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Objective Preeclampsia (PE) is a pregnancy-specific condition featured by high blood pressure, edema, and proteinuria. Research about the role of microRNA (miR)-203 in PE remains insufficient. This experiment is designed to investigate the specific role of miR-203 in trophoblasts in PE. Study Design miR-203 expression in placenta tissues of normal pregnant women and PE patients was examined to analyze the relevance between miR-203 and PE diagnostic efficiency and between miR-203 and blood pressure (systolic pressure and diastolic pressure) and proteinuria of PE patients. miR-203 expression was downregulated in hypoxia-cultured trophoblasts using miR-203 inhibitor to assess matrix metalloproteinase-9 (MMP-9) level. Then, the angiogenesis of trophoblasts with different treatments was determined. Subsequently, the target relation between miR-203 and insulin-like growth factor receptor 1 (IGF-1R) was predicted and verified. Additionally, the effect of IGF-1R in the mechanism of miR-203 modulating trophoblast vascular remodeling was detected. Results miR-203 was overexpressed in the placenta of PE patients and it acted as a promising diagnostic indicator for PE. Moreover, miR-203 was positively associated with blood pressure (systolic pressure and diastolic pressure) and proteinuria of PE patients. miR-203 silencing in hypoxia-cultured trophoblasts enhanced trophoblast vascular remodeling. Mechanically, miR-203 bound to IGF-1R to suppress its transcription. IGF-1R downregulation counteracted the promotive effect of miR-203 silencing on trophoblast vascular remodeling. Conclusion miR-203 was overexpressed in PE, and it targeted IGF-1R to limit trophoblast vascular remodeling. Key Points miR-203 is overexpressed in the placenta of PE patients. miR-203 acts as a potential diagnostic marker for PE. miR-203 targets IGF-1R to reduce trophoblast vascular remodeling in PE. [ABSTRACT FROM AUTHOR]

nscription factor-κB (NF-κB) signaling pathway, and its effect on renal fibrosis in diabetic nephropathy (DN) rats. Methods: A rat DN model was established, and the renal tubular epithelial cells (NRK-52E) were cultured with high sugar to simulate an in vitro DN model, qRT-PCR was used to detect the expression level of miR-203, Western blot was used to detect the expressions of PEG3 and NF-κB proteins. Dual luciferase reporter gene technology was used to detect the targeting relationship between miR-203 and PEG3. The miR-203 mimic (miR-203 mimic) and negative control (mimic NC), PEG3 high expression recombinant vector (pcDNA-PEG3) and negative control (pcDNA-NC) were constructed, and injected and transfected into DN rats and DN model cells respectively to set the control group, model group, miR-203 mimic group, mimic NC group, miR-203 mimic+pcDNA-PEG3 group, and miR-203 mimic+pcDNA-NC group. The 24 h urine protein, blood sugar, serum creatinine (SCr) and urea nitrogen (BUN) in rats were detected, electron microscopy and Masson staining were used to detect renal tissue lesions and fibrosis changes; ELISA was used to detect the contents of IL-6, IL-1β, Collagen Ⅰand TGF-β1 in cells； Western blot was used to detect the protein expressions of IL-6, IL-1β, Collagen Ⅰ，α-SMA and TGF-β1 in kidney tissue. Results: The expressions of miR-203 in kidney tissue and renal tubular epithelial cells of DN rats were decreased (P<0.05), the expression of PEG3/NF-κB was increased in kidney tissue and renal tubular epithelial cells of DN rats (P<0.05). There was a targeted binding site between miR-203 and PEG3. Up-regulating the expression of miR-203 could inhibit the activation of PEG3/NF-κB in DN rats and cell models, reduce the expression of inflammation-fibrosis related factors, and alleviate the pathological symptoms of DN such as renal tissue structural damage and decreased renal function in rats (P<0.05). pcDNA-PEG3 could partially reverse the above effects of miR-203(P<0.05). Conclusion: miR-203 can target to negatively regulate the PEG3/NF-κB pathway and up-regulate the expression of miR-203, which can target to inhibit the activation of the PEG3/NF-κB pathway and play the role of anti-inflammatory-fibrosis in the kidney of DN rats. [ABSTRACT FROM AUTHOR]

Aim: In this study, we aimed to explore the effects of microRNA‐203 (miR‐203) on Porphyromonas gingivalis lipopolysaccharide (P.g. LPS)‐stimulated periodontal ligament cells (PDLCs) and identify potential molecular targets for periodontitis treatment. Methods: Periodontal ligament cells were stimulated by P.g. LPS, followed by quantification of miR‐203 and AP‐1 expression. Next, loss‐ and gain‐of‐function experiments were applied in P.g. LPS‐induced PDLCs. The proliferation, apoptosis, and differentiation of PDLCs were determined, and mineralized nodule numbers were counted. Functional assays were used to identify interactions among miR‐203, activator protein‐1 (AP‐1), and intercellular adhesion molecule‐1 (ICAM‐1). In addition, expression of osteogenesis‐related genes and release of proinflammatory factors were analyzed. Results: miR‐203 was found to be downregulated while AP‐1 was upregulated in PDLCs stimulated by P.g. LPS. The overexpression of miR‐203 promoted P.g. LPS‐stimulated PDLC proliferation and differentiation, inhibited apoptosis, and increased the number of mineralized nodules. miR‐203 was verified to downregulate AP‐1/ICAM‐1 axis. miR‐203 overexpression reduced the secretion of proinflammatory factors while increasing the expression of osteogenesis‐related genes in P.g. LPS‐stimulated PDLCs, which was reversed by overexpressing AP‐1 and ICAM‐1. Conclusion: These experimental data demonstrated the potential inhibitory effects of overexpressed miR‐203 on periodontitis development by promoting PDLC differentiation and suppressing inflammatory responses through AP‐1/ICAM‐1 axis. [ABSTRACT FROM AUTHOR]

ObjectiveSquamous cell carcinoma (SCC) occurring in the tonsils (TSCC) has a poorer prognosis than SCC occurring in other regions of the oral cavity (non-tonsillar SCC [NTSCC]) because it easily metastasizes to distant organs. This study aimed to elucidate the molecular mechanisms underlying the migration and invasion of TSCC cells in vitro.Materials and methodsThis study focused on differential microRNA (miRNA) expression using microRNA microarrays and quantitative polymerase chain reaction in canine TSCC and NTSCC tissues and cell lines. A target gene of the miRNA involved in cell migration and invasion was validated by wound healing, transwell, and luciferase assays.ResultsmiR-203 expression was lower in TSCC tissues than in the normal oral mucosa and NTSCC tissues. Transfection of the miR-203 mimic resulted in the downregulation of mesenchymal marker protein expression and attenuation of cell migration and invasion in TSCC cells, but not in NTSCC cells. A dual-luciferase assay revealed that miR-203 directly targeted the mesenchymal transcription factor SLUG. SLUG overexpression enhances the migration of TSCC cells.ConclusionOur study indicates that the miR-203/SLUG axis may be involved in the metastatic mechanisms of TSCC.

