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BACKGROUND: Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. METHODS: A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. RESULTS: DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). CONCLUSIONS: Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

Asunto(s)

Colitis Ulcerosa , Ferroptosis , Ginsenósidos , MicroARNs , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Ginsenósidos/farmacología , MicroARNs/genética , Ratones , Ferroptosis/efectos de los fármacos , Humanos , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Regulación hacia Arriba/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Sulfato de Dextran/toxicidad , Apoptosis/efectos de los fármacos

RESUMEN

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunohistochemical data shown in Fig. 1A on p. 5, colony formation data shown in Figs. 2C, H and M and 6D on p. 6 and p. 10 respectively, the western blots in Fig. 2B, Transwell cell migration and invasion assay data in Fig. 3B, D and F, and immunofluorescence data in Fig. 4C had already appeared in previously published articles written by different authors at different research institutes (some of which have subsequently been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 45: 72, 2021; DOI: 10.3892/or.2021.8023].

RESUMEN

PURPOSE: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatment allows decent survival rates but often with life-long morbidity. Molecular classification provides a base for novel therapeutic approaches. However, these groups are heterogeneous. MicroRNA-125a has a tumor suppressor function. It is downregulated in several tumors. The expression of microRNA-125a in MB patients remains unclear. Therefore, this study was designed to evaluate the expression of microRNA-125a in molecular groups of pediatric MB patients in Egyptian population and its clinical significance. METHODS: Formalin-fixed, paraffin-embedded tissue blocks from 50 pediatric MB patients were retrospectively collected. Immunohistochemistry for ß-catenin, GAB1, YAP1, and p53 was done for molecular classification. MicroRNA-125a expression analysis was done using qRT-PCR. Follow-up data were obtained from patients' records. RESULTS: MicroRNA-125a expression was significantly lower in MB patients showing large cell/anaplastic (LC/A) histology and in the non-WNT/non-SHH group. Lower levels of microRNA-125a showed a tendency toward poor survival rates; however, difference was not significant. Infants and larger preoperative tumor size were significantly associated with lower survival rates. On a multivariate analysis, preoperative tumor size was an independent prognostic factor. CONCLUSION: MicroRNA-125a expression was significantly lower in categories of pediatric MB patients with worse prognosis namely LC/A histology and the non-WNT/non-SHH group suggesting a pathogenetic role. MicroRNA-125a expression could represent a promising prognostic factor and a potential therapeutic target in the non-WNT/non-SHH group which represents the most common and the most heterogeneous group of pediatric MBs coupled with the highest rates of disseminated disease. Preoperative tumor size represents an independent prognostic factor.

Asunto(s)

Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , MicroARNs , Lactante , Humanos , Niño , Pronóstico , Meduloblastoma/patología , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , MicroARNs/genética

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Osteoblasts are important regulators of bone formation, but their roles in ankylosing spondylitis (AS) remain unclear. This study aims to explore the role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) MEG3 in AS. Serum from AS patients as well as AS mesenchymal stem cells (ASMSCs) and healthy donors mesenchymal stem cells (HDMSCs) was collected. Accordingly, poorly expressed MEG3 and TNF alpha induced protein 3 (TNFAIP3) as well as overexpressed microRNA-125a-5p (miR-125a-5p) were noted in the serum of AS patients and in ASMSCs during the osteogenic induction process. Meanwhile, the interaction among MEG3, miR-125a-5p, and TNFAIP3 was determined and their effect on osteoblast activity was examined in vitro and in vivo. Overexpression of MEG3 and TNFAIP3 or inhibition of miR-125a-5p was found to inactivate the Wnt/ß-catenin pathway, thus suppressing osteogenic differentiation of MSCs. MEG3 competitively bound to miR-125a-5p to increase TNFAIP3 expression, thereby inactivating the Wnt/ß-catenin pathway and repressing the osteogenic differentiation of MSCs. In proteoglycan (PG)-induced AS mouse models, MEG3 also reduced osteogenic activity of MSCs to inhibit AS progression through the miR-125a-5p/TNFAIP3/Wnt/ß-catenin axis. Therefore, up-regulation of MEG3 or depletion of miR-125a-5p holds potential of alleviating AS, which sheds light on a new therapeutic strategy for AS treatment.

