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Cytarabine (Ara-C) is a commonly used chemotherapeutic drug for the treatment of leukemia, known for its significant tolerability. The down regulation of miR-203 in leukemia cells suggests its potential involvement in the pathogenesis of leukemia. In this study, we investigated the effects and possible mechanisms of miR-203 and Ara-C on proliferation and apoptosis of human leukemia K562 cells which were cultured with Ara-C and/or with transfection of miR-203 expression vectors. Our results showed that the combination of Ara-C and miR-203 synergistically inhibited the proliferation of K562 cells and the sensitivity of leukemia cells to Ara-C was increased by 2.5-fold with trasfection of miR-203. The proportion of apoptotic cells in the Ara-C and miR-203 combination group was higher than Ara-C or control plasmid group. Caspase-3 and caspase-9 activities were increased in Ara-C and miR-203 combination group. miR-203 down regulated the protein level of Bcr/abl in K562 cells compared with plasmid control. In conclusion, Ara-C in combination with miR-203 has a synergistic effect of proliferation inhibition and apoptosis induction in chronic myelogenous leukemia K562 cells, which may be associated with miR-203 down regulating Bcr/abl, thereby inhibiting cell proliferation and promoting cell apoptosis. [ABSTRACT FROM AUTHOR]

Background: Canine atopic dermatitis (CAD) is a common genetically predisposed, inflammatory, and pruritic skin disorder that affects dogs globally. To date, there are no specific biomarkers available to diagnose CAD, and the current diagnosis is based on a combination of criteria including patient history, clinical signs, and exclusion of other relevant differential diagnoses. Methods and results: We examined the gene expression of phosphodiesterase 4D (PDE4D) in peripheral blood mononuclear cells (PBMCs), as well as miR-203 and miR-483 in plasma, in three groups: healthy dogs, CAD dogs, and other inflammatory pruritic skin diseases (OIPSD) such as pemphigus foliaceus, scabies, cutaneous lymphoma, and dermatophytosis. Our results showed that PDE4D gene expression in the CAD group is statistically higher compared to those in the healthy and OIPSD groups, suggesting PDE4D may be a specific marker for CAD. Nevertheless, no correlation was found between PDE4D gene expression levels and the lesion severity gauged by CAD severity index-4 (CADESI-4). We also showed that miR-203 is a generic marker for clinical dermatitis and differentiates both CAD and OIPSD inflammatory conditions from healthy controls. Conclusions: We show that PDE4D is a potential marker to differentiate CAD from non-atopic healthy and OIPSD while miR-203 may be a potential marker for general dermatologic inflammation. Future study of PDE4D and miR-203 on a larger scale is warranted. [ABSTRACT FROM AUTHOR]

Objective: Circular ribose nucleic acids (circRNAs) are implicated in tumor progression and drug resistance of prostate cancer (PCa). The current work explored the function of circ_0005203 (circTHSD4) in the malignancy and docetaxel (DTX) resistance of PCa. Methods: circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells. In addition, we performed a Western blot (WB) assay to detect high-mobility-group A2 protein (HMGA2) levels. Besides, functional associations of two molecules were investigated through dual luciferase reporter assay. Cell Counting Kit (CCK)-8, colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells, whereas flow cytometry was performed to determine cell apoptosis. Furthermore, a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells. Results: According to RT-qPCR results, circTHSD4 was up-regulated within PCa tissues and cells, which predicted the dismal prognostic outcome of PCa cases. circTHSD4 silencing within PCa cells markedly suppressed cell growth, migration, and colony formation. circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model. Further, circTHSD4 silencing enhanced docetaxel (DTX) sensitivity in PCa cells. Furthermore, we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR-203. Conclusion: Together, our findings suggest that circTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR-203/HMGA2 axis. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths worldwide. Circular RNA (circRNA) circ_0088036 is a recently discovered circRNA known for its roles in rheumatoid arthritis. The study aimed to study the function of circ_0088036 in lung adenocarcinoma (LUAD). Circ_0088036 expressions were analyzed in the Gene Expression Omnibus (GEO) database. The relationship between circ_0088036 expressions and clinicopathological data of LUAD was assessed. The messenger RNA and protein levels were analyzed by quantitative real-time polymerase chain reaction and Western blot. Cell viability, apoptosis, and invasion were tested by Cell Counting Kit-8, flow cytometry, and transwell assay. The direct interaction between microRNA-203 (miR-203) and circ_0088036 or specificity protein 1 (SP1) was confirmed by dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation assays. Circ_0088036 was overexpressed in LUAD from the analysis of the GEO database. The poor prognosis was found in the patients with high expressions of circ_0088036. The level of Circ_0088036 was increased in LUAD tissues and cells. In terms of function, the deletion of circ_0088036 inhibited LUAD tumorigenesis in vitro by repressing cell growth, invasion, and epithelial-mesenchymal transition (EMT). In mechanism, circ_0088036 could competitively sponge miR-203, thereby affecting the expressions of the target gene SP1. In addition, lessening of miR-203 and enlarging of SP1 could eliminate the anticancer effect of short hairpin RNA-circ_0088036 on LUAD cells. Besides, the knockout of circ_0088036 hindered the growth of xenografted tumors in vivo. Circ_0088036 promoted the LUAD cell growth, invasion, and EMT via modulating the miR-203/SP1 axis in LUAD. [ABSTRACT FROM AUTHOR]

Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA‐203 (miR‐203) as a senescence‐associated microRNA that regulates NAD+ homeostasis. We found that the blood miR‐203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR‐203 (TgN (miR‐203)) showed resistance to aging‐induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR‐203 significantly prevented D‐gal‐induced cardiomyocyte senescence and mitochondrial damage, while miR‐203 knockdown aggravated these effects. Mechanistically, miR‐203 inhibited PARP1 expression by targeting its 3′UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR‐203 as a genetic tool for anti‐heart aging by restoring NAD+ function in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Introduction. A more in-depth description of molecular events that disrupt the functioning of the p53 signaling pathway is important for understanding the mechanisms of formation and progression of diffuse B-large cell lymphoma (DCCL), as well as its sensitivity to treatment. The p53 protein exhibits its oncosuppressive function and mediates the antitumor effects of drugs by regulating transcription and/or maturation of a wide range of target genes, including MIR-34A, MIR34B/C, MIR-129-2 and MIR-203. In the tumor tissue of lymphomas, in comparison with normal lymphoid tissue, a decrease in the level of microRNAs encoded by these genes is shown.Aim. The aim of this study was to conduct a comprehensive analysis of the methylation of the genes of the p53-responsive microRNAs MIR-34A, MIR-34B/C, MIR-203 and MIR-129-2, as well as mutations in the DNA-binding domain and destruction of the polyadenylation signal of the TP53 gene in DLBCL.Materials and methods. 136 DNA samples isolated from tumor tissue of patients with DLBCL and 11 DNA samples obtained from lymph nodes with reactive B-cell follicular hyperplasia were analyzed. The methylation status of MIR-203 and MIR-129-2 genes was determined by the method of methyl-specific polymerase chain reaction, MIR-34A and MIR-34B/C genes by the method of methyl-sensitive analysis of high-resolution melting curves. In tumor samples, rs78378222 genotyping was performed by polymerase chain reaction with restriction fragment length polymorphism, resulting in the destruction of the polyadenylation signal, and the nucleotide sequence of the region of the TP53 gene encoding the DNA-binding domain was determined by capillary direct sequencing by Sanger.Results. The methylation detected in lymphoma tissue was tumor-specific. The frequency of analyzed aberrations in the TP53 gene and methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 was 21, 23, 55, 65 and 66 %, respectively. At the same time, methylation of the analyzed genes of p53-responsive microRNAs and aberrations in the TP53 gene in the tumor tissue of patients with DLBCL were independent events with a tendency to mutual exclusion. At the same time, it was shown that in the vast majority of lymphoma samples, the methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes was combined.Conclusion. Along with aberrations in TP53, methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes may be an important cause of decreased expression of miR-34a, miR-34b, miR-34c, miR-129 and miR-203 in DLBCL. The combined methylation of the MIR-203, MIR-129-2 and MIR-34B/C genes, as well as the MIR-34B/C and MIR-34A pairs, potentially has a more pronounced pro-tumor effect due to the presence of common targets in the microRNAs encoded by them.