ABSTRACT Hepatitis B virus (HBV) infection targets host restriction factors that inhibit its replication and survival. Previous studies have shown that barriers to autointegration factor1 (BANF1) inhibited the replication of herpes simplex virus and vaccinia virus by binding to phosphate backbone of dsDNA. To date, no reports are available for the interplay between BANF1 and HBV. In this study, we elucidated the mechanisms by which HBV inhibit BANF1. First, the effect of HBV on BANF1 was observed in Huh-7, Hep G2, and Hep G2.2.15 cells. Huh-7 cells were transfected with pHBV1.3 or HBx plasmids. The results showed that there was a decreased expression of BANF1 in Hep G2.2.15 cells (P ≤ 0.005) or in HBV/HBx expressing Huh-7 cells (P ≤ 0.005), whereas BANF1 overexpression decreased viral replication (P ≤ 0.05). To study whether phosphorylation/dephosphorylation of BANF1 was responsible for antiviral activity, mutants were created, and it was found that inhibition due to mutants was less significant compared to BANF1 wild type. Previous studies have shown that HBV, at least in part, could regulate the expression of host miRNAs via HBx. It was found that miR-203 expression was high in Hep G2.2.15 cells (P ≤ 0.005) compared to Hep G2 cells. Next, the effect of HBx on miR-203 expression was studied and result showed that HBx upregulated miR-203 expression (P ≤ 0.005). Overexpression of miR-203 downregulated BANF1 expression (P ≤ 0.05) and viral titer was upregulated (P ≤ 0.05), while inhibition of miR-203, reversed these changes. In conclusion, BANF1 downregulated HBV, whereas HBV inhibited BANF1, at least in part, via HBx-mediated miR-203 upregulation in hepatic cells. IMPORTANCE In this study, for the first time, we found that BANF1 inhibited HBV replication and restricted the viral load. However, as previously reported for other viruses, the results in this study showed that BAF1 phosphorylation/dephosphorylation is not involved in its antiviral activity against HBV. HBV infection inhibited the intracellular expression of BANF1, via HBx-mediated upregulation of miR-203 expression. Overexpression of miR-203 downregulated BANF1 and increased the viral titer, while inhibition of miR-203 reversed these changes. This study helped us to understand the molecular mechanisms by which HBV survives and replicates in the host cells.

Abstract Background Increasing studies indicated that microRNA-203 (miR-203) may play an important part in the prognosis of CRC. Nevertheless, the prognostic and influential mechanism of miR-203 expression in CRC remains to be inconclusive. Accordingly, we conducted the current study to investigate the biomarker performance of miR-203 in CRC. Methods In the present study, we conducted an evidence synthesis of the published literatures to identify the prognostic roles of miR-203 in patients with CRC. Moreover, several bioinformatics methods were applied for exploring the biomarker roles of miR-203. Results It was demonstrated that elevated miR-203 expression was clearly related to worse overall survival (HR: 1.55, 95% CI: 1.07–2.24, P = 0.021) for CRC. The gene Ontology (GO) analysis indicated that miR-203 targets were primarily involved in a series of GO items closely associated with the molecular pathogenesis of CRC. The pathway analysis exhibited the potential signal pathways of miR-203 involved in CRC including pathways in cancer, wnt pathway, prolactin signaling pathway, proteoglycans in cancer, FoxO pathway, focal adhesion and Ras pathway. By constructing a protein-protein interaction (PPI) network of the targets of miR-203, ten crucial proteins and a significant network module were retrieved and found to serve important roles in the molecular pathogenesis of CRC. Conclusions Our results indicated that miR-203 may function as a promising biomarker to monitor CRC survival outcomes and progression. Notably, large-scale prospective cohort studies and biological experiments are required to confirm our conclusions.

Cutaneous squamous cell carcinoma (CSCC) is a malignant proliferation of cutaneous epithelium that has been observed to have an alarming rise in incidence. Numerous studies have demonstrated microRNAs (miRNAs or miRs) as important biomarkers in the diagnosis, prognosis, and treatment of CSCC. This study aims to investigate the effects of miR-203 on the behaviors of CSCC cells and possible mechanisms associated with protein regulator of cytokinesis-1 (PRC1) and Wnt/β-catenin signaling pathway. PRC1 was suggested as a target of miR-203 in squamous cell carcinoma cell line 1 (SCL-1) cells by dual-luciferase reporter gene assay. Based on the immunohistochemical staining and qRT-PCR, PRC1 was abundantly expressed while miR-203 was poorly expressed in CSCC tissues. miR-203 mimic or inhibitor was transfected into SCL-1 cells to upregulate or downregulate its expression. Upregulation of miR-203 downregulated PRC1 expression to block the Wnt/β-catenin signaling pathway. By conducting 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch test, and Transwell and flow cytometric analyses, miR-203 was witnessed to restrain SCL-1 cell proliferation, migration, and invasion while accelerating their apoptosis. The rescue experiments addressed that inhibition of the Wnt/β-catenin signaling pathway conferred the anti-tumor effect of miR-203. These results establish a tumor-suppressive role for miR-203 in CSCC cell line SCL-1. Hence, miR-203 has promising potential as a therapeutic target for CSCC.

The present study aimed to evaluate the underlying mechanism of microRNA-203 (miR-203) in renal cell carcinoma (RCC) involving the PI3K/AKT signaling pathway. The results revealed downregulated miR-203 and upregulated CAV1 in RCC tissues. Upregulated miR-203 and downregulated CAV1 increased E-cadherin expression and cell apoptosis, decreased β-catenin and N-cadherin expression and cell proliferation, migration and invasion, and blocked cell cycle entry. CAV1, a target gene of miR-203, decreased by up-regulated miR-203, and silencing CAV1 led to the inactivation of PI3K/AKT signaling pathway. In conclusion, our findings suggested that miR-203-mediated direct suppression of CAV1 inhibits EMT of RCC cells via inactivation of the PI3K/AKT signaling pathway.

Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial-mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration. [ABSTRACT FROM AUTHOR]

Background: Septic shock, the most serious complication of sepsis, is a life-threatening disease that is mainly characterized by hypoperfusion and multiple organ failure. Various aberrantly expressed microRNAs (miRNAs) have been reported to be related to septic shock. We explored the regulatory effect of microRNA-203 (miR-203) on lung injury in septic shock mice. Methods: Microarray-based gene expression profiling related to septic shock identified the differentially expressed gene vanin-1 (VNN1) and potential regulatory miR-203. miR-203 was predicted to mediate VNN1 expression, thus affecting septic shock, which was investigated by treatment with miR-203 mimic, miR-203 inhibitor, and siRNA-VNN1 in septic shock mouse models. Polymorphonuclear neutrophils (PMNs) and pulmonary alveolar macrophages in bronchoalveolar lavage fluid (BALF) as well as the wet/dry ratio of the lung were also measured to assess lung injury. Additionally, the effects of miR-203 on inflammatory cytokines, oxidative stress indexes, blood biochemical indexes, serine-threonine protein kinase (AKT) signaling pathway-related factors, and apoptosis-related factors were determined. Results: VNN1 was verified to be targeted and negatively regulated by miR-203. In mouse models of septic shock, weak expression of miR-203, high expression of VNN1, and inhibition of AKT signaling pathway were identified. In response to miR-203 mimic and VNN1 gene silencing, mouse models of septic shock displayed reduced apoptosis, MDA, ALT, and AST in lung tissues, decreased levels of TNF-α, IL-1β, IFN-γ, IL-10, and IL-6, in serum, and reduced PMN and PAM levels in BALF, in addition to elevated SOD activity. Notably, the presence of miR-203 mimic led to AKT signaling pathway activation. Conclusion:This study shows that upregulating miR-203 can alleviate lung injury through activation of the AKT signaling pathway by downregulating VNN1 in septic shock.