Asunto(s)

Células Madre Mesenquimatosas , MicroARNs , Espondilitis Anquilosante , Animales , Ratones , Apoptosis , beta Catenina/metabolismo , Diferenciación Celular/genética , MicroARNs/metabolismo , Osteogénesis/genética , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/farmacología , Vía de Señalización Wnt/genética

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder impacting multiple organs, influenced by genetic factors, especially those related to the immune system. However, there is a need for new biomarkers in SLE. MicroRNA-125a (miR-125a) levels are decreased in T cells, B cells, and dendritic cells of SLE patients. MiR-125a plays a regulatory role in controlling the levels of tumor necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12), which are crucial pro-inflammatory cytokines in SLE pathogenesis. AIM: To assess the levels of miR-125a, IL-12, and TNF-α in SLE patients' plasma, evaluating their diagnostic and prognostic value. METHODS: The study included 100 healthy individuals, 50 newly diagnosed (ND), and 50 SLE patients undergoing treatment. The patients were monitored for a duration of 24 wk to observe and record instances of relapses. MiR-125a expression was measured using real-time reverse transcription polymerase chain reaction, while ELISA kits were used to assess IL-12 and TNF-α production. RESULTS: The results showed significantly reduced miR-125a expression in SLE patients compared to healthy individuals, with the lowest levels in ND patients. TNF-α and IL-12 expression levels were significantly elevated in SLE patients, especially in the early stages of the disease. Receiver operating characteristic curve analyses, and Cox-Mantel Log-rank tests indicated miR-125a, TNF-α, and IL-12 as proper diagnostic biomarkers for SLE. A negative correlation was found between plasma miR-125a expression and IL-12/TNF-α levels in SLE patients. CONCLUSION: Decreased miR-125a levels may be involved in the development of SLE, while elevated levels of IL-12 and TNF-α contribute to immune dysregulation. These findings offer new diagnostic and prognostic markers for SLE. Moreover, the negative correlation observed suggests an interaction between miR-125a, TNF-α, and IL-12. Further research is necessary to uncover the underlying mechanisms that govern these relationships.

RESUMEN

Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their downstream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly­pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a­5p (miR­125a­5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti­apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter­driven, miR­125a­5p expressing, poly­L­lysine­conjugated magnetite iron poly­pharmacologic nanodrug (pL­MNP­pSur­125a) was reported. The cancer cells self­activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1­expressing/­non­expressing cancer cells in vitro and in vivo. It was demonstrated that pL­MNP­pSur­125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL­MNP­pSur­125a also downregulated the expression of TDO2 in the human KB cervical carcinoma cells. PL­MNP­pSur­125a decreased the viability of various BIRC5­expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5­non­expressing HMEC­1 endothelial cells. In vivo, pL­MNP­pSur­125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human­ABCB1­expressing and ABCB1­non­expressing tumor xenograft models. In conclusion, pL­MNP­pSur­125a is an easy­to­prepare and a promising poly­pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1­related drug resistance after prolonged chemotherapeutic treatments.

Asunto(s)

Antineoplásicos , MicroARNs , Nanopartículas , Neoplasias , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Células Endoteliales , Humanos , MicroARNs/genética , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pez Cebra/genética

RESUMEN

Lower extremity deep vein thrombosis (LEDVT) is a disorder of venous return caused by abnormal blood clotting. LEDVT can obstruct the lumen and is the third most common vascular disease after cerebrovascular disease and coronary artery disease. LncRNAs are associated with thrombosis and potentially affect the pathogenesis of DVT. However, no studies have reported the effect of LINC01123 on LEDVT. The aim of this study was to investigate the effect of LINC01123 on LEDVT in rats via the miR-125a-3p/interleukin 1 receptor type 1 (IL1R1) axis. Lentiviral vectors that altering LINC01123, miR-125a-3p and IL1R1 expression were pre-injected into the tail vein of rats, and an LEDVT model was established 1 day later. Detection of LINC01123, miR-125a-3p and IL1R1 expression was performed. Inflammatory factors in femoral venous blood, the length and weight of the thrombus, the histomorphological changes were determined in the rat model. The targeting relation of miR-125a-3p with LINC01123 or IL1R1 was verified. The results presented that LEDVT rats expressed high LINC01123 and IL1R1 and low miR-125a-3p expression levels. After silencing LINC01123 or elevating miR-125a-3p, the rate of thrombosis, length and weight of thrombus, and levels of inflammatory factors were reduced. The targeting relation was presented between miR-125a-3p with LINC01123 or IL1R1. Elevating IL1R1 was available to turn around the action of silence of LINC01123 on LEDVT rats. All in all, suppression of LINC01123 restrains LEDVT via miR-125a-3p to target IL1R1.