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Circ_0038467 and miR-203 exert important functions in lipopolysaccharide (LPS)-induced inflammation, which contributes to osteoarthritis (OA). Our preliminary deep sequencing analysis revealed altered expression of Circ_0038467 and miR-203 in OA and a close correlation between them. This study was therefore to explore crosstalk between them in OA. The expression of Circ_0038467, mature miR-203, and miR-203 precursor in OA patients and controls was determined using RT-qPCR. An overexpression assay was performed to explore the role of Circ_0038467 in regulating the expression of mature miR-203 and miR-203 precursor. Cell apoptosis was analyzed by cell apoptosis assay. Circ_0038467 was upregulated in OA and positively correlated with mature miR-203 but not that of miR-203 precursor. In chondrocytes, increased expression levels of both Circ_0038467 and miR-203 were observed after LPS treatment. In chondrocytes, overexpression of Circ_0038467 increased the expression levels of mature miR-203 but not that of miR-203 precursor. Overexpression of Circ_0038467 and miR-203 increased cell apoptosis. Then, the miR-203 inhibitor reversed the effects of overexpression of Circ_0038467 on cell apoptosis. Interestingly, Circ_0038467 was detected in both the cytoplasm and nucleus. Circ_0038467 directly interacted with the precursor miR-203. Therefore, Circ_0038467 is highly expressed in OA and it may promote the production of mature miR-203 to increase apoptosis of chondrocytes induced by LPS.

AbstractObjective This study aims to investigate the association between miR-203 expression and the prognostic value in patients with esophageal cancer by the method of systematic review and meta-analysis.Methods We searched PubMed, Web of Science, Embase, and Cochrane Library to collect studies on the relationship between miR-203 expression and the prognostic value of esophageal cancer up to July 2023. Stata 15.0 statistical software was used for data analysis. Hazard ratio (HR) and 95% confidence interval (CI) were used as effect sizes.Results A total of 6 studies were included in this review, including 476 patients with esophageal cancer. The results showed that miR-203 low expression was associated with worse overall survival (OS) in patients with esophageal cancer compared with miR-203 high expression (HR = 2.80, 95%CI: 1.99 ∼ 3.93, p

Aim: To examine the expression of miR-203 and its target genes survivin and p63 in condyloma acuminatum (CA) and to determine their relationships with clinical recurrence. Methods: Case and control groups were assessed for general data and the expression levels of miR-203, survivin and p63. The case group received carbon dioxide laser treatment, had a 3-month follow-up period, and was then divided into recurrence and non-recurrence groups. The relevant data were analyzed using SPSS v. 25.0 software. Results:miR-203 was identified as an independent protective factor against the recurrence of CA, while wart number, survivin and p63 were independent risk factors for CA recurrence. Conclusion:miR-203 could be a specific clinical bioindicator for the prognosis and recurrence of CA. [ABSTRACT FROM AUTHOR]

The purpose of the study was to present up-to-date data on the frequency and significance of a number of p53-responsive oncosuppressive micrornas genes methylation in malignant neoplasms of the blood system.Material and methods. The search for available literary sources published in the Pubmed and RISC databases was carried out. A total of 399 articles were found, of which 62 were included in this review.Results. The p53 protein regulates a whole class of microRNAs – highly conserved small RNA molecules that affect gene expression mainly by suppressing translation. МicroRNAs play an important role in all cellular processes and can have both oncosuppressive and pro-oncogenic properties. Impaired expression of p53-activated oncosuppressive micrornas in various tumors may be associated with specific epigenetic mechanisms (DNA methylation and histone deacetylation). The review examines the molecular and genetic characteristics of oncosuppressive micrornas functioning in normal hematopoiesis, the violation of expression of which is shown in the development of hemoblastoses, namely: miR-34a, miR-34b/c, miR-145, miR-143 and miR-203. It is known that the transcription of the genes of these microRNAs is carried out and regulated from their own promoters. The latest published research results on the diagnostic, prognostic and clinical significance of gene methylation of the microRNAs under consideration in malignant neoplasms of the blood system are presented. According to literature data, common targets for mir-34a, mir-34b/c, mir-145, mir-143 and miR-203 microRNAs are mRNAs of a number of pro-oncogenes, namely: transcription factor C-MYC, positive cell cycle regulators at the G1/S transition point of CDK4, CDK6 and CYCLIN-D1 phases, anti-apoptotic proteins MDM2, MDM4, BCL2 and MCL1, as well as DNMT3A and DNMT3B methyltransferases and other molecules. In this regard, it should be noted that there are positive feedbacks between p53 and microRNAs activated by it, as well as negative feedbacks between p53-responsive micrornas and C-MYC and DNA methyltransferases.Conclusion. Thus, the data presented in the review clarify the current understanding of the work of the regulatory network of the p53 protein and the micrornas activated by it, and also emphasize the functional association of p53-responsive microRNAs.

Abstract Background miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. Methods Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3ʹUTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. Results Akirin2, an activator of NF‐κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF‐κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF‐κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF‐κB, IL-1β and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. Conclusion A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF‐κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling.

This study aims to investigate the association between miR-203 expression and the prognostic value in patients with esophageal cancer by the method of systematic review and meta-analysis. We searched PubMed, Web of Science, Embase, and Cochrane Library to collect studies on the relationship between miR-203 expression and the prognostic value of esophageal cancer up to July 2023. Stata 15.0 statistical software was used for data analysis. Hazard ratio (HR) and 95% confidence interval (CI) were used as effect sizes. A total of 6 studies were included in this review, including 476 patients with esophageal cancer. The results showed that miR-203 low expression was associated with worse overall survival (OS) in patients with esophageal cancer compared with miR-203 high expression (HR = 2.80, 95%CI: 1.99 ∼ 3.93, p < 0.001). The results of Egger's (p = 0.154) and Begg's Tests (p = 0.221) indicated no obvious publication bias. Sensitivity analysis verified the robustness of the results obtained in this study. The expression of miR-203 is significantly correlated with the prognostic value in patients with esophageal cancer. Esophageal cancer patients with high expression of miR-203 had better prognosis than those with low expression of miR-203. Due to the limited studies included in this meta-analysis, more trials are needed to confirm the conclusions of this study in the future. [ABSTRACT FROM AUTHOR]

Circ_0038467 and miR-203 exert important functions in lipopolysaccharide (LPS)-induced inflammation, which contributes to osteoarthritis (OA). Our preliminary deep sequencing analysis revealed altered expression of Circ_0038467 and miR-203 in OA and a close correlation between them. This study was therefore to explore crosstalk between them in OA. The expression of Circ_0038467, mature miR-203, and miR-203 precursor in OA patients and controls was determined using RT-qPCR. An overexpression assay was performed to explore the role of Circ_0038467 in regulating the expression of mature miR-203 and miR-203 precursor. Cell apoptosis was analyzed by cell apoptosis assay. Circ_0038467 was upregulated in OA and positively correlated with mature miR-203 but not that of miR-203 precursor. In chondrocytes, increased expression levels of both Circ_0038467 and miR-203 were observed after LPS treatment. In chondrocytes, overexpression of Circ_0038467 increased the expression levels of mature miR-203 but not that of miR-203 precursor. Overexpression of Circ_0038467 and miR-203 increased cell apoptosis. Then, the miR-203 inhibitor reversed the effects of overexpression of Circ_0038467 on cell apoptosis. Interestingly, Circ_0038467 was detected in both the cytoplasm and nucleus. Circ_0038467 directly interacted with the precursor miR-203. Therefore, Circ_0038467 is highly expressed in OA and it may promote the production of mature miR-203 to increase apoptosis of chondrocytes induced by LPS. [ABSTRACT FROM AUTHOR]