Myocardial ischaemia‐reperfusion (I/R) injury is a serious illness with high morbidity and mortality. Mounting evidence indicates the utility of sevoflurane (SEV) in the treatment of myocardial I/R injury. This study aimed to explore the molecular mechanisms underlying the protective action of SEV against myocardial I/R injury. A rat model of myocardial I/R injury was established, and I/R rats were treated with different concentrations of SEV. MicroRNA‐203 (miR‐203) and doublecortin (DCX) expression levels were determined using reverse transcription‐quantitative polymerase chain reaction. Putative target relationship between miR‐203 and DCX was explored using dual‐luciferase reporter gene assay and RNA‐binding protein immunoprecipitation assay. Ischaemia‐reperfusion rats were treated with SEV, miR‐203 antagomir or sh‐DCX, followed by determination of oxidative stress‐ and inflammation‐related factor levels using nitrite and enzyme‐linked immunosorbent assays, and that of apoptosis‐related factors using Western blot analysis. The apoptotic rate of myocardial tissues was determined using TdT‐mediated dUTP‐biotin nick end labeling (TUNEL) staining, and the infract area was evaluated using triphenyltetrazolium chloride staining. The results showed miR‐203 was poorly expressed and DCX was highly expressed in myocardial tissues of I/R rats. Sevoflurane was found to elevate miR‐203, and miR‐203, in turn, could target and reduce DCX expression. Sevoflurane, miR‐203 overexpression or DCX silencing resulted in declined oxidative stress, inflammation, apoptosis and infarct area, ultimately alleviating myocardial I/R injury. Collectively, these findings showed that SEV‐activated miR‐203 exhibited suppressive effects on myocardial I/R injury in rats and highlighted the SEV/miR‐203/DCX axis as a promising therapeutic target for myocardial I/R injury management. [ABSTRACT FROM AUTHOR]

miR-203 has been indicated to be a tumor suppressor in esophageal cancer, however, the underlying molecular mechanisms by which it functions are not fully understood. The present study aimed to investigate the molecular mechanisms underlying the regulatory activities of microRNA (miR)-203 in esophageal cancer. The miR-203 mimic/inhibitor, Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) overexpression plasmid and MAP3K1 small interfering (si)RNA were transfected into TE-1 cells. miR-203 and MAP3K1 mRNA expression were detected via reverse transcription-quantitative PCR analysis, while MAP3K1 protein expression was detected via western blot analysis. Dual-luciferase reporter assay was used to determine whether MAP3K1 was a direct target of miR-203. Cell proliferation and invasion abilities were assessed via MTT and Matrigel assays, respectively. Cell apoptosis was analyzed via flow cytometry, Caspase 8/3 Assay kits and western blot analysis. The results demonstrated that MAP3K1 was a direct target of miR-203. Overexpression of MAP3K1 reversed the suppressed cell proliferation and invasion abilities induced by miR-203 mimic, as well as the inhibitory effect of miR-203 mimic on cell apoptosis. Furthermore, MAP3K1 siRNA weakened the effect of miR-203 inhibitor on cell proliferation, apoptosis and invasion. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been reported to serve pivotal roles in the regulation of papillary thyroid cancer (PTC) development; thus, the aim of this study is to identify the impact of miR-203 and AKT3 on the epithelial–mesenchymal transition (EMT), migration and invasion of PTC. MiR-203 and AKT3 expression in PTC tissues and cells were tested. TPC-1 cells and K1 cells were screened for follow-up experiments. Apoptosis-related proteins (Bcl-2 and Bax), EMT-related proteins (Vimentin and E-cadherin), proliferation-associated proteins (Ki67 and CDK4), invasion- and migration-related protein (MMP-2 and MMP-9) were verified. The effects of upregulated miR-203 and downregulated AKT3 on the biological characteristics of PTC cells in each group were detected via the gain- and loss-of-function assays. The targeting relationship between miR-203 and AKT3 was verified.MiR-203 expression declined and AKT3 heightened in PTC tissues and cells. Upregulated miR-203 and downregulated AKT3 reduced the tumor volume and weight, suppressed cell migration, colony formation, proliferation, invasion, proliferation-associated proteins (Ki67 and CDK4), invasion- and migration-related protein (MMP-2 and MMP-9) and promoted cell apoptosis, raised E-cadherin and decreased Vimentin protein expression in TPC-1 cells. On the contrary, the K1 cells with the downregulated miR-203 or upregulated AKT3 exhibited an opposite result. This study suggests that upregulated miR-203 suppresses EMT, invasion, proliferation and migration as well as induces apoptosis of PTC cells via downregulated AKT3. [ABSTRACT FROM AUTHOR]

We report a nanomechanical genosensor based on an atomic force microscope (AFM) cantilever functionalized with complementary strands of miRNA-203 and miRNA-205, which are potential biomarkers of metastasis in head and neck squamous cell carcinomas (HNSCC), especially in cervical lymph nodes. Hybridization with the corresponding complementary strand led to cantilever deflections that increased almost linearly with the concentration of either miRNA-203 or miRNA-205 in the fluid cell where AFM experiments were made. The detection limit was ca. 95 nM and 97 nM for miRNA-203 or miRNA-205, respectively, with higher deflections observed for miRNA-205 due to the larger number of interaction groups during hybridization. Selectivity was proven by measuring negligible cantilever deflections for non-specific miRNA sequences. The cantilever functionalization process during genosensor design was confirmed by fluorescence microscopy and AFM imaging. The use of a single genosensor platform for detecting different miRNA molecules is advantageous for diagnosis and prognosis of cases where multiple biomarkers may be relevant, as in the case of HNSCC metastasis. [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is the most common type of thyroid carcinoma. PTC has a considerably high five-year survival rate; however, the possibility of recurrence is also high. Therefore, there is a requirement to clarify the molecular mechanism of PTC to promote understanding regarding the development of the disease and further improve prognosis. A number of studies have demonstrated that microRNAs (miRNAs or miRs) contribute to the progression of PTC. The present study revealed that the expression level of miR-203 was significantly lower in PTC tissues and cell lines compared with in the normal controls. In addition, inhibition of miR-203 was identified to be associated with an overexpression of survivin, which was observed in PTC samples. miR-203 regulates the expression of Bcl-2 via its downstream regulator survivin. Furthermore, the present study identified that inhibition of miR-203 histone acetylation was associated with high expression levels of miR-203 in PTC tissue samples. In summary, the results indicate that miR-203 functions as a biomarker and may serve as a candidate target for the development of novel therapeutic strategies to treat PTC. [ABSTRACT FROM AUTHOR]

Background/Aims: Prior studies have shown that bufalin inhibits cellular proliferation and induces apoptosis in various human cancers. MicroRNA-203 (miR-203) has been shown to function as an important regulator of tumor progression at various stages. In this study, we investigated the effect of miR-203 expression and bufalin treatment on glioma cell proliferation and stem cell-like phenotypes. Methods: We used cell viability assay, colony formation assay, cell apoptosis assay and neurosphere formation assay to dectect the treatment effect of bufalin on U251 and U87 cells. Cells were transfected with the miR-203 mimic without bufalin treatment or cells were transfected with anti-miR-203 under bufalin treatment, the above expreiments were repeated. RT-PCR was employed to quantify miR-203 expression. Western blot was performed to detect the stem cell-like (CSC) markers, OCT4 and SOX2. Luciferase activity assay was used to determine whether the SPARC is the target of miR-203. Results: Bufalin treatment inhibited cell proliferation, colony formation, and CSC phenotypes and increased cell apoptosis and expression of miR-203. Furthermore, overexpression of miR-203 led to similar outcomes as bufalin treatment with respect to the cell viability, colony formation, cell apoptosis and the phenotypes of glioma cells. While anti-miR-203 attenuated the inhibitory effects of bufalin as promoting cell proliferation, colony formation and CSC phenotyes and inhibiting cell apoptosis. In addition, we identified SPARC as a novel target gene of miR-203. Conclusions: These findings suggest that miR-203 plays an important role in bufalin’s ability to inhibit the growth of glioma cells and the development of stem cell-like phenotypes.