Asunto(s)

MicroARNs , ARN Largo no Codificante , Trombosis de la Vena , Animales , Modelos Animales de Enfermedad , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/patología , MicroARNs/metabolismo , ARN Largo no Codificante/genética , Ratas , Trombosis de la Vena/genética

RESUMEN

BACKGROUND: microRNA-125a-5p (miR-125a) is a tumor suppressor gene whose role in autophagy remains poorly understood. In the current study, we aimed to investigate the methylation status of miR-125a, its transfection into SK-BR3 cells, and its effects on autophagy. METHODS: Sixty samples of tumor and non-tumor adjacent tissue were collected and the methylation status of miR-125a was evaluated by methylation-specific PCR (MSP). The effect of 5-Aza-dC on miR-125a expression was investigated in the SK-BR3 cells. Cells were also transfected with miR-125a mimic/antimiR. The expression of miR-125a and its target genes was evaluated by Real-Time PCR. Protein levels of ATG5 and LC3 were assessed by Western blotting. HER2 expression was investigated by immunocytochemistry (ICC). RESULTS: The data showed that the miR-125a promoter CpG Island was significantly hypermethylated in breast cancer tissues (p < 0.01) and in SK-BR3 cells. The 5-Aza-dC could significantly increase miR-125a expression by decreasing its methylation (p < 0.05). In addition, Western blot analysis indicated the expression of ATG5 and LC3 II/ LC3I, as autophagy biomarkers, was significantly reduced in SK-BR3 cells transfected with miR-125a (p < 0.05). CONCLUSIONS: Our data showed miR-125a expression was significantly decreased in tumor tissues due to its promoter hypermethylation. Overexpression of miR-125a was associated with a reduction in autophagy, which could provide a new therapeutic avenue for advanced-stage breast cancer treatment.

Asunto(s)

Neoplasias de la Mama , MicroARNs , Autofagia/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo

RESUMEN

Multiple myeloma (MM) is a hematological malignancy with a high prevalence and is characterized by the clonal expansion of malignant plasma cells. As a new tumor suppressor, defective in sister chromatid joining (DIS3) was reported to be a gene closely related to MM. This study elucidated the biological functions and underlying mechanisms of DIS3 in MM. DIS3 mRNA and protein levels were detected using RT-qPCR and western blotting, respectively. Methyl thiazolyl tetrazolium assays, flow cytometry analyses, Transwell assays, and wound healing assays were performed to detect the proliferation, apoptosis, invasion, and migration of MM cells. The binding relationship between miR-125a/b-5p and DIS3 was verified using luciferase reporter assays and RNA pulldown assays. Xenograft tumor models were established in nude mice to investigate the effects of miR-125a/b-5p and DIS3 on tumor growth in vivo. DIS3 levels were downregulated in MM cells, and DIS3 upregulation inhibited the malignant behaviors of MM cells. Mechanistically, miR-125a/b-5p directly targeted the 3' untranslated region of DIS3. The expression of miR-125a/b-5p was upregulated in MM cells, miR-125a/b-5p knockdown inhibited the malignant behaviors of MM cells, and the inhibitory effect was reversed by DIS3 downregulation. The results of in vivo experiments indicated that miR-125a/b-5p promoted tumor growth by downregulating DIS3. Overall, miR-125a/b-5p promotes MM cellular processes and xenograft tumor growth by targeting DIS3.