Objective: The epidermis possesses the capacity to replace dying cells and to heal wounds, thanks to resident stem cells, which have self‐renewal properties. In skin physiology, miRNAs have been shown to be involved in many processes, including skin and hair morphogenesis. Recently, differentiation of epidermal stem cells was shown to be promoted by the miR‐203. The miR‐203 is upregulated during epidermal differentiation and is of interest because of significant targets. Methods: By utilizing a bioinformatic tool, we identified a target site for miR‐203 in the survivin mRNA. Silencing miR‐203 was managed with the use of antagomir; the silencing of survivin was performed with a siRNA. Survivin expression was determined by qPCR or immunofluorescence in cultured cells, and by immunohistochemistry in skin sections. Involucrin expression was used as marker of keratinocyte differentiation. A rice extract with previously demonstrated anti‐aging properties was evaluated on miR‐203 modulation. Results: In this study, we identified a miR‐203/survivin axis, important for epidermal homeostasis. We report that differentiation of keratinocyte is dependent on the level of miR‐203 expression and that inhibition of miR‐203 can increase the expression of survivin, an epidermal marker of stemness. Conclusion: In summary, our findings suggest that miR‐203 target 3′UTR region of survivin mRNA and directly represses survivin expression in the epidermis. The rice extract was identified as modulator of miR‐203 and pointed out as a promising microRNA‐based strategy in treating skin changes occurring with aging. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of lycorine hydrochloride (LH) on the proliferation, migration and invasion of human gastric cancer cell line MGC-803 and its possible mechanism. Methods Cell proliferation ability was detected by MTT assay and colony formation assay. Distribution of cell cycle was detected by flow cytometry. The migration ability of cells was detected by wound healing assay. Transwell assay was used to detect the invasion ability of cells. RT-qPCR was used to detect the effects of LH on gene expression of cell migration and invasion. Results The inhibitory rate of LH on MGC-803 cells was concentration and time dependent (P＜0.05, P＜0.01), and the IC50 value at 48 h was 3.76 μmol/L. The colony formation of MGC-803 cells was significantly inhibited by LH, and the colony formation was completely inhibited when the concentration reached 20 μmol/L (P＜0.01). Cell cycle was arrested in S phase after LH treatment (P＜0.01). With the increase of LH concentration, cell migration and invasion were significantly inhibited (P＜0.01), the expression level of miR-203 gene was up-regulated, while the expression levels of Slug, MMP2 and MMP9 were down-regulated in a concentration-dependent manner (P＜0.05, P＜0.01). Conclusions LH significantly inhibited the proliferation of MGC-803 cells, induced cell cycle arresting in the S phase, and inhibited cell migration and invasion. The expression level of miR-203 gene was up-regulated.

In recent years, malignant breast cancer metastasis has caused a great increase in mortality. Research on the genetic and molecular mechanisms of malignant breast cancer has continued to deepen, and targeted therapy has become the general trend. Among them, competing endogenous RNA (ceRNA)-related molecules have received much attention. Homeobox transcript antisense RNA (HOTAIR) has been reported to function extensively as a ceRNA in breast cancer. Notably, miR-203 and Caveolin 1 (CAV1) have also been found to play a role in breast cancer. However, the relationship between the three remains unclear. In this study, we present a new mechanic through bioinformatics tool and basic experiments: the HOTAIR/miR-203/CAV1 axis, which complemented the role network of HOTAIR as a ceRNA, thus, it will provide a novel potential idea for breast cancer research and therapy. [ABSTRACT FROM AUTHOR]

Increased CD44 antigen activity has been reported in recurrent cases of UBC. To date, no reliable biomarker is available with high significance and specificity for non-invasive detection of UBC. This study aimed to identify a CD44-linked microRNAs (miRNAs) (miR-9, miR-34a, miR-203) for non-invasive diagnosis of bladder cancer from other urinary tract malignancies. The expression of CD44-linked miRNAs was examined in serum, urine, and tissue specimens of Indian UBC patients (N = 25). For this purpose, healthy subjects (N = 25) and benign prostatic hyperplasia (BPH) (N = 10) patients were taken as controls. The relative expression of miRNAs was analyzed in serum, urine, and tissue samples using real-time quantitative reverse transcription PCR (qRT-PCR). The diagnostic potential of these miRNAs was accessed by plotting ROC curve. Increased miR-9 expression was observed in serum of UBC patients than healthy and BPH controls. In UBC patients, miR-34a expression was lower than healthy controls but non-significant as compared to BPH. miR-203 expression was considerably higher in serum of UBC patients but non-significant as compared to BPH controls. miR-203 was found to be considerably higher in urine samples from UBC patients as compared to BPH and healthy controls. The diagnostic potential of these miRNAs was evaluated using the ROC curve. Higher miR-203 levels in the urine of Indian UBC patients demonstrate its non-invasive diagnostic ability out of the three miRNAs studied. Our results characterize the non-invasive diagnostic potential of CD44-linked miR-203 in the urine of Indian UBC patients, which could be utilized in clinical settings in future after validation in larger patient cohort. [ABSTRACT FROM AUTHOR]

BackgroundResection of colorectal liver metastasis (CRLM) can be curative. Predicting which patients may benefit from resection, however, remains challenging. Some microRNAs (miRNAs) become deregulated in cancers and contribute to cancer progression. We hypothesized that miRNA expression can serve as a prognostic marker of survival after CRLM resection.ResultsMiR-203 was significantly overexpressed in tumors of short-term survivors compared to long-term survivors. R1/R2 margin status and high clinical risk score (CRS) were also significantly associated with short-term survival (both p = 0.001). After adjusting for these variables, higher miR-203 expression remained an independent predictor of shorter survival (p = 0.010). In the serum cohort, high CRS and KRAS mutation were significantly associated with short-term survival (p = 0.005 and p = 0.026, respectively). After adjusting for CRS and KRAS status, short-term survivors were found to have significantly higher miR-203 levels (p = 0.016 and p = 0.033, respectively).Materials and methodsWe employed next-generation sequencing of small-RNAs to profile miRNAs in solid tumors obtained from 38 patients who underwent hepatectomy for CRLM. To validate, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed on 91 tumor samples and 46 preoperative serum samples.ConclusionsAfter CRLM resection, short-term survivors exhibited significantly higher miR-203 levels relative to long-term survivors. MiR-203 may serve as a prognostic biomarker and its prognostic capacity warrants further investigation.