Background: It has been reported that miR-203 expression was aberrant in various types of cancers, and it could be used as a prognostic biomarker. Therefore, in this study, we aimed to evaluate the prognostic value of miR-203 expression in solid tumors by using meta-analysis and The Cancer Genome Atlas (TCGA) datasets. Methods: By doing a literature research in PubMed, Embase and the Cochrane Library (last update by December 2016), we were able to identify the studies assessing the prognostic role of miR-203 in various tumors. We then used TCGA datasets to validate the results of meta-analysis. Results:33 studies from 26 articles were qualified and enrolled in this meta-analysis. Pooled analyses showed that higher expression of miR-203 in tissues couldn’t predict poor overall survival (OS) and progression-free survival (PFS) in solid tumors. However, the results of subgroup analyses revealed that the upregulation of tissue miR-203 expression was associated with poor OS in colorectal cancer (hazard ratio (HR)=1.81, 95% confidence intervals (CI) 1.31-2.49; P

Background: Septic shock, the most serious complication of sepsis, is a life-threatening disease that is mainly characterized by hypoperfusion and multiple organ failure. Various aberrantly expressed microRNAs (miRNAs) have been reported to be related to septic shock. We explored the regulatory effect of microRNA-203 (miR-203) on lung injury in septic shock mice. Methods: Microarray-based gene expression profiling related to septic shock identified the differentially expressed gene vanin-1 (VNN1) and potential regulatory miR-203. miR-203 was predicted to mediate VNN1 expression, thus affecting septic shock, which was investigated by treatment with miR-203 mimic, miR-203 inhibitor, and siRNA-VNN1 in septic shock mouse models. Polymorphonuclear neutrophils (PMNs) and pulmonary alveolar macrophages in bronchoalveolar lavage fluid (BALF) as well as the wet/dry ratio of the lung were also measured to assess lung injury. Additionally, the effects of miR-203 on inflammatory cytokines, oxidative stress indexes, blood biochemical indexes, serine-threonine protein kinase (AKT) signaling pathway-related factors, and apoptosis-related factors were determined. Results: VNN1 was verified to be targeted and negatively regulated by miR-203. In mouse models of septic shock, weak expression of miR-203, high expression of VNN1, and inhibition of AKT signaling pathway were identified. In response to miR-203 mimic and VNN1 gene silencing, mouse models of septic shock displayed reduced apoptosis, MDA, ALT, and AST in lung tissues, decreased levels of TNF-α, IL-1β, IFN-γ, IL-10, and IL-6, in serum, and reduced PMN and PAM levels in BALF, in addition to elevated SOD activity. Notably, the presence of miR-203 mimic led to AKT signaling pathway activation. Conclusion:This study shows that upregulating miR-203 can alleviate lung injury through activation of the AKT signaling pathway by downregulating VNN1 in septic shock. [ABSTRACT FROM AUTHOR]

Abstract Ischemia reperfusion injury (IRI), a complex phenomenon often encountered in surgery, can lead to local and distant tissue destruction and sometimes even death. microRNA-203 (miR-203) has been reported to negatively regulate ischemia induced microglia activation with a feedback to myeloid differentiation primary-response gene 88 (MYD88). Accordingly, our study is to verify the effect of miR-203 and MYD88 on mice in IRI after total knee arthroplasty (TKA). After establishment of IRI mouse model, heart rate (HR) and mean arterial pressure (MAP) in mice were determined. The functional role of miR-203 in IRI was determined using ectopic expression, knockdown and reporter assay experiments. Levels of interferon γ (IFN-γ), interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were detected, and expression of miR-203, MYD88, toll-like receptor 4 (TLR4), Faslg, Cleaved-Caspase-3, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) was evaluated. Initially, HR and MAP were decreased in IRI mice. Forced expression of miR-203 and silencing of MYD88 increased levels of SOD and IL-10 but decreased levels of MDA, CK, LDH, TNF-α, IL-6 and IFN-γ. Additionally, forced expression of miR-203 and silencing of MYD88 increased Bcl-2 expression but decreased MYD88, TLR4, Cleaved-Caspase-3, Falsg and Bax expression. MYD88, a target gene of miR-203, was decreased following miR-203 promotion, while the TLR signaling pathway inactivation occurred following MYD88 silencing. Generally, our study demonstrated the protective effects of miR-203 on mice with IRI after TKA through inhibiting TLR signaling pathway by negatively regulating MYD88. Highlights • The effect of miR-203 on mice with IRI after TKA by targeting MYD88 is explored. • MYD88 is highly expressed in mice with IRI and regulated negatively by miR-203. • TLR signaling pathway is activated in mice with IRI. • MiR-203 alleviates IRI by suppressing TLR signaling pathway via decrease of MYD88. • The study provides a theoretical basis for the treatment of IRI after TKA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the role of microRNA-203 in laryngeal cancer and its underlying mechanism in regulating cell invasion and apoptosis. PATIENTS AND METHODS: MicroRNA-203 expression in laryngeal cancer tissues and paracancerous tissues was detected by quantitative real time-polymerase chain reaction (qRTPCR). The regulatory effects of microRNA-203 on the invasion and apoptosis of laryngeal cancer cells were detected by transwell assay and flow cytometry, respectively. Dual-Luciferase reporter gene assay was performed to access the binding condition of microRNA-203 and LASP1. Both mRNA and protein levels of LASP1 in laryngeal cancer cells were detected after transfection with microRNA-203 mimic or microRNA-203 inhibitor by qRT-PCR and Western blot, respectively. Rescue experiments were finally performed to detect whether microRNA-203 regulates laryngeal cancer development via targeting LASP1. RESULTS: MicroRNA-203 was lowly expressed in laryngeal cancer tissues and cell lines. MicroRNA-203 knockdown in Hep-2 cells can promote the invasion and inhibit the apoptosis of laryngeal cancer cells. Subsequently, LASP1 was predicted to be the target gene of microRNA-203, which was further verified by the Dual-Luciferase reporter gene assay. LASP1 expression was negatively regulated by microRNA-203. Furthermore, rescue experiments showed that the regulatory effects of microRNA-203 on the invasion and apoptosis of laryngeal cancer cells were reversed by LASP1. CONCLUSIONS: We showed that lowly expressed microRNA-203 could promote the invasion and inhibit apoptosis of laryngeal cancer cells via inhibiting LASP1. [ABSTRACT FROM AUTHOR]