Asunto(s)

MicroARNs , Mieloma Múltiple , Regiones no Traducidas 3'/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , Mieloma Múltiple/genética

RESUMEN

Cervical squamous cell carcinoma (CSCC), the most common cervical malignancy, is more likely to invade and metastasize than other cervical cancers. miR-125a, a tumor suppressor gene, has been confirmed to be associated with cancer metastasis. However, the role of miR-125a in CSCC and the underlying mechanism are unknown. miR-125a expression was confirmed by real-time quantitative PCR (RT-qPCR), and the Rad51 expression level was measured by western blotting analysis. CSCC cell proliferation, migration and invasion were assessed with functional assays, including CCK-8, colony formation, wound healing and Transwell assays. Our data confirmed that miR-125a is expressed at low levels in CSCC tissues and cells. Functionally, the overexpression of miR-125a greatly prevented the proliferation, migration and invasion of CSCC cells, and the inhibition of miR-125a expression strongly enhanced these behaviors in CSCC cells. Moreover, the expression of Rad51, a miR-125a target gene, greatly reversed the miR-125-mediated inhibition of CSCC cell proliferation, migration and invasion. In addition, we discovered that miR-125a downregulated the levels of phosphorylated PI3K, AKT and mTOR through Rad51 in CSCC cells. miR-125a, a tumor suppressor, can attenuate the malignant behaviors of CSCC cells by targeting Rad51. Therefore, the miR-125a/Rad51 axis might be a target for CSCC therapy.

Asunto(s)

Carcinoma de Células Escamosas , MicroARNs , Recombinasa Rad51 , Neoplasias del Cuello Uterino , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Humanos , MicroARNs/genética , Recombinasa Rad51/genética , Neoplasias del Cuello Uterino/genética

RESUMEN

BACKGROUND: Neuroblastoma (NB) is an infrequent childhood malignancy of the peripheral sympathetic nervous system and is accountable for about 10% of pediatric tumors. microRNA (miR)-125a has been implicated to serve as a tumor suppressor in various cancers. Herein, we set out to ascertain whether miR-125a exerts antitumor effects in NB. METHODS: Downregulated miRNAs were identified by miRNA microarray analysis of NB tissues and paracancerous tissues. The expression of miR-125a in NB tissues and cells was detected by reverse transcription-quantitative (RT-q) PCR, followed by prognostic analysis. Gene Ontology (GO) enrichment analysis was performed on target genes of differentially expressed miRNAs. Cell proliferation, apoptosis, and differentiation were detected by cell counting kit-8 (CCK-8), Hoechst staining, immunofluorescence, and western blot. NB cells were injected into nude mice to detect tumorigenic, apoptotic, and differentiation activities in vivo. Dual-luciferase assay and chromatin immunoprecipitation (ChIP) were carried out to verify the binding relationship between miR-125a and PHOX2B or histone deacetylases 2 (HDAC2), respectively. Finally, rescue experiments were conducted. RESULTS: miR-125a was downregulated in NB tissues and cells, which was associated with poor prognosis. miR-125a reduced NB cell proliferation and augmented apoptosis and differentiation. NB cells with miR-125a overexpression decreased cell tumorigenesis and increased apoptosis and differentiation in xenograft tumor tissues. miR-125a targeted PHOX2B, which was highly expressed in NB tissues and cells. HDAC2, highly expressed in NB tissues and cells, repressed miR-125a transcription through histone deacetylation. Overexpression of HDAC2 or PHOX2B rescued the effects of miR-125a on NB cell proliferation, apoptosis, and differentiation. CONCLUSION: HDAC2 inhibited miR-125a transcription through deacetylation, and miR-125a suppressed NB development through binding to PHOX2B.

Asunto(s)

MicroARNs , Neuroblastoma , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Niño , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Neuroblastoma/genética