Numerous microRNAs (miRNAs) have been found to have an aberrant expression in the peripheral blood or psoriasis patients' lesions. Psoriasis was shown to have the abnormal expression of microRNA-203 (miR-203). It is a skin-specific signal that governs cellular proliferation in a protein kinase C-dependent manner and is mostly generated by keratinocytes. This work evaluated the expression levels of the circulating miR-203 target genes SOCS3, SOCS6, TP63, TNF-, IL8, and IL24 in psoriasis patients. Using a relative quantitation PCR technique, we determined the expression levels of miR-203 and its target genes (SOCS3, SOCS6, TP63, TNF-, IL8, and IL24) in the plasma of 120 psoriatic patients and matched healthy controls. The disease characteristics of the patients were then correlated with the expression results. We also conducted numerous enrichment analyses for the diseases, functions, and pathways connected to the under-researched biomarkers. Compared to healthy controls, psoriatic patients had significantly increased levels of miR-203 expression; 7.1 (4.4–9.9). In contrast, psoriatic patients had significantly lower expression of all the examined genes compared to healthy controls. Regarding all the study biomarkers, the receiver operating characteristic (ROC) curve analysis demonstrated significant sensitivity and specificity for differentiating between psoriatic patients and healthy controls. According to the results of the disease matching score generated by miR-203 and its target genes, psoriasis was ranked first with a score of 4.45. The third-place finisher with a value of 3.98, it also demonstrated that miR-203 and its target genes are connected to various skin disorders. Our results show that miR-203 contributes to psoriasis pathogenesis not only locally in skin lesions but also in circulation, indicating that it may contribute to the systemic symptoms of the illness. MiR-203 overexpression in psoriasis suggests that miR-203 may be involved in an anti-inflammatory response because it targets both SOCS gene family members and pro-inflammatory cytokines.

Objective: To investigate the relationship between the expression of serum miR-203 and miR-217 and the efficacy and prognosis of patients with acute myeloid leukemia. Methods: 101 patients with acute myeloid leukemia treated in our hospital from April 2010 to April 2014 were selected as the AML group. The AML group was further divided into the complete remission group and the relapse group according to the treatment effect, and 101 healthy patients who underwent physical examination in our hospital during the same period were selected as the healthy group. The expression levels of serum miR-203 and miR-217 in each group were detected by fluorescence quantitative PCR, and the relationship between the expression levels of serum miR-203 and miR-217 and the clinicopathological features of the patients was analyzed. Kakaplan-Meier method was used to analyze the survival of AML patients with different serum miR-203 and miR-217 levels. Results: Compared with the healthy group, the serum miR-203 and miR-217 levels in the AML group were significantly lower (P<0.05). Compared with the complete response group, the serum miR-203 and miR-217 levels in the relapse group were significantly lower(P<0.05). Serum miR-203 levels were associated with leukocyte count in AML patients (P<0.05), while serum miR-217 levels were associated with platelet count in AML patients(P<0.05). The 5-year survival rate of AML patients with relatively high expression of serum miR-203 and miR-217 was higher than those with relatively low expression of serum miR-203 and miR-217, respectively (Log RankmiR-203=17.870, Log RankmiR-217=28.926, all P=0.000). Conclusion: The expression levels of serum miR-203 and miR-217 are closely related to AML. Detection of serum miR-203 and miR-217 expression levels might be helpful in evaluating the efficacy and prognosis of AML patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of tubeimoside-1 on the phenotype of skin squamous cell carcinoma SCL-1 cells and possible mechanism of action. Methods: SCL-1 cells were divided into the control group and the treatment groups, including different doses (5, 10, 20 μg/mL) of tubeimoside-1 groups, si-NC group, si-circ_0000376 group, tubeimoside-1+ pcDNA group, and tubeimoside-1+pcDNA-circ_0000376 group. CCK-8 method was used to detect cell proliferation inhibition rate.Transwell was used to detect cell migration and invasion. Flow cytometry was used to detect cell apoptosis. Western blot was used to detect the protein expression of Ki-67, MMP-2, MMP-9, Bcl-2 and Bax. RT-qPCR method was used to detect the expression of circ_0000376 and miR-203. The dual luciferase reporter gene experiment was used to verify the regulatory relationship between circ_0000376 and miR-203. Results: Compared with the control group, the proliferation inhibition rate, apoptosis rate and the Bax protein expression of cells in the tubeimoside-1 group were significantly increased (F=772.61, 352.20, 277.56, all P

Abstract Background Circ_0000396 was found to be down-regulated in the rheumatoid arthritis (RA) patients and had a high diagnostic value. However, the function and mechanisms underlying circ_0000396 in RA progression remain unclear. Methods The expression of circ_0000396, microRNA (miR)-203 and HMG-box transcription factor 1 (HBP1) was detected using qRT-PCR and western blot. The proliferative and apoptotic capabilities of rheumatoid arthritis synovial fibroblasts (RASFs) were measured by colony formation, CCK-8, flow cytometry and western blot assays, respectively. The levels of interleukins (IL)-6, IL-1β, IL-8 and tumor necrosis factor-α (TNF-α) were detected using enzyme-linked immunosorbent assay (ELISA). The target correlations between miR-203 and circ_0000396 or HBP1 were validated using pull-down and dual-luciferase reporter assay. Results Circ_0000396 was decreased in RA synovial tissues and RASFs, and overexpression of circ_0000396 suppressed cell proliferation, induced cell apoptosis and reduced the release of inflammatory cytokine IL-6, IL-1β, IL-8 and TNF-α in RASFs, while circ_0000396 deletion functioned oppositely. MiR-203 was confirmed to be a target of circ_0000396, and miR-203 reversed the protective effects of circ_0000396 on the dysfunction and inflammation of RASFs. HBP1 was a target of miR-203, and silencing miR-203 inhibited RASFs malignant changes by regulating HBP1. In addition, circ_0000396 could regulate HBP1 by sponging miR-203, and HBP1 decrease attenuated the effects of circ_0000396 on RASF growth and inflammation. Conclusion Circ_0000396 inhibited the growth and inflammation in RASFs by regulating miR-203/HBP1 axis, providing a potential therapeutic target for RA.

Background: miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. Methods: Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3ʹUTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. Results: Akirin2, an activator of NF‐κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF‐κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF‐κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF‐κB, IL-1β and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. Conclusion: A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF‐κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling. [ABSTRACT FROM AUTHOR]

Abstract Background The biological role of miR-203 and the underlying mechanisms on the proliferation of epidermal stem cells (ESCs) have not yet been reported during the progression of chronic wound healing in diabetes mellitus. Our previous studies have observed that the expression of miR-203 showed a marked upregulation and ESC proliferation capacity was impaired in diabetes mellitus skin wounds in rats. Methods Wound models were established in normal rats and rats with type 2 diabetes. Expression level of miR-203 and the alteration of ESCs’ number and function were detected. ESCs were isolated from the back skin of fetal rats to assess the effects of glucose in vitro. An antagomir to miR-203 was used to assess its effect on ESCs. Using microarray analysis, we further identified potential target genes and signaling pathways of miR-203. Results We found that high glucose significantly upregulated the expression of miR-203 and subsequently reduced the number of ESCs and impaired their proliferation capacity. Meanwhile, over-expression of miR-203 reduced the ESCs’ numbers and impaired the proliferation capacity via downregulation of the Notch and Wnt signaling pathways. Conversely, inhibition of miR-203 enhanced the proliferation capacity. Additionally, silencing miR-203 in skin of rats with type 2 diabetes accelerated wound healing and improved healing quality via the upregulation of the Notch and Wnt signaling pathways. Finally, over-expression of miR-203 downregulated genes ROCK2, MAPK8, MAPK9, and PRKCA. Conclusion Our findings demonstrated that induced expression of miR-203 by high glucose in type 2 diabetic rats decreased the number of ESCs and impaired ESC proliferation capacity via downregulating genes related to Notch and Wnt signaling pathways, resulting in a delayed wound healing.