Background Osteoarthritis (OA) is a common degenerative joint disease, which seriously impacts the health of elderly. However, there is no effective treatment for curing this disease until now. Numerous studies reported that long noncoding RNAs (lncRNAs) are closely related to the pathogenesis of OA. Therefore, the study aims to investigate the effect of maternally expressed gene 3 (MEG3) on lipopolysaccharide (LPS)-induced inflammatory injury of ATDC5 cells. Methods Different concentrations (0, 1, 5, and 10 μg/ml) of LPS were used to induce ATDC5 cells injury. The specific expressing vectors were then transfected into ATDC5 cells to alter MEG3, Sirt1 and miR-203 expressions. Flow cytometry, luciferase reporter, qRT-PCR and western blot assays were used to detect cell viability, apoptosis, and the expressions of apoptosis-related proteins and pro-inflammatory factors (IL-1β, IL-6, IL-8 and TNF-α). Meanwhile, ELISA was used for analyzing the concentrations of inflammatory cytokines in culture supernatant. Besides, the key pathways of PI3K/AKT and NF-κB were examined by western blot. Results LPS decreased cell viability, increased cell apoptosis, promoted the release of pro-inflammatory factors, and down-regulated MEG3 expression, Moreover, MEG3 knockdown alleviated LPS-induced inflammatory injury. MEG3 acted as a competing endogenous RNAs (ceRNA) for miR-203, and MEG3 knockdown reduced inflammatory injury by regulating miR-203. Furthermore, miR-203 positively regulated Sirt1 expression, and Sirt1 alleviated LPS-induced inflammatory injury via mediating PI3K/AKT and NF-κB pathways. Conclusion This study showed that MEG3 knockdown alleviated LPS-induced inflammatory injury in ATDC5 cells by regulating miR-203 expression. Hence, the findings may offer a potential treatment perspective of OA. [ABSTRACT FROM AUTHOR]

Pre‑eclampsia (PE) is a common but complex condition that can occur in pregnancy. It is estimated to affect 3‑8% of pregnancies worldwide. PE development is thought to be multifactorial and to involve the dysregulation of microRNA (miR) expression. However, the precise mechanisms of PE development remain unclear. The present study aimed to illustrate the association between miR‑203 expression and PE development in samples of human placenta collected from mothers with (n=18) and without (n=20) PE. It was demonstrated that miR‑203 expression was significantly increased in the PE placenta compared with the normal placenta samples, while the expression of vascular endothelial growth factor A (VEGFA) was decreased. In vitro experiments revealed that miR‑203 overexpression significantly downregulated VEGFA expression and inhibited the proliferation, migration and invasion ability of HTR‑8/SVneo cells. Suppression of miR‑203 expression alleviated these effects. A luciferase reporter assay confirmed the interaction of the 3'‑untranslated region of VEGFA with miR‑203. Thus, miR‑203 may have significant contribution to the development of PE by targeting VEGFA in the human placenta and may have potential as a biomarker or therapeutic target in the treatment of PE. [ABSTRACT FROM AUTHOR]

Primary liver cancer (hepatocellular carcinoma, HCC) is a leading cause of cancer-related deaths, and alternative ways to treat this disease are urgently needed. In recent years, novel approaches to cancer treatment have been based on microRNAs, small non-coding RNA molecules that play a crucial role in cancer progression by regulating gene expression. Overexpression of some microRNAs has shown therapeutic potential, but whether or not this was the case for microRNA-203 (miR-203) in liver cancer was unknown. Therefore, the aim of this study was to investigate the effect of miR-203 overexpression in liver cancer and explore the related mechanisms. Liver cancer cells from the HepG2 and Hep3B cell lines were transfected with either miR-203 mimics or negative control RNA, and then the cells were subjected to cell viability, cell proliferation, and Western blotting assays. As a result of microRNA-203 overexpression, HepG2 and Hep3B cell viability and cell proliferation significantly declined. Furthermore, microRNA-203 overexpression led to inhibited expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3)/protein kinase B (Akt), c-Jun, and p38 mitogen-activated protein kinases (p38 MAPK), and restored glycogen synthase kinase 3 (GSK 3) activity in HepG2 cells. Our results suggest that c-Jun, p38 MAPK, PIK3CA/Akt, and GSK3 signaling involved in the effect of miR-203 on the proliferation of HCC cells. [ABSTRACT FROM AUTHOR]

