruiting TAF15 protein, ultimately accelerating the wound healing process in DFU. [ABSTRACT FROM AUTHOR]

In the last decade, numerous circRNAs were discovered by virtue of the RNA-Seq technique. With the deepening of experimental research, circRNAs have brought to light the key biological functions and progression of human diseases. CircRNA ITCH has been demonstrated to be a tumor suppressor in numerous cancers, and recently it was found to play an important role in bone diseases, diabetes mellitus, and cardiovascular diseases. However, the functions of circ-ITCH have not been completely understood. In this review, we comprehensively provide a conceptual framework to elucidate circ-ITCH biological functions of cell proliferation, apoptosis and differentiation, and the pathological mechanisms of inflammation, drug resistance/toxicity, and tumorigenesis. Finally, we summarize its clinical applications in various diseases. This research aimed at clarifying the role of circ-ITCH, which could be a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Accumulating data suggested that circular RNAs (circRNAs) played important roles in the development of human cancer. However, the potential mechanism of circRNAs in ovarian cancer remains unclear. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the levels of circRNA itchy E3 ubiquitin protein ligase (circ-ITCH), microRNA-106a (miR-106a) and E-cadherin (CDH1). Cell Counting Kit-8 (CCK-8) and Transwell assay were carried out to measure cell proliferation and invasion. Glucose consumption, lactate production, and ATP level were assessed by the glucose, lactate, and ATP assay kits, respectively. Cell apoptosis was detected by Flow cytometry. The binding sites were predicted by StarBase v.2.0 or microT-CDS and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assays. CDH1 protein level was determined by western blot. The functional role of circ-ITCH was measured by xenograft tumor model in vivo. Results: Circ-ITCH was down-regulated in ovarian cancer and positively correlated with 5-year overall survival of patients with ovarian cancer. RNase R digestion assay confirmed that circ-ITCH was more stable than its linear mRNA form. Moreover, circ-ITCH was mainly distributed in the cytoplasm of ovarian cancer cells. Functionally, circ-ITCH overexpression hindered proliferation, invasion, glycolysis and promoted apoptosis of ovarian cancer cells. Besides, circ-ITCH overexpression inhibited ovarian cancer cell progression by targeting miR-106a. Additionally, CDH1 was a target of miR-106a, and the protein level of CDH1 was negatively regulated by miR-106a. Similarly, CDH1 knockdown recovered the inhibition effects of miR-106a inhibitor or circ-ITCH overexpression on the progression of ovarian cancer cells. Importantly, circ-ITCH up-regulated the protein level of CDH1 by sponging miR-106a in ovarian cancer cells. Circ-ITCH overexpression suppressed the growth of ovarian cancer cells in vivo. Conclusion: Circ-ITCH suppressed proliferation, invasion, glycolysis, and promoted apoptosis of ovarian cancer cells by modulating the miR-106a/CDH1 axis. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is the most prevailing primary bone tumour and the third prevalent tumour in children and adolescents. Despite advanced treatments, the survival rate of OS has not been effectively improved. Here, we intended to investigate the functional impacts of circ-ITCH on OS. Methods: Circ-ITCH expression in OS tissues and cells was evaluated utilizing qRT-PCR. Viability and proliferation of MG63 and Saos-2 cells were determined by utilizing CCK-8 assay and BrdU assay. Transwell assay was utilized to investigate migration and invasion. Western blot was utilized to distinguish apoptosis and metastasis-related proteins expression. Sequentially, the above-mentioned parameters were reassessed when up-regulating miR-22. Results: Circ-ITCH was low expressed in OS tissues and cells. Overexpressing circ-ITCH facilitated apoptosis and repressed viability, proliferation, migration and invasion in MG63 and Saos-2 cells. MiR-22 expression was reduced by overexpressing circ-ITCH. The decline of viability, proliferation, migration and invasion made by overexpressing circ-ITCH was alleviated by up-regulating miR-22. Conclusively, circ-ITCH suppressed PTEN/PI3K/AKT and SP-1 pathways via down-regulating miR-22. Conclusion: Circ-ITCH took effects on apoptosis, viability, proliferation, migration and invasion through restraining PTEN/PI3K/AKT and SP-1 pathways via down-regulating miR-22 in MG63 and Saos-2 cells. Low expression of circ-ITCH is observed in osteosarcoma tissues and cell lines; Overexpression circ-ITCH suppresses miR-22 expression; Circ-ITCH promotes proliferation and represses apoptosis by up-regulating miR-22; Circ-ITCH promotes migration and invasion by up-regulating miR-22; Circ-ITCH activates PTEN/PI3K/AKT and SP-1 pathways by up-regulating miR-22. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to explore the correlation of circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH) with pathological features as well as its predictive value on prognosis in prostate cancer patients. METHODS: Three hundred and twenty-four patients with prostate cancer underwent radical prostatectomy were consecutively included in this retrospective study, and patients' specimens of tumor as well as paired adjacent tissues were collected for detection of circ-ITCH expression. Patients' baseline characteristics and survival data were obtained from follow-up records, and correlation of circ-ITCH with patients' pathological features and survival was determined. RESULTS: Circ-ITCH expression was decreased in tumor tissue compared with paired adjacent tissues (P < 0.001), and it presented with good value in distinguishing tumor tissues from paired adjacent tissues with area under curve (AUC) of 0.812 (95%CI: 0.780–0.845). Circ-ITCH low expression was associated with advanced pathologic T stage (P = 0.002) and high risk of lymph node metastasis (P = 0.047) in prostate cancer patients. As for prognosis, patients with circ-ITCH high expression had longer disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Additionally, circ-ITCH (high vs. low) independently predicted better survival, while Gleason score (> 7 vs. ⩽ 7) and surgical margin status (positive vs. negative) independently predicted worse survival in prostate patients underwent radical prostatectomy. CONCLUSIONS: Circ-ITCH is downregulated in prostate cancer tissues, and its low expression correlates with advanced pathologic T stage, high lymph mode metastasis risk and poor survival in prostate cancer patients underwent radical prostatectomy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to evaluate the correlation of circular RNA itchy E3 ubiquitin protein ligase (Circ-ITCH) expression with clinicopathological features and survival in patients with epithelial ovarian cancer (EOC), and to explore its effect on cells proliferation as well as apoptosis in EOC cells. METHODS: Seventy-seven EOC patients underwent surgery were retrospectively reviewed. Tumor tissues and paired adjacent tissues samples were collected, and Circ-ITCH expression was evaluated by quantitative polymerase chain reaction (qPCR). Blank mimic, Circ-ITCH mimic, blank inhibitor and Circ-ITCH inhibitor plasmids were transfected into SKOV3 cells and OVCAR-3 cells, and Counting Kit-8 (CCK-8) was performed to assess cells proliferation and Annexin V (AV)/propidium iodide (PI) was conducted to detect cells apoptosis. RESULTS: Median value of Circ-ITCH relative expression was 0.697 (0.367–1.106) in tumor tissues, which was lower compared with paired adjacent tissues (1.690 (0.867–2.813)) (P < 0.001), and it negatively correlated with tumor size (P = 0.005) as well as International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001) in EOC patients. Multivariate Cox's analysis revealed that high Circ-ITCH expression was an independent predictive factor for favorable OS in EOC patients. Moreover, further in vitro experiments disclosed that Circ-ITCH expression was decreased in several EOC cell lines compared with normal ovarian epithelial cell line, and it inhibited cells proliferation while promoted cells apoptosis in SKOV3 and OVCAR-3 cells. CONCLUSIONS: Circ-ITCH correlates with small tumor size, decreased FIGO stage and prolonged OS, and it inhibits cells proliferation while promotes cells apoptosis in EOC. [ABSTRACT FROM AUTHOR]