Abstract Background Esophageal cancer is one of the most common cancers worldwide with poor prognosis and high mortality. The transcription factor SNAI1, encoding Snail1, is important for metastatic progression in esophageal cancer whereas the microRNA (miRNA)-203 has been shown to function as an inhibitor of metastasis in EC. The Snail1 protein is stabilized in EC partially by the deubiquitinating enzyme USP26; however, how USP26 is regulated is not completely known. Methods Expression of SNAI1 and USP26 messenger RNA (mRNA) and miR-203 was performed in datasets within The Cancer Genome Atlas and Gene Expression Omnibus, respectively. Expression of Snail1 and USP26 protein and miR-203 was determined in the normal esophageal cell line HET-1A and EC cell lines Kyse150 and TE-1 using western blot and quantitative polymerase chain reaction, respectively. TargetScan was used for in situ prediction of miR-203 targets and in vitro heterologous reporter assays using the wild-type and miR-203 seed mutant of the 3′ Untranslated region (UTR) of USP26 were used to investigate whether USP26 is a target of miR-203. Effects of increasing miR-203 using MIR203A/5P mimic on USP26 and Snail1 in the HET-1A, Kyse150 and TE-1 cell lines were performed using western blot and cycloheximide-based protein stability analysis. Effects of modulating miR-203 in Kyse150 and TE-1 cell lines on in vitro pro-metastatic effects were analyzed by invasion assay, scratch wound-healing assay, and chemosensitivity to 5-fluoruracil (5-FU). In vivo lung metastasis assay was used to study the effect of modulating miR-203 in Kyse150 cells. Results SNAI1 mRNA and HSA/MIR203 was higher and lower, respectively, in EC patients compared to tumor-adjacent normal tissues. No changes in expression of USP26 mRNA were observed in these datasets. MIR/203 expression was downregulated whereas protein expression of both Snail1 and USP26 were higher in EC cell lines Kyse150 and TE-1 compared to normal esophageal cell line HET-1A. USP26 was predicted as a potential target of miR-203 by TargetScan Release 2.0. Reporter assays confirmed USP26 as a target of miR-203 in the EC cell lines. Transfection of EC cell lines with MIR203 mimic decreased USP26 protein expression and Snail1 protein stability indicating the ability of miR-203 to regulate Snail1 protein levels via USP26. Exogenous increase in miR-203 in the EC cell lines significantly inhibited Snail-1 mediated in vitro pro-metastatic function of invasion, wound-healing, and increased chemosensitivity to 5-FU. Finally, overexpression of miR-203 inhibited in vivo lung metastasis of Kyse150 cells, which was reversed following overexpression of USP26, indicating a direct role of miR-203-mediated regulation of USP26 in metastatic progression of EC. Conclusions Cumulatively, these results establish an important mechanism by which decrease in miR-203 expression potentiates metastatic progression in EC via USP26-mediated stabilization of Snail1. Hence, miR-203 can serve as a biomarker of metastasis in EC and is a potential target for therapeutic intervention in EC.

Liver cancer has high rates of morbidity and mortality, and its treatment is a global health challenge. Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancer cases. B-lymphoma Mo-MLV insertion region 1 (BMI1) has been identified as a proto-oncogene, which contributes to the initiation and progression of many malignant tumors. BMI1 expression is upregulated in HCC, and it influences the occurrence and development of HCC by various mechanisms, such as the INK4a/ARF locus, NF-κB signaling pathway, and PTEN/PI3K/AKT signaling pathway. In addition, the expression of BMI1 is related to prognosis and recurrence of HCC. Hence, there is clear evidence that BMI1 is a novel and valid therapeutic target for HCC. Accordingly, the development of therapeutic strategies targeting BMI1 has been a focus of recent research, providing new directions for HCC treatment. This review summarizes the role of BMI1 in the occurrence and treatment of HCC, which will provide a basis for using BMI1 as a potential target for the development of therapeutic strategies for HCC. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) and miRNAs (microRNAs) are considered as key regulators of several biological processes, including dental development. In this study, we explored the lncRNAs and miRNAs which are involved in dental development. Method: Real-time PCR was performed to identify the candidate lncRNAs and miRNAs involved in dental development. Bioinformatics analysis and luciferase assay were carried out to establish the regulatory relationships between MALAT1, miR-203 and miR-200c in dental development. Results: Among all candidate lncRNAs, only MALAT1 was highly expressed in differentiated human dental pulp cells (hDPCs), and among all candidate miRNAs which are down-regulated in differentiated hDPCs, miR-203, and miR-200c are most decreased. Furthermore, MALAT1 was up-regulated while miR-203 and miR-200c were down-regulated in differentiated hDPCs in a time-dependent manner. MiR-203 and miR-200c were proved to bind to MALAT1. Moreover, BMI1 was identified as a target gene of miR-203 or miR-200c, and BMI1 was time-dependently decreased in hDPCs cultured with odontogenic medium. On the contrary, dentin sialophosphoprotein (DSPP), dentin matrix protein-1 (DMP-1), osteocalcin (OCN), and alkaline phosphatase (ALP), were time-dependently increased in hDPCs cultured with odontogenic medium. Finally, the overexpression of MALAT1 and the knockdown of miR-203/miR-200c both significantly increased the levels of BMI1, DSPP, DMP-1, OCN, and ALP, while the effect of knockdown of miR-203/miR-200c was much stronger than that of the overexpression of MALAT1. Conclusion: Our results demonstrated that MALAT1 functions as a competing endogenous RNA of miR-203 and miR-200c and accordingly promotes BMI1 expression. Therefore, MALAT1 may serve as a biomarker for dental development. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fei Le, 1 Ping Luo, 2 Qian Ouyang, 3 Xiaoming Zhong 4 1Department of Head and Neck Surgery, Jiangxi Province Cancer Hospital, Nanchang City, Jiangxi Province, 330029, People’s Republic of China; 2Department of Surgical Oncology, Nanchang Third Hospital Surgical Oncology, Nanchang City, Jiangxi Province, 330002, People’s Republic of China; 3Department of Intensive Medicine, Jiangxi Province Cancer Hospital, Nanchang City, Jiangxi Province, 330029, People’s Republic of China; 4Department of Tumor Radiotherapy, Jiangxi Province Cancer Hospital, Nanchang City, Jiangxi Province, 330029, People’s Republic of ChinaCorrespondence: Xiaoming ZhongDepartment of Tumor Radiotherapy, Jiangxi Province Cancer Hospital, No. 519 Beijing East Road, Nanchang City, Jiangxi Province 330029, People’s Republic of ChinaTel +86 15979192617Email nlsxhwdccm24@163.comObjective: This study aimed to assessment the functions of lncRNA WT1-AS in papillary thyroid carcinoma (PTC).Methods: Expression levels of WT1-AS in PTC and non-tumor tissues from 66 PTC patients were measured and compared by performing qPCR and paired t test, respectively. Cell proliferation (CCK-8) assay was performed to evaluate the effects of the overexpression of WT1-AS, miR-203 and survivin on the proliferation of IHH-4 (a human PTC cell line) cells.Results: We found that WT1-AS was significantly downregulated in PTC and associated with clinical stages. In PTC tissues, WT1-AS was negatively correlated with survivin but positively correlated with miR-203. In PTC cells, WT1-AS overexpression led to significantly upregulated miR-203 and downregulated survivin. MiR-203 overexpression failed to affect WT1-AS but downregulated survivin. Cell proliferation assay showed that overexpression of WT1-AS and miR-203 led to decreased, while survivin overexpression led to increased proliferation of PTC cells. In addition, survivin overexpression attenuated the effects of WT1-AS and miR-203 overexpression.Conclusion: Therefore, WT1-AS may downregulate survivin by upregulating miR-203 in PTC to inhibit cancer cell proliferation.Keywords: WT1-AS, papillary thyroid carcinoma, survivin, miR-203