Background/Aims: Prior studies have shown that bufalin inhibits cellular proliferation and induces apoptosis in various human cancers. MicroRNA-203 (miR-203) has been shown to function as an important regulator of tumor progression at various stages. In this study, we investigated the effect of miR-203 expression and bufalin treatment on glioma cell proliferation and stem cell-like phenotypes. Methods: We used cell viability assay, colony formation assay, cell apoptosis assay and neurosphere formation assay to dectect the treatment effect of bufalin on U251 and U87 cells. Cells were transfected with the miR-203 mimic without bufalin treatment or cells were transfected with anti-miR-203 under bufalin treatment, the above expreiments were repeated. RT-PCR was employed to quantify miR-203 expression. Western blot was performed to detect the stem cell-like (CSC) markers, OCT4 and SOX2. Luciferase activity assay was used to determine whether the SPARC is the target of miR-203. Results: Bufalin treatment inhibited cell proliferation, colony formation, and CSC phenotypes and increased cell apoptosis and expression of miR-203. Furthermore, overexpression of miR- 203 led to similar outcomes as bufalin treatment with respect to the cell viability, colony formation, cell apoptosis and the phenotypes of glioma cells. While anti-miR-203 attenuated the inhibitory effects of bufalin as promoting cell proliferation, colony formation and CSC phenotyes and inhibiting cell apoptosis. In addition, we identified SPARC as a novel target gene of miR-203. Conclusions: These findings suggest that miR-203 plays an important role in bufalin's ability to inhibit the growth of glioma cells and the development of stem cell-like phenotypes. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-17 signaling serves an important role in the development and pathogenesis of psoriasis; a chronic skin disease characterized by increased dermal vascularity and the hyperproliferation of keratinocytes. microRNA (miR)-203 is preferentially expressed in the skin and is an important regulator of keratinocyte differentiation. miR-203 has been implicated in a number of skin diseases, including psoriasis. However, the role of miR-203 in IL-17-induced vascular endothelial growth factor (VEGF) secretion has yet to be elucidated. The present study demonstrated that miR-203 expression was upregulated in the ears of IL-17-stimulated mice and IL-17-treated HaCaT cells. In addition, the IL-17-induced increase in miR-203 expression activated the Janus kinase/signal transducer and activator of transcription signaling pathway and promoted VEGF secretion in HaCaT cells. Furthermore, miR-203 was observed to bind to the 3'-untranslated region of suppressor of cytokine signaling 3 (SOCS3) and inhibited SOCS3 expression. The results suggest that miR-203 expression may be upregulated by IL-17 stimulation, and miR-203 is a positive regulator of IL-17-induced VEGF secretion. The present study may support potential therapeutic strategies for the treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) is a serious disease which threatens public health. Exosomes (exos) contain certain genetic information and are important communication vehicles between cells. In the present study, different exosomal microRNAs (miRs), which exhibit a notable association between expression levels in plasma and AMI were assessed to support the development of new diagnostic and clinical assessment markers of patients with AMI. In total, 93 individuals, including 31 healthy controls and 62 patients with AMI, were recruited for the present study. Data on age, blood pressure, glucose levels, lipid levels and coronary angiography images were collected from the enrolled individuals, and plasma samples were collected. Plasma exos were extracted and verified using ultracentrifugation, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). Exo-miR-4516 and exo-miR-203 in plasma exos were identified by exosomal miRNA sequencing analysis, reverse transcription-quantitative PCR was performed to detect the levels of exo-miR-4516 and exo-miR-203 in plasma exos, and ELISA was performed to detect the levels of secretory frizzled-related protein 1 (SFRP1) in samples. The correlation analysis between exo-miR-4516, exo-miR-203 and SFRP1 in plasma exos and AMI was presented as receiver operating characteristic curves (ROCs) of the SYNTAX score, cardiac troponin I (cTnI), low-density lipoprotein (LDL) and each indicator separately. Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed to predict relevant enrichment pathways. Exos were successfully isolated from plasma by ultracentrifugation, which was confirmed by TEM, NTA and WB. Exo-miR-4516, exo-miR-203 and SFRP1 levels in plasma were significantly higher in the AMI group compared with the healthy control group. ROCs demonstrated that exo-miR-4516, exo-miR-203 and SFRP1 levels had a high diagnostic efficiency in predicting AMI. Exo-miR-4516 was positively correlated with SYNTAX score, and plasma SFRP1 was positively correlated with plasma cTnI and LDL. In conclusion, the data demonstrated that exo-miR-4516, exo-miR-203 and SFRP1 levels could be used in combination to diagnose and assess the severity of AMI. The present study was retrospectively registered (TRN, NCT02123004). [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that microRNA-203 (miR-203) is abnormally expressed in many human tumor tissues and significantly associated with the occurrence, development and clinical outcomes of human tumors. The aim of this study was to determine the target genes and functional significance of miR-203 in osteosarcoma cells. We found reduced expression of miR-203 in osteosarcoma tissues and cells (MG63 and U2-OS) compared with the adjacent normal tissues and normal osteoblastic cells (hFOB1.19), respectively. In vitro studies further demonstrated that exogenous miR-203 overexpression inhibited osteosarcoma cell proliferation and invasion, and promoted apoptosis. At the molecular level, our results confirmed that apoptosis, cell cycle and invasion-related proteins were regulated by miR-203. Our findings also revealed that Runt-related transcription factor 2 (RUNX2) was directly negatively regulated by miR-203. These results suggested that miR-203 may function as a tumor suppressor and may therefore have therapeutic potential in the treatment of human osteosarcoma. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer (GC). Expression of microRNA-203 (miR-203) has been reported to decrease in GC. In addition, overexpression of miR-203 inhibits grow of GC cells in vitro and in vivo. However, whether miR-203 affects cell migration and invasion of GC remains unclear. This study aimed to reveal the role of miR-203 on migration and invasion of GC, and its potential mechanisms. METHODS: Synthetic pre-miR-203 (miR-203), anti-miR-203 and scrambled negative control RNAs was transfected into the gastric cancer SGC7901 cells to generate miR-203 or anti-miR-203-transfected stable clones. The roles of miR-203 on cell invasion and motility were then analyzed by Transwell migration assay and Wound healing assay in vitro. Using siRNA to targeting ERK1/2, Slug, and E-cadherin or Slug cDNA transfection (to increase Slug expression) to examine the miR-203 signaling pathway. We also examined the efficacies of miR-203 or anti-miR-203 on peritoneal metastasis of SGC7901 cells in the nude mouse model. RESULTS: Overexpression of miR-203 inhibits SGC7901 cell invasion and motility, followed by decreased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as increased E-cadherin expression. Re-expression of Slug in miR-203/SGC7901cells decreased E-cadherin expression and restored the invasive phenotypes. Targeting E-cadherin in miR-203/SGC7901cells also restored the invasive phenotypes. Inhibition of miR-203 promotes SGC7901 cell invasion and motility, followed by increased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as decreased E-cadherin expression. Targeting ERK1/2 or Slug in antimiR-203/SGC7901cells increased E-cadherin expression and reversed the invasive phenotypes. In addition, targeting ERK1/2 decreased Slug and increased the E-cadherin expression. Significantly, we found that miR-203 could exert marked inhibition of the peritoneal metastasis of SGC7901 in nude mice in vivo. Targeting miR-203 could exert marked promotion of the peritoneal metastasis of SGC7901 in nude mice in vivo. CONCLUSIONS: miR-203/ERK1/2/Slug/E-cadherin signaling pathway plays an essential role on SGC7901 cell invasion and motility. miR-203 can be novel modalities to prevent peritoneal metastasis of invasive cancers such as gastric cancer. [ABSTRACT FROM AUTHOR]

Background: It has been reported that miR-203 expression was aberrant in various types of cancers, and it could be used as a prognostic biomarker. Therefore, in this study, we aimed to evaluate the prognostic value of miR-203 expression in solid tumors by using meta-analysis and The Cancer Genome Atlas (TCGA) datasets. Methods: By doing a literature research in PubMed, Embase and the Cochrane Library (last update by December 2016), we were able to identify the studies assessing the prognostic role of miR-203 in various tumors. We then used TCGA datasets to validate the results of meta-analysis. Results:33 studies from 26 articles were qualified and enrolled in this meta-analysis. Pooled analyses showed that higher expression of miR-203 in tissues couldn't predict poor overall survival (OS) and progression-free survival (PFS) in solid tumors. However, the results of subgroup analyses revealed that the upregulation of tissue miR-203 expression was associated with poor OS in colorectal cancer (hazard ratio (HR)=1.81, 95% confidence intervals (CI) 1.31-2.49; P<0.001), pancreatic cancer (HR=1.19, 95% CI 1.09-1.31; P<0.001) and ovarian cancer (HR=1.85, 95% CI 1.45-2.37; P<0.001); but it had opposite association in liver cancer (HR=0.52, 95% CI 0.28-0.97; P=0.040) and esophageal cancer (HR=0.41, 95% CI 0.25-0.66; P<0.001). Based on TCGA datasets, we found the same results for pancreatic cancer and esophageal cancer, but not for colorectal cancer and liver cancer. Moreover, patients with high circulating miR-203 in blood had significantly poor OS and PFS in colorectal cancer and breast cancer. Conclusion: Our study showed that the prognostic values of tissue miR-203 varied in different tumor types. In addition, the upregulation of circulating miR-203 in blood was associated with poor prognosis in colorectal cancer and breast cancer. [ABSTRACT FROM AUTHOR]

RAS protein activator like 2 (RASAL2) has been reported to be dysregulated in various types of cancer. It has previously been demonstrated that RASAL2 is hypomethylated in hepatocellular carcinoma (HCC). However, the expression pattern of RASAL2 and its potential role in HCC remain to be elucidated. The present study demonstrated that the expression of RASAL2 was upregulated in HCC tissues, compared with in normal liver tissues, by using immunohistochemistry. In addition, Cell Counting Kit-8 assay and invasion assay revealed that knockdown of RASAL2 inhibited the growth and invasion of HCC cells. Western blotting results indicated that the inhibition of RASAL2 reduced the levels of phosphorylated-AKT. Notably, RASAL2 was observed to be a direct target of miR-203 in HCC in luciferase activity assays. Furthermore, overexpression of miR-203 exhibited a similar effect to RASAL2 knockdown in HCC cells. These results indicated that RASAL2 serves a tumor oncogenic role in HCC and may be considered a potential target in HCC. [ABSTRACT FROM AUTHOR]