RESUMEN

OBJECTIVE: Long noncoding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1) and its target microRNA-125a (miR-125a) are reported to regulate immune and inflammation process in allergic rhinitis (AR). Hence, this study intended to investigate the correlation between lnc-NEAT1 and miR-125a expressions, as well as their clinical values in pediatric AR patients. METHODS: Peripheral blood mononuclear cell samples from 80 pediatric AR patients, 40 disease controls (DCs), and 40 healthy controls (HCs) were collected to detect lnc-NEAT1 and miR-125a expressions by reverse transcription-quantitative polymerase chain reaction. For pediatric AR patients only, serum interferon-gamma (IFN-γ) and interleukin (IL)-10 were measured by enzyme linked immunosorbent assay; meanwhile, T helper (Th) 1 and Th2 cells in CD4+ T cells were analyzed by flow cytometry. RESULTS: Lnc-NEAT1 was overexpressed, while miR-125a downregulated in pediatric AR patients compared to DCs and HCs (all p < 0.001). Moreover, lnc-NEAT1 expression negatively correlated with miR-125a expression in pediatric AR patients (p = 0.002), but not in DCs (p = 0.226) or HCs (p = 0.237). Furthermore, in pediatric AR patients, lnc-NEAT1 expression positively associated with TNSS (p < 0.001), sneezing score (p = 0.006), and congestion score (p = 0.008); miR-125a expression was negatively related to TNSS (p < 0.001), itching score (p = 0.040), and sneezing score (p = 0.005). Additionally, lnc-NEAT1 expression positively, while miR-125a expression negatively correlated with Th2 cells and IL-10 (all p < 0.05), but they were not correlated with Th1 cells or IFN-γ in pediatric AR patients. CONCLUSION: Circulating lnc-NEAT1 and miR-125a are aberrantly expressed and linked with Th2 cells and symptom severity in pediatric allergic rhinitis.

Asunto(s)

MicroARNs , ARN Largo no Codificante , Rinitis Alérgica , Niño , Humanos , Leucocitos Mononucleares , MicroARNs/genética , ARN Largo no Codificante/genética , Rinitis Alérgica/genética , Células Th2

RESUMEN

MicroRNA (miR)­125a­5p represses tafazzin phospholipid­lysophospholipid transacylases (TAFAZZIN) expression and inhibits the epithelial­mesenchymal transition (EMT) of ovarian cancer cells. EMT was found to have a crucial role in the acquisition of chemoresistance. Thus, the present study aimed to determine whether miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer. The expression of miR­125a­5p/TAFAZZIN and its association with chemotherapy response were determined in tissue samples from patients with breast cancer. Furthermore, the effects of miR­125a­5p on breast cancer cells were elucidated using cell proliferation and cell apoptosis assays. Then, the regulatory mechanism of miR­125a­5p in breast cancer was investigated by reverse transcription­quantitative PCR, western blotting, dual­luciferase reporter and RNA immunoprecipitation assays. The results demonstrated that miR­125a­5p inhibited the EMT of MCF­7/adriamycin (Adr) breast cancer cells, as well as decreased the proliferation and increased the apoptosis of breast cancer cells treated with Adr/docetaxel. In addition, miR­125a­5p downregulated the expression levels of TAFAZZIN, Transglutaminase 2, phosphorylated­AKT, N­cadherin, vimentin and proliferating cell nuclear antigen, and significantly increased those of E­cadherin, cleaved caspase-3 and Bax in MCF7/Adr cells. Similar results were obtained with small interfering RNA­TAFAZZIN. Moreover, TAFAZZIN was identified as a direct target of miR­125a­5p in MCF7/Adr breast cancer cells. In addition, increased miR­125a­5p expression was observed in breast tumors from patients exhibiting a chemotherapy response, and TAFAZZIN mRNA expression was elevated in patients with no chemotherapy response. Hence, miR­125a­5p expression was negatively correlated with TAFAZZIN mRNA expression in breast cancer tissues. All these data suggested that miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer and, therefore, has potential as a novel therapeutic target for this disease.

Asunto(s)

Aciltransferasas/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , MicroARNs/genética , Aciltransferasas/metabolismo , Animales , Antibióticos Antineoplásicos , Apoptosis/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Modelos Biológicos , Interferencia de ARN , Transducción de Señal