Meixian Chen,1,* Lisheng Zhou,1,* Zhaoxia Liao,1 Xijiu Ye,1 Xujun Xuan,2 Beibei Gu,1 Fuding Lu1 1Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Andrology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fuding LuDepartment of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaTel +86-13560371081Email lfd19870901@126.comBackground: Osteosarcoma is one of the most common primary bone cancers with predominant occurrence in children and adolescents. This study aimed to determine the effects of sevoflurane treatment on the osteosarcoma progression and to explore the underlying molecular mechanisms.Materials and methods: The mRNA and protein expression levels were determined by qPCR and Western blot, respectively. Osteosarcoma cell proliferation, apoptosis and invasion were determined by MTT, caspase-3 activity, colony formation and Transwell invasion assays, respectively. The interaction between miR-203 and WNT2B 3ʹ untranslated region was confirmed by luciferase reporter assay.Results: Sevoflurane treatment for 6 hrs concentration-dependently suppressed cell viability, increased caspase-3 activity and up-regulated miR-203 expression in both U2OS and MG63 cells. MiR-203 overexpression suppressed cell viability, increased caspase-3 activity and suppressed cell growth and invasion of osteosarcoma cells. In addition, miR-203 knockdown attenuated the tumor-suppressive effects of sevoflurane treatment on osteosarcoma cells. Mechanistic studies showed that miR-203 repressed the expression of WNT2B in U2OS cells, and inhibition of miR-203 attenuated the suppressive effects of sevoflurane on WNT2B expression. More importantly, WNT2B overexpression attenuated the effects of sevoflurane treatment on cell viability, caspase-3 activity, cell growth and invasion of U2OS cells. MiR-203 overexpression suppressed Wnt/β-catenin signalling. Similarly, sevoflurane suppressed the activity of Wnt/β-catenin signalling, which was partially reversed by miR-203 knockdown and WTN2B overexpression.Conclusion: Our data showed the tumor-suppressive effects of sevoflurane on osteosarcoma cells, and mechanistic studies revealed that sevoflurane inhibited osteosarcoma cell proliferation and invasion partly via targeting the miR-203/WNT2B/Wnt/β-catenin axis.Keywords: osteosarcoma, proliferation, invasion, sevoflurane, miR-203, WNT2B, Wnt/β-catenin

Abstract AB209371 gene has been characterized as an oncogenic lncRNA in liver cancer. However, its involvement in ovarian carcinoma (OC) is unknown. In the present study, we analyzed the roles of AB209371 in OC. We found that AB209371 gene and Survivin gene were up-regulated in OC and positively correlated with OC development. AB209371 over-expression led to up-regulated Survivin in OC cells, while Survivin over-expression failed to affect AB209371. In addition, AB209371 over-expression led to down-regulated miR-203. However, miR-203 over-expression failed to affect AB209371, but down-regulated the expression of Survivin. In addition, over-expressions of AB209371 and Survivin resulted in the increased proliferation rate of OC cells. Over-expression MiR-203 played the opposite role and attenuated the effects of AB209371 over-expression. Therefore, AB209371 may down-regulate miR-203 to up-regulate Survivin, thereby promoting OC cell proliferation. Our study provided novel insights into the pathogenesis of OC.

The circRNA circAGFG1 is reported to be important in triple‐negative breast cancer progression. However, the mechanism of circAGFG1 in non‐small‐cell lung cancer (NSCLC) remains unknown. In this study, expression of circAGFG1 was determined by real‐time PCR in 20 pairs of NSCLC tissues and adjacent tissues. Next, functional experiments with circAGFG1 were performed in vitro to evaluate the role of circAGFG1 in tumor metastasis and growth. Meanwhile, a dual luciferase reporter assay, RNA pull‐down and RNA immunoprecipitation experiments were used to explore the interaction between circAGFG1 and miR‐203. Our results revealed that expression levels of circAGFG1 and miR‐203 are upregulated in non‐small‐cell lung cancer tissues. CircAGFG1 enhances NSCLC cell proliferation, invasion, migration and epithelial‐mesenchymal transition in vitro. Mechanistic analyses indicated that circAGFG1 acts as a sponge for miR‐203 to repress the effect of miR‐203 on its target, ZNF281. In conclusion, our study suggests that circAGFG1 promotes NSCLC growth and metastasis though a circAGFG1/miR‐203/ZNF281 axis and may represent a novel therapeutic target.

Abstract Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well‐established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P

The importance of miRNA prognostic signature in cancer, particular cancer metastasis is increasingly being realized. Bone metastasis from several primary human cancers can be managed in clinics by surgical intervention but the prognostic impact of miRNA signature on post-surgery outcome of patients is unknown. This study evaluated a miRNA signature for post-operative outcome of patients with bone metastatic disease. First, the miRNAs, miR-135, miR-203, miR-10b, miR-194, miR-886, and miR-124 were evaluated in bone metastatic tissues, relative to adjacent control tissue. The cohorts of samples (n = 44) consisted of bone metastatic cancer patients with primary lung (n = 18) or breast cancer (n = 26). miR-203 was significantly down-regulated while miR-10b was significantly up-regulated in bone metastasis. Additionally, miR-135 was significantly differentially expressed in the primary lung cancer patients while miR-194 in primary breast cancer patients. The low miR-203- high miR-10b expression was designated high risk group and, compared to the low risk group (high miR-203-low miR-10b expression). Patients with the signature high risk fared significantly better with surgical intervention, in terms of survival at 12 months time point (40% survival with surgery vs. 10% survival without surgery), as revealed by retrospective analysis of patient data. This work reveals potential utilization of miRNA expression levels in not only the general prognosis of cancer metastasis but also the prognosis of surgical intervention with implication for better stratification of patients.

Purpose: Altered miRNAs play a crucial role in the emergence of the breast cancer stem cell (BCSC) phenotype. The interplay between miRNAs and methylation enzymes has been documented. One of the most aggressive breast cancer cell lines, MDA-MB-231, has expressed much more DNMT3B than DNMT3A. This study aims to evaluate the ability of miR-203 restoration and miR-150 inhibition to regulate DNMT3B and DNMT3A to modify the methylation level of BCSC-associated genes. Methods: MDA-MB-231 cells were transfected with miR-203 mimic or miR-150 inhibitor or DNMT3B siRNA, and downstream analysis was performed by flow cytometry, real-time PCR and Western blotting. Results: DNMT3A and DNMT3B are regulated both by miR-203a-3p and miR-150-5p. Transfection with miR-203 mimic and miR-150 inhibitor significantly reduced the CD44+CD24− subpopulation and down-regulated the expression of CD44 mRNA by increasing promoter methylation levels. SiRNA knockdown of DNMT3B increased the CD44+CD24− subpopulation and the expression of CD44 and ALDH1A3 by decreasing methylation density. The inhibition of miR-150 down-regulated OCT3/4 and SOX2 expression without affecting methylation levels, while miR-203 restoration and miR-150 inhibition down-regulated NANOG expression by elevating the methylation level. A positive-feedback loop was found between miR-203 and its target DNMT3B, as restoring miR-203 suppressed DNMT3B, while knocking down DNMT3B up-regulated miR-203. The restoration of miR-203 and knockdown of DNMT3B decreased methylation levels and increased the expression of miR-141 and miR-200c. Conclusions: The study concluded that miR-203 and miR-150 play a role in the regulation of genes involved in BCSC methylation, including other miRNAs, by targeting DNMT3B and DNMT3A. [ABSTRACT FROM AUTHOR]