Background Liver resection or partial hepatectomy (PH) is still the most commonly used therapeutic option for hepatocellular carcinoma (HCC) at present. However, the impaired regenerative ability induced by the accompanied liver cirrhosis is an important risk factor of posthepatectomy liver failure, and posthepatectomy liver failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. MicroRNA(miR)-203 is a tumor suppressor of HCC and may act as a positive intermediary in A20-enhanced interleukin (IL-6)/signal transducer and activator of transcription 3 (STAT3) pro-proliferative signals, which may promote liver regeneration after PH. However, its direct pro-proliferative effect on cirrhotic liver after hepatectomy is unknown. Materials and methods Liver cirrhosis was induced by intraperitoneal injection of 50% CCl4–olive oil solution in adult male Wistar rat. Rats with liver cirrhosis received portal vein injection of physiological saline, miR-203 lentivirus, or control empty lentivirus, and then 70% PH was performed under ether anesthesia 7 d later. Liver samples were harvested at 0, 24, 36, and 72 h after 70% PH. Hepatic expressions of cyclin D1 and Ki67 were checked to evaluate the liver regenerative ability. Hepatic expressions of IL-6, suppressor of cytokine signaling 3 (SOCS3), and phospho-STAT3 were also tested to clarify the mechanisms of miR-203 in liver regeneration. Results The regeneration of miR-203 overexpression cirrhotic liver after 70% PH was enhanced and peaked at 24 and 36 h after 70% PH. The cyclin D1–positive liver cells/high-power field (HPF) in miR-203 overexpression liver markedly increased at 24 and 36 h after 70% PH compared with 0-h samples. When comparing with the control groups, cyclin D1–positive liver cells/HPF in miR-203 overexpression liver were also significantly increased at 24 and 36 h after 70% PH. A similar result of the Ki67-positive liver cells/HPF was achieved at 36 h after 70% PH. The hepatic expression of IL-6 showed a rising tendency after 70% PH, and the levels of IL-6 are significantly higher in miR-203 overexpression livers. Hepatic expression of SOCS3 was negatively expressed with hepatic miR-203 expression level, and the reduced expression of SOCS3 facilitated the phosphorylation of STAT3. Conclusions By targeting SOCS3 and then enhancing proliferating IL-6/STAT3 signaling pathway, hepatic overexpression of miR-203 can facilitate the initiation of liver regeneration and enhance the potency of liver regeneration after 70% PH in cirrhotic rat. Together with the tumor suppressive effect on HCC, miR-203 would be an ideal candidate for promoting liver regeneration in HCC patients undergoing liver resection without the risk of tumorigenesis or cancer recurrence. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a common gastrointestinal malignancy in our country. It is accepted that the etiology of colorectal cancer is a multi-factor and multi-step process. However, the mechanism of CRC is still unclear. Micro-RNAs (miRNA) are short noncoding RNAs and function as a negative regulator of gene expression at post-transcriptional level, participating in tumor cell proliferation, invasion, migration and even drug resistance. It is accepted that mir-203 acts as a tumor suppressor. However, its expression in colon cancer is still a controversy. The implication of Mir-203 in various cellular biological activities including tumorigenesis, progression, diagnose, prognosis, chemoresistance will be summarized in this article With the purpose of better understanding of the role of microRNA-203 in gene network of colorectal cancer may help exploit the whole potential of mir-203 in coloretal cancer. [ABSTRACT FROM AUTHOR]

Objective: Squamous cell carcinoma (SCC) occurring in the tonsils (TSCC) has a poorer prognosis than SCC occurring in other regions of the oral cavity (non-tonsillar SCC [NTSCC]) because it easily metastasizes to distant organs. This study aimed to elucidate the molecular mechanisms underlying the migration and invasion of TSCC cells in vitro ., Materials and Methods: This study focused on differential microRNA (miRNA) expression using microRNA microarrays and quantitative polymerase chain reaction in canine TSCC and NTSCC tissues and cell lines. A target gene of the miRNA involved in cell migration and invasion was validated by wound healing, transwell, and luciferase assays., Results: miR-203 expression was lower in TSCC tissues than in the normal oral mucosa and NTSCC tissues. Transfection of the miR-203 mimic resulted in the downregulation of mesenchymal marker protein expression and attenuation of cell migration and invasion in TSCC cells, but not in NTSCC cells. A dual-luciferase assay revealed that miR-203 directly targeted the mesenchymal transcription factor SLUG . SLUG overexpression enhances the migration of TSCC cells., Conclusion: Our study indicates that the miR-203/SLUG axis may be involved in the metastatic mechanisms of TSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Noguchi and Matsui.)

MicroRNA ( miR)-203 is downregulated and acts as an anti-oncomir in melanoma cells. Here, using human and canine melanoma cells, we elucidated the effects of miR-203 on cyclic adenosine monophosphate response element binding protein ( CREB)/microphthalmia-associated transcription factor ( MITF)/ RAB27a pathway, which is known to be important for the development and progression of human melanoma. In this study, we showed that miR-203 directly targeted CREB1 and regulated its downstream targets, MITF and RAB27a. miR-203 significantly suppressed the growth of human and canine melanoma cells and inhibited melanosome transport through the suppression of the signalling pathway. In conclusion, miR-203 was shown to be a common tumour-suppressive miRNA in human and canine melanoma and thus to play a crucial role in the biological mechanisms of melanoma development. [ABSTRACT FROM AUTHOR]

microRNA-203 (miR203) plays an important role in the formation and development of multiple types of cancers. However, its role in hepatic carcinogenesis has not been well studied. Mitogen-activated protein kinase signaling is known to be activated in hepatocellular carcinoma (HCC), but there is a lack of effective drugs targeting this pathway for HCC treatment. In this study, we investigated the role of miR203 in HCC and the underlying mechanism. We found that miR203 was significantly downregulated in HCC cell lines and patient tissues compared with a hepatocyte cell line (L02) or normal liver tissues. Restoration of miR203 inhibited HCC cell growth and induced cell cycle arrest and apoptosis. In primary and xenograft HCC mouse models, miR203 also significantly blocked HCC growth. Bioinformatic analysis indicated that miR203 directly binds to the 3'UTR of NRas mRNA, resulting in decreased expression of NRas and inactivation of mitogen-activated protein kinase (MAPK) signaling. Activation of MAPK signaling by ectopic NRas expression rescued the cell proliferation blocked by miR203. Together, our findings illustrate the fundamental role of miR203 as a natural inhibitor of RAS/MAPK signaling in hepatic carcinogenesis in vitro and in vivo . In light of the critical and universal activation of the MAPK pathway in HCC, miR203 has the potential to serve as a nucleotide drug for the treatment of HCC with activated MAPK signaling., Competing Interests: None., (AJCR Copyright © 2023.)

The oncogene B-cell-specific Moloney murine leukemia virus insertion site-1 (Bmi-1) is overexpressed in multiple myeloma (MM). Our previous study demonstrated that Bmi-1 silencing sensitized MM cells to bortezomib. Translational regulation has emerged as a prominent underlying mechanism of Bmi-1 regulation, particularly via microRNA targeting. The present study determined that Bmi-1 may be directly targeted by miR-203 using a luciferase assay. In addition, enforced expression of miR-203 led to significant downregulation of Bmi-1 protein and mRNA expression levels. Furthermore, restoration of miR-203 significantly inhibited cell growth and G1/S transition in MM cells. miR-203 was downregulated in MM patients, and a negative correlation between the expression of miR-203 and Bmi-1 was observed. The results of the present study indicated that miR-203 exerts growth-inhibiting effects in MM through the suppression of Bmi-1 expression. In conclusion, the present study demonstrated that Bmi-1 is a direct functional target of miR-203 in MM. [ABSTRACT FROM AUTHOR]