Abstract While recent evidence has uncovered that circular RNAs (circRNAs) are vital regulators of carcinogenesis, their role in papillary thyroid cancer (PTC) is not clearly understood. In this study, we reveal that lower levels of circRNA circ-ITCH are expressed in PTC tissues than in normal adjacent tissues. Gain-of-functional assays show that circ-ITCH overexpression suppresses PTC cell proliferation and invasion and promotes apoptosis in vitro. Overexpression of circ-ITCH also leads to impaired tumor growth in vivo. Bioinformatics analysis and luciferase reporter assays demonstrate that circ-ITCH sponges miR-22-3p to upregulate the expression of CBL, an E3 ligase of nuclear β-catenin. Elevated levels of CBL suppress activation of the Wnt/β-catenin pathway and consequently attenuates PTC progression. In summary, our study reveals a novel signaling pathway of circ-ITCH/miR-22-3p/CBL/β-catenin involved in PTC development and progression. [ABSTRACT FROM AUTHOR]

Background: Circ-ITCH is a circRNA generated from several exons of itchy E3 ubiquitin protein ligase (ITCH) and tumor suppressor served as a sponge for certain miRNAs targeting their parental transcripts of ITCH. However, the role of circ- ITCH in bladder cancer (BCa) was not reported. In the present study, we investigated the role of circ-ITCH in BCa. Methods: Quantitative real-time PCR was used to detect the expression of circ-ITCH and survival analysis was adopted to explore the association between circ-ITCH expression and the prognosis of BCa. BCa cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion, cell cycle and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effect of circ-ITCH in BCa. Biotin-coupled probe pull down assay, Biotin-coupled miRNA capture, Fluorescence in situ hybridization and Luciferase reporter assay were conducted to confirm the relationship between the circ-ITCH and the microRNA. Results: In the present study, we found that circ-ITCH, is down-regulated in BCa tissues and cell lines. BCa patients with low circ-ITCH expression had shortened survival. Enforced- expression of circ-ITCH inhibited cells proliferation, migration, invasion and metastasis both in vitro and in vivo. Mechanistically, we demonstrated that circ-ITCH up-regulates the expression of miR-17 and miR-224 target gene p21 and PTEN through 'sponging' miR-17 and miR-224, which suppressed the aggressive biological behaviors of BCa. Conclusions: circ-ITCH acts as a tumor suppressor by a novel circ-ITCH/miR-17, miR-224/p21, PTEN axis, which may provide a potential biomarker and therapeutic target for the management of BCa. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR), the most frequent complication of diabetes mellitus, is the principal cause of acquired blindness worldwide. Although the roles of circRNAs have been extensively explored, the detailed physiological and pathological functions of circRNAs in DR are less understood. Here, we studied the biological effects of circ-ITCH in diabetic retinal pigment epithelial cells (RPEs) and explored the underlying mechanisms. As our results shown, the RNA expression of circ-ITCH was significantly lower in RPEs isolated from diabetic rats than they were in those isolated from normal rats. While diabetes induced an increase in MMP-2, MMP-9 and TNF-α in RPEs, circ-ITCH overexpression exerted an inhibitory on these increases and knockdown of circ-ITCH reversed the inhibitory. In addition, increased expression of miR-22 in RPEs correlated with diabetes and downregulation of circ-ITCH. Remarkably, in the presence of miR-22 mimics, the effects of circ-ITCH on the MMP-2 and MMP-9 were both antagonized. Collectively, our data supports a cellular signaling cascade in which circ-ITCH-inhibited miR-22 activity modulates the expression of MMP-2, MMP-9 and TNF-α in DR. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a new type of endogenous noncoding RNAs with closed circular structure. Emerging evidence indicates that circRNAs play crucial roles in many biological processes by regulating linear RNA transcription, downstream gene expression and protein production. Meanwhile, recent studies have suggested that circRNAs have the potential to be oncogenic or anti-oncogenic and play vital regulatory roles in the initiation and progression of tumors. Circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH), a novel circular RNA originated from several exons of ITCH and located on chromosome 20q11.22, was proved to be declined in many malignant tumors, such as melanoma and ovarian cancer, resulting in tumor occurrence and progression. This review summarizes the biogenesis, characteristics, and functions of circRNAs, as well as recent progression regarding the biological functions and potential molecular mechanisms of circ-ITCH, and future challenges in cancer research. Unlabelled Image [ABSTRACT FROM AUTHOR]