MiR-203 was identified as a hub of a potential regulatory miRNA network in central nervous system. Overexpressing of miR-203 in the frontal cortex of C57BL/6J wild type mouse induced neurodegeneration by increasing the apoptotic pathway and neuron death. AFF4, a transcription factor, was identified as a new bona fida protein target of miR-203 in CNS. The miRNA:mRNA interaction of miR-203 and AFF4 was verified using Dural-luciferase assay. Down-regulated expression of AFF4 was induced by overexpressing miR-203 both in vitro and in vivo. Open field test, Y maze and Morris water maze test were conducted for the behavioral assessment of the mice with stereotactic injection of lentiviral vector overexpressing miR-203 in the hippocampus. No anxiety-like behavior or impaired cognition was noticed in these mice. Consistent with the results of the behavioral assessment, the electron micrograph and Nissl staining revealed no significant change in the synaptic density and no neuron injuries in the hippocampus of mice overexpressing miR-203, respectively. Our results indicated that instead of promoting neurodegenerative phenotype, a more profound function should be ascribed to miR-203 in regulating neuron behavioral activities and cognition. Neuron-type specific functions of miR-203 are likely to be executed via its various downstream protein interactors. • We reported that AFF4, a transcription factor, was identified as a new bona fida protein target of miR-203 in CNS. • The miRNA:mRNA interaction of miR-203 and AFF4 was verified using Dural-luciferase assay. • Down-regulated expression of AFF4 was induced by overexpressing miR-203 both in vitro and in vivo. • Open field test, Y maze and Morris water maze test were conducted for the behavioral assessments of the mice with stereotactic injection of lentiviral vector overexpressing miR-203 in the hippocampus. • The electron micrograph and Nissl staining revealed no significant change in the synaptic density and no neuron injuries in the mice overexpressing miR-203 in the hippocampus. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Emerging evidence reveals the importance of long non-coding RNAs (lncRNAs) in the development and progression of keloid formation. However, the roles and molecular mechanism of lncRNA LINC01116 in the progression of keloid formation remain largely unknown.Methods: The expression levels of LINC01116, microRNA-203 (miR-203) and SMAD family member 5 (SMAD5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration and invasion were detected by Cell counting Kit-8 (CCK-8) assay and transwell assay. Flow cytometry and western blot assay were used to examine cell apoptosis and extracellular matrix (ECM) production. The interaction between miR-203 and LINC01116 or SMAD5 was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays.Results: LINC01116 and SMAD5 were upregulated while miR-203 was downregulated in keloid tissues and keloid fibroblasts. LINC01116 knockdown suppressed the proliferation, migration, invasion, and ECM production but induced apoptosis in keloid fibroblasts through enhancing miR-203 and inhibiting SMAD5. Moreover, SMAD5 was identified as a direct target of miR-203 and miR-203 could directly bind to LINC01116. Besides, LINC01116 regulated SMAD5 expression by targeting miR-203.Conclusion: Downregulation of LINC01116 inhibited the progression of keloid formation by regulating miR-203/SMAD5 axis, which might provide a novel target for keloid therapy. [ABSTRACT FROM AUTHOR]

Introduction: Protein kinase C theta (PKCθ) is expressed in ER‐negative breast cancer and promotes cancer stem cells (CSCs) phenotype. PKCθ gene (PRKCQ) is predicted to be a target for tumor suppressor miR‐203. Herein, we aim to validate this prediction and evaluate the ability of miR‐203 to inhibit migration of breast cancer cell line enriched with CSCs, MDA‐MB‐231, via PRKCQ targeting. Methods: Cells were transfected with miR‐203 mimic, PRKCQ siRNA and negative control; then real‐time PCR, migration assay, western blotting, reporter assay, and chromatin accessibility assay were performed. Results: Our findings displayed significant decrease in PRKCQ mRNA level and luciferase signals in cells with restored miR‐203 expression, therefore, validated PRKCQ as a direct target of miR‐203. Additionally, inhibiting PRKCQ by siRNA led to significant inhibition of miR‐203 expression and significant decrease of chromatin accessibility at miR‐203 promoter region 466–291 upstream TSS. Both of miR‐203 re‐expression and PRKCQ suppression resulted in altering migration ability of MDA‐MB‐231 through regulating AKT pathway and genes involved in breast cancer stem cells, CD44 and ALDH1A3. Expression of CDK5, GIV, and NANOG was significantly downregulated in miR‐203 mimic‐transfected cells, while PRKCQ siRNA‐transfected cells displayed downregulation of OCT3/4, SOX2, and NANOG. Furthermore, we found that miR‐224 expression was enhanced while miR‐150 was downregulated after ectopic expression of miR‐203. Conclusion: The study highlighted the negative feedback loop between miR‐203 and its target PRKCQ and the interplay between them in regulating genes involved in BCSCs. The study also concluded "microRNA‐mediated microRNA regulation" as an event in breast cancer cells. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is one of the leading causes of high mortality worldwide. Long non-coding RNA myocardial infarction associated transcript (MIAT) and mitochondrial coupling factor 6 (CF6) aggravate MI. This study aimed to elucidate whether miR-203 interacted with MIAT and CF6 in MI. Results revealed that MIAT and CF6 expressions were upregulated and that miR-203 was downregulated in mouse myocardial tissues after MI, as well as in hypoxic mouse cardiomyocytes. The overexpression of MIAT in mouse cardiomyocytes raised CF6 expression, whereas the knockdown of MIAT had the opposite effect. Mechanistically, the luciferase reporter and RNA pull-down assays corroborated the binding between miR-203 and CF6 3′UTR and between miR-203 and MIAT. The simultaneous overexpression of miR-203 and MIAT restored the reduction of CF6 caused by miR-203 overexpression alone, and the overexpression of miR-203 diminished the percentage of infarct area and the apoptosis of cardiomyocytes in vivo. Our findings corroborate that overexpressing miR-203 alleviates MI via interacting with MIAT and CF6. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression and clinical significance of microribonucleic acid (mi R)-203 and mi R-4317 in gastric cancer tissues. Methods: A total of 92 gastric cancer patients admitted to our hospital from January 2014 to December 2016 were selected. Real-time quantitative PCR (qRT-PCR) was used to detect mi R-203 and mi R- in gastric cancer tissues and their corresponding adjacent tissues. 4317 expression, analysis of the relationship between mi R-203, mi R-4317 expression and clinicopathological parameters of gastric cancer patients, all patients were followed up for 3 years, according to the median expression of mi R-203 and mi R-4317 in gastric cancer tissue The patients were divided into mi R-203 high expression group (49 cases), mi R-203 low expression group (43 cases), mi R-4317 high expression group (51 cases), mi R-4317 low expression group (41 cases) ). Analyze the relationship between mi R-203, mi R-4317 and the prognosis and the factors affecting the prognosis. Results: The relative expression levels of mi R-203 and mi R-4317 in gastric cancer tissues were significantly lower than those in adjacent tissues (P<0.05). There was no significant difference in the relative expression of mi R-203 and mi R-4317 in gastric cancer tissues of patients with gastric cancer of different gender, age and tumor size (P>0.05), moderately poorly differentiated, TNM stage III to IV, and lymph node metastasis The relative expression levels of mi R-203 and mi R-4317 in gastric cancer tissues of gastric cancer patients were significantly lower than those of well-differentiated gastric cancer patients with TNM staging from stage I to II and no lymph node metastasis (P<0.05). The 3-year survival rate of the mi R-203 high expression group was significantly higher than that of the mi R-203 low expression group (P<0.05), and the 3-year survival rate of the mi R-4317 high expression group was significantly higher than that of the mi R-4317 low expression group (P <0.05). COX multivariate analysis showed that poorly differentiated, TNM stage III-IV, lymph node metastasis, low expression of mi R-203, and low expression of mi R-4317 were independent risk factors affecting the prognosis of gastric cancer patients (P<0.05). Conclusion: The expression of mi R-203 and mi R-4317 is abnormally low in gastric cancer tissues, and their levels are closely related to the prognosis of gastric cancer, and the prognosis of gastric cancer patients is related to the degree of differentiation, clinical stage, and lymph node metastasis. [ABSTRACT FROM AUTHOR]