Growing evidence from recent studies has revealed that microRNA-203 (miR-203) might be an attractive prognostic biomarker for cancer. But controversy still remains. The aim of this meta-analysis was to summarize available evidences and clarify the preliminary predictive value of miR-203 for prognosis in cancer patients. Eligible studies were identified through multiple research strategies in PubMed, EMBASE and Web of Science up to October 2015. Key statistics such as pooled hazard ratios (HR) with 95 % confidence intervals (CIs) were utilized to calculate patient survival. 13 eligible studies with 1600 patients were ultimately enrolled in this meta-analysis. Our results failed to show a significant relation between upregulated miR-203 expression and a favorable overall survival (OS) (HR 1.00, 95 % CI 0.65-1.36) in a random effect model. However, in subgroup analysis, we found that high expression of miR-203 was significantly associated with poor OS in Caucasian patients (HR 1.31, 95 % CI 1.06-1.55). In contrast, for Asian patients, over-expression of miR-203 was an independent prognostic factor for better and OS (HR 0.59, 95 % CI 0.22-0.96). It also suggested that cancer types and miRNA assay method were significant associated with prognosis. The over-expression of miR-203 was effectively predictive of worse prognosis in breast cancer (HR 6.35, 95 % CI 1.34-11.36), pancreatic cancer (HR 1.19, 95 % CI 1.08-1.30), ependymoma (HR 1.35, 95 % CI 1.10-1.61), but for glioma patients, elevated miR-203 is a potential biomarker for predicting better progression of cancer (HR 0.26, 95 % CI −0.02 to 0.54). Besides, for direct miRNA profiling studies, over-expression of miR-203 was an independent prognostic factor for worse OS (HR 6.35, 95 % CI 1.34-11.36). This meta-analysis indicated that ethnicity, tumor type and miRNA assay method mainly contributed to heterogeneity. Considering the insufficient evidence, further relevant studies are warranted. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3′ untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR-203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti-chemoresistance drugs. [ABSTRACT FROM AUTHOR]

Chemotherapeutic resistance is the main reason of the failure in clinical treatment of gastric cancer. Berberine (BER) is the active compound of traditional Chinese medicine Huang Lian. The aim of this present study is to evaluate the effect of BER on cisplatin resistance in gastric cancer cells and to investigate its possible mechanism. Gastric cancer cell lines SGC-7901 and BGC-823 and their respective cisplatin-resistant variants SGC-7901/DDP and BGC-823/DDP were used in this study. We found that BER treatment significantly reversed cisplatin sensitivity and induced caspase-dependent apoptosis in SGC-7901/DDP and BGC-823/DDP cells; BER treatment induced miR-203 expression, and overexpression of miR-203 mimicked the cisplatin-sensitizing effect of BER. Importantly, we showed that miR-203 was able to target the 3′UTR of Bcl-w. Therefore, we conclude that BER treatment reduces cisplatin resistance of gastric cancer cells by modulating the miR-203/Bcl-w apoptotic axis. BER may be a novel agent to enhance chemotherapeutic responses in cisplatin-resistant gastric cancer patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the correlation between a lack of folic acid and the abnormal expression of microRNA (miR)-203 and miR-375 in cervical cancer. In total, 60 tissue samples of cervical intraepithelial neoplasia (CIN) or stage IA-IIA cervical cancer (study group), and 30 samples without soluble interleukin or malignancy (control group) were examined. The expression of miR-203 and miR-375 was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the difference in expression levels was quantified using the 2-Cq method. In addition, CaSki cervical cancer cells were cultured in vitro and treated with various concentrations of folic acid. The DNA methylation states of miR-203 and miR-375 were subsequently detected by methylation-specific PCR, and the expression levels were evaluated using RT-PCR. miR-203 and miR-375 were significantly downregulated in CIN and cervical cancer tissues, compared with the control group. There was a marked difference in terms of the expression levels of miR-375 between the two groups (P<0.05). In CaSki cells, as the concentration of folic acid increased, the positive rate of DNA methylation of miR-203 and miR-375 decreased, while the expression levels of miR-203 and miR-375 demonstrated a gradual increase, which indicated that the latter two parameters were negatively correlated (P<0.05). Compared with normal cervical tissue, the expression levels of miR-203 and miR-375 were downregulated in CIN and cervical cancer. Methylation of these two miRs was apparent in CaSki cells, and was associated with a lack of folic acid. Therefore, reduced levels of folic acid, leading to increased methylation of miR-203 and miR-375, may be significant events during cervical carcinogenesis. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection targets host restriction factors that inhibit its replication and survival. Previous studies have shown that barriers to autointegration factor1 (BANF1) inhibited the replication of herpes simplex virus and vaccinia virus by binding to phosphate backbone of dsDNA. To date, no reports are available for the interplay between BANF1 and HBV. In this study, we elucidated the mechanisms by which HBV inhibit BANF1. First, the effect of HBV on BANF1 was observed in Huh-7, Hep G2, and Hep G2.2.15 cells. Huh-7 cells were transfected with pHBV 1.3 or HBx plasmids. The results showed that there was a decreased expression of BANF1 in Hep G2.2.15 cells ( P  ≤ 0.005) or in HBV/HBx expressing Huh-7 cells ( P  ≤ 0.005), whereas BANF1 overexpression decreased viral replication ( P  ≤ 0.05). To study whether phosphorylation/dephosphorylation of BANF1 was responsible for antiviral activity, mutants were created, and it was found that inhibition due to mutants was less significant compared to BANF1 wild type. Previous studies have shown that HBV, at least in part, could regulate the expression of host miRNAs via HBx. It was found that miR-203 expression was high in Hep G2.2.15 cells ( P  ≤ 0.005) compared to Hep G2 cells. Next, the effect of HBx on miR-203 expression was studied and result showed that HBx upregulated miR-203 expression ( P  ≤ 0.005). Overexpression of miR-203 downregulated BANF1 expression ( P  ≤ 0.05) and viral titer was upregulated ( P  ≤ 0.05), while inhibition of miR-203, reversed these changes. In conclusion, BANF1 downregulated HBV, whereas HBV inhibited BANF1, at least in part, via HBx-mediated miR-203 upregulation in hepatic cells. IMPORTANCE In this study, for the first time, we found that BANF1 inhibited HBV replication and restricted the viral load. However, as previously reported for other viruses, the results in this study showed that BAF1 phosphorylation/dephosphorylation is not involved in its antiviral activity against HBV. HBV infection inhibited the intracellular expression of BANF1, via HBx-mediated upregulation of miR-203 expression. Overexpression of miR-203 downregulated BANF1 and increased the viral titer, while inhibition of miR-203 reversed these changes. This study helped us to understand the molecular mechanisms by which HBV survives and replicates in the host cells.

Neuroblastoma (NB) is the most common solid extracranial tumor in children. However, the molecular mechanism of NB remains to be elucidated. In the present study, reverse transcription quantitative polymerase chain reaction data demonstrated that the expression of Sam68 was significantly upregulated in NB tissues compared with their matched adjacent normal tissues. Furthermore, it was revealed that reduced expression of miR-203 and increased expression of Sam68 co-existed in NB tissues. Knockdown of Sam68 reduced the proliferation, migration and invasion of human SK-N-SH and SH-SY5Y NB cells. Similarly, overexpression of miR-203 also inhibited the proliferation, migration and invasion of these two cell lines. It was further demonstrated that the protein expression level of Sam68 was negatively mediated by miR-203 in the SK-N-SH and SH-SY5Y NB cells. Additionally, data from a dual luciferase reporter assay confirmed that miR-203 directly targeted Sam68 by binding to its 3'-untranslated region. In conclusion, the present study suggested for the first time, to the best of our knowledge, that the aberrant downregulation of miR-203 may contribute to the aberrant upregulation of Sam68 in NB and that miR-203 has an inhibitory role in malignant progression of NB by targeting Sam68. The present study provided evidence to support miR-203/Sam68 as a novel diagnostic or therapeutic targets for NB. [ABSTRACT FROM AUTHOR]