Abstract Background We previously reported that miR-203 functions as a tumor suppressor in ovarian cancer cells by directly targeting transcription factor Snai2 and inhibiting epithelial to mesenchymal transition (EMT), whereas BIRC5/survivin promotes EMT. In this study, we tested our hypothesis that miR-203 inhibits ovarian tumor metastasis by suppressing EMT through targeting BIRC5, using an orthotopic ovarian cancer mouse model. Methods We overexpressed miR-203 in ovarian cancer SKOV3 and OVCAR3 cells using a lentiviral vector and examined cell migration and invasion using transwell plates. The small molecule inhibitor, YM155, was used to inhibit survivin expression. miR-203-expressing and control SKOV3 cells were intrabursally injected into immunocompromised NSG female mice. Primary tumors in ovaries and metastatic tumors were collected to determine the expression of survivin and EMT markers using Western blot and immunostaining. Results Overexpression of miR-203 inhibits EMT by targeting BIRC5 in ovarian cancer SKOV3 and OVCAR3 cells. miR-203 expression enhances the ability of the survivin inhibitor YM155 to reduce tumor cell migration and invasion in vitro. We further showed that miR-203 expression attenuated the TGFβ pathway in both SKOV3 and OVCAR3 cells. miR-203 expression also inhibited primary tumor growth in ovaries and metastatic tumors in multiple peritoneal organs including liver and spleen. Conclusion miR-203 inhibits ovarian tumor metastasis by targeting BIRC5/survivin and attenuating the TGFβ pathway.

Background/Aims: Little is known how miR-203 is involved in epidermal stem cells (ESCs) differentiation and scar formation. Methods: We first used luciferase assay to determine the interaction of miR-203 with the 3’-UTR in regulation of Hes1 expression. We then used flow cytometry to analyze the effects of miR-203 expression on the differentiation of ESCs to MFB by determination of CK15 ratio and α-SMA. To confirm the results of flow cytometry analysis, we used Western blot to examine the expression of α-SMA, Collagen I (Col I), and Collagen III (Col III), as well as the expression of Notch1, Jagged1, and Hes1 in ESCs after the treatment of pre-miR-203 or anti-miR-203. Finally, we examined the effects local anti-miR-203 treatment on would closure and scar formation using a mouse skin wound model. Results: Pre-miR-203 treatment increased ESCs differentiation to MFB cells, as indicated by decreased CK15 ratio and increased MFB biomarkers. This phenomenon was reversed by overexpression of Hes1 in ESCs. In addition, skin incision increased expression of miR-203 in wound tissue. Local treatment of anti-miR-203 could accelerate wound closure and reduce scar formation in vivo, which was associated with increased re-epithelialization, skin attachment regeneration, and collagen reassignment. Finally, we confirmed that anti-miR-203 treatment could inhibit ESCs differentiation in vivo via increasing Hesl expression. Conclusion: Taken together, our results suggested that overexpression of miR-203 in ESCs after skin wound may be a critical mechanism underlying the scar formation.

Background: Infection-induced preterm birth is a major cause of neonatal mortality and morbidity and leads to preterm premature rupture of placental chorioamniotic membranes. The loss of amniotic epithelial cells and tensile strength preceding membrane rupture is poorly understood. We hypothesized that intrauterine bacterial infection induces changes in microRNA (miRNA) expression, leading to amniotic epithelial cell loss and membrane weakening.Methods: Ten pregnant pigtail macaques received choriodecidual inoculation of either group B Streptococcus (GBS) or saline (n = 5/group). Placental chorioamniotic membranes were studied using RNA microarray and immunohistochemistry. Chorioamniotic membranes from women with preterm premature rupture of membranes (pPROM) and normal term pregnancies were studied using transmission electron microscopy.Results: In our model, an experimental GBS infection was associated with changes in the miRNA profile in the chorioamniotic membranes consistent with epithelial to mesenchymal transition (EMT) with loss of epithelial (E-cadherin) and gain of mesenchymal (vimentin) markers. Similarly, loss of desmosomes (intercellular junctions) was seen in placental tissues from women with pPROM.Conclusions: We describe EMT as a novel mechanism for infection-associated chorioamniotic membrane weakening, which may be a common pathway for many etiologies of pPROM. Therapy based on anti-miRNA targeting of EMT may prevent pPROM due to perinatal infection. [ABSTRACT FROM AUTHOR]

High fructose intake is a risk factor for liver fibrosis. Polydatin is a main constituent of the rhizome of Polygonum cuspidatum, which has been used in traditional Chinese medicine to treat liver fibrosis. However, the underlying mechanisms of fructose‐driven liver fibrosis as well as the actions of polydatin are not fully understood. In this study, fructose was found to promote zinc finger E‐box binding homeobox 1 (ZEB1) nuclear translocation, decrease microRNA‐203 (miR‐203) expression, increase survivin, activate transforming growth factor β1 (TGF‐β1)/Smad signalling, down‐regulate E‐cadherin, and up‐regulate fibroblast specific protein 1 (FSP1), vimentin, N‐cadherin and collagen I (COL1A1) in rat livers and BRL‐3A cells, in parallel with fructose‐induced liver fibrosis. Furthermore, ZEB1 nuclear translocation‐mediated miR‐203 low‐expression was found to target survivin to activate TGF‐β1/Smad signalling, causing the EMT in fructose‐exposed BRL‐3A cells. Polydatin antagonized ZEB1 nuclear translocation to up‐regulate miR‐203, subsequently blocked survivin‐activated TGF‐β1/Smad signalling, which were consistent with its protection against fructose‐induced EMT and liver fibrosis. These results suggest that ZEB1 nuclear translocation may play an essential role in fructose‐induced EMT in liver fibrosis by targeting survivin to activate TGF‐β1/Smad signalling. The suppression of ZEB1 nuclear translocation by polydatin may be a novel strategy for attenuating the EMT in liver fibrosis associated with high fructose diet. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the expression levels and clinical significance of microRNA (miR)-203 and miR-133b in laryngeal carcinoma. A total of 154 patients with laryngeal carcinoma (research group) along with 100 healthy individuals (control group) were enrolled in the study. The patients were admitted to Yidu Central Hospital of Weifang (Weifang, China) from February 2016 to October 2018. Fasting venous blood (5 ml) was extracted from all subjects to determine the expression levels of serum miR-203 and miR-133b by reverse transcription-quantitative polymerase chain reaction (PCR) and to compare them among patients with different pathological characteristics. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic values of miR-203 and miR-133b for laryngeal carcinoma. The research group showed significantly lower expression levels of miR-203 and miR-133b than the control group (P<0.05). According to ROC curve analysis, when the cut-off value was 0.659, the sensitivity and specificity of miR-203 in diagnosing laryngeal carcinoma were 60.00 and 90.26%, respectively, whereas when the cut-off value was 1.398, the sensitivity and specificity of miR-133b were 55.00 and 87.66%, respectively. The sensitivity and specificity of the joint detection were 70.00 and 83.77%, respectively, when the cut-off value was 0.416. In the research group, miR-203 was expressed significantly different in patients with different pathological stages and tumor types (P<0.050). The expression of miR-133b varied significantly in patients with different pathological stages, differentiation degrees and lymph node metastasis (P<0.050). In conclusion, miR-203 and miR-133b were expressed at low levels in patients with laryngeal carcinoma. The expression of miR-203 was related to tumor-node-metastasis (TNM) stage and tumor type, whereas the expression of miR-133b was related to TNM stage, differentiation degree, as well as lymph node metastasis. Joint detection of miR-203 and miR-133b is expected to be an excellent marker for the diagnosis and treatment of laryngeal carcinoma. [ABSTRACT FROM AUTHOR]