RESUMEN

AIMS: In this study, we aimed to decipher the impact of enhancer of zeste homolog 2 (EZH2) in psoriasis as well as the underlying mechanism. METHODS: A mouse model of psoriasis was developed by means of imiquimod induction, with the expression of EZH2, microRNA-125a-5p (miR-125a-5p), and SFMBT1 determined. The role of EZH2, miR-125a-5p, and SFMBT1 in malignant phenotypes of HaCaT cells and the development of psoriasis in vivo was subsequently investigated through gain- and loss-of-function experiments. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were conducted to explore the relationship between EZH2 or SFMBT1 and miR-125a-5p. Finally, the effects of EZH2 and miR-125a-5p on the transforming growth factor ß (TGFß)/SMAD pathway were analyzed. RESULTS: Overexpressed SFMBT1 and EZH2 was detected while miR-125a-5p were downregulated in psoriasis tissues and human keratinocyte (HaCaT) cells. EZH2 increased the levels of IL-17A-induced cytokines and promoted the malignant phenotypes of HaCaT cells. Functionally, EZH2 reduced miR-125a-5p expression while miR-125a-5p targeted SFMBT1 to activate the TGFß/SMAD pathway in vitro. Knockdown of EZH2 or up-regulation of miR-125a-5p inhibited cell proliferation and the levels of IL-17A-induced cytokines, but increased the expression of TGFß1 and the extent of smad2 and smad3 phosphorylation in HaCaT cells. Notably, EZH2 contributed to the development of psoriasis in vivo by inhibiting the TGFß/SMAD pathway via impairment of miR-125a-5p-mediated SFMBT1 inhibition. CONCLUSION: Taken together, the results of the current study highlight the ability of EZH2 to potentially inactivate the TGFß/SMAD pathway via upregulation of miR-125a-5p-dependent SFMBT1during the progression of psoriatic lesions.

RESUMEN

Tissue­specific transplantation antigen P35B (TSTA3) expression is upregulated in esophageal squamous cell carcinoma and breast cancer, and functions as an oncogene in breast cancer. However, the roles and underlying mechanisms of TSTA3 in lung cancer have not been fully elucidated. The current study aimed to reveal the role of TSTA3 in lung cancer and explore whether TSTA3 may be modulated by microRNA (miR)­125a­5p to activate ß­catenin signaling. Immunohistochemical staining and western blotting were used to analyze TSTA3 expression in lung cancer tissues and cells. Cell functions were assessed via Cell Counting Kit­8, flow cytometry, wound­healing, Transwell and in vivo tumor formation assays. The effect of TSTA3 on the activation of ß­catenin signaling was determined using western blot and immunofluorescence analyses. The association between miR­125a­5p and TSTA3 was determined by western blotting and luciferase gene reporter assay. The present study revealed that, compared with normal tissues and cells, TSTA3 expression was significantly increased in lung cancer tissues and cell lines, and high TSTA3 expression predicted a poor prognosis and more malignant clinical features in patients with lung cancer. TSTA3 upregulation significantly enhanced ß­catenin expression and promoted its nuclear accumulation. In addition, TSTA3 expression was negatively regulated by miR­125a­5p, which was downregulated in lung cancer. Furthermore, TSTA3 overexpression markedly promoted cell proliferation, migration, invasion and tumorigenesis, and suppressed cell apoptosis. TSTA3 downregulation abolished the effects of miR­125a­5p downregulation on promoting lung cancer cell malignant transformation. Overall, the current study demonstrates that TSTA3 is regulated by miR­125a­5p and functions as an oncogene in lung cancer via promoting the activation of ß­catenin signaling.

Asunto(s)

Carbohidrato Epimerasas/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Cetona Oxidorreductasas/genética , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Carcinoma Pulmonar de Células Pequeñas/genética , Anciano , Animales , Apoptosis/genética , Carbohidrato Epimerasas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Proliferación Celular/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cetona Oxidorreductasas/metabolismo , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Ratones , Persona de Mediana Edad , Proteínas Oncogénicas/genética , Neumonectomía , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/cirugía , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo

RESUMEN

Cervical cancer (CC), also known as invasive cervical carcinoma, is one of the most common gynecologic malignancies. The aim of the present study was to investigate the function of microRNA (miR)-125a-5p on CC progression and cisplatin (DDP) resistance. For this purpose, reverse transcription-quantitative PCR (RT-qPCR) was used to assess the expression of miR-125a-5p and LIMK1 in CC tissues, corresponding normal tissues and cells (human CC cell lines: C-33A, CaSKi; human cervical epithelial cells: HUCEC). Cisplatin (DDP) resistant cervical cancer cell lines were established (C-33A/DDP and CaSKi/DDP cell lines). RT-qPCR results demonstrated that miR-125a-5p or LIM kinase 1 (LIMK1) expression was downregulated or upregulated in C-33A/DDP and CaSKi/DDP cells, respectively. MTT assay, flow cytometry analysis and Western blotting were employed to detect the proliferation, apoptosis rate, IC50 of DDP and the expression of drug resistance-related proteins (P-glycoprotein and glutathione S-transferase-π). The targeting relationship between miR-125a-5p and LIMK1 was confirmed by the TargetScan database and dual-luciferase reporter gene assay. In CC tissues and cell lines, compared with normal tissues or HUCEC, miR-125a-5p expression was downregulated and LIMK1 expression was upregulated. The transfection with miR-125a-5p mimics decreased the proliferation of CaSKi/DDP cells, increased the apoptosis rate, reduced the IC50 of DDP, and downregulated the expression of drug resistance-related proteins; conversely, LIMK1 overexpression decreased the apoptosis rate, increased the IC50 of DDP, and upregulated the expression of drug resistance-related proteins. The luciferase reporter gene assay demonstrated that miR-125a-5p targeted and negatively regulated LIMK1. miR-125a-5p could partially reverse the effect of LIMK1 on the proliferation, apoptosis, IC50 of DDP and the expressions of drug resistance-related proteins. The findings of the present study indicated that miR-125a-5p sensitizes CC cells to DDP by targeting LIMK1, hence increasing the anticancer efficacy of cisplatin.

RESUMEN

OBJECTIVE: This study aimed to investigate the correlations of long non-coding RNA ANRIL (lncRNA ANRIL), microRNA (miR)-34a, miR-125a and miR-186 with disease risk, clinical features and prognosis of multiple myeloma (MM). METHOD: Totally, 87 MM patients and 30 controls were recruited. LncRNA ANRIL and its target miRNAs (miR-34a, miR-125a and miR-186) in bone marrow derived plasma cells were detected by RT-qPCR. Treatment response was assessed and survivals were calculated in MM patients. RESULTS: LncRNA ANRIL expression was increased, while miR-34a, miR-125a and miR-186 expressions were reduced in MM patients compared with controls. Meanwhile, lncRNA ANRIL negatively correlated with miR-34a and miR-125a but not miR-186 in MM patients, while did not correlate with miR-34a, miR-125a or miR-186 in controls. In MM patients, lncRNA ANRIL high expression associated with higher beta-2-microglobulin (ß2-MG) and more advanced international staging system (ISS) stage; miR-125a high expression associated with lower ß2-MG, less advanced ISS stage and less t (14; 16) abnormality; miR186 high expression associated with increased albumin; while miR-34a did not associate with any clinical features. Furthermore, lncRNA ANRIL high expression associated with decreased complete response (CR), while miR-34a high and miR-125a high expression associated with increased CR and objective response rate. Additionally, lncRNA ANRIL high expression associated with shorter progression-free survival (PFS), while miR-34a high expression associated with prolonged overall survival (OS), and miR-125a high expression associated with longer PFS and OS. CONCLUSION: LncRNA ANRIL and its target miRNAs might serve as biomarkers for assisting with personalized treatment and prognosis improvement of MM.

Asunto(s)

MicroARNs/genética , Mieloma Múltiple/genética , ARN Largo no Codificante/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Pronóstico , Análisis de Supervivencia

RESUMEN

BACKGROUND: Spinal cord injury (SCI) may cause loss of locomotor function, and macrophage is a major cell type in response to SCI with M1- and M2-phenotypes. The protective role of bone marrow mesenchymal stem cells (BMMSC)-derived exosomes (B-Exo) in SCI has been underscored, while their regulation on M2 macrophage polarization and the mechanism remain to be clarified. METHODS: A rat model of SCI was developed and treated with extracted B-Exo. Recovery of motor function was assessed by Basso-Beattie-Bresnahan (BBB) score. The apoptosis and degeneration of neurons, and macrophage polarization were evaluated. Subsequently, genes differentially expressed in the rat spinal cord after B-Exo treatment were analyzed. Later, the relationships between B-Exo and interferon regulatory factor 5 (IRF5) or macrophage polarization were clarified. Later, the upstream microRNAs (miRNAs) of IRF5 were validated by bioinformatics prediction and dual-luciferase experiments. Finally, the role of miR-125a in the neuroprotection of SCI was verified by rescue experiments. RESULTS: B-Exo promoted the recovery of locomotor function and M2-phenotype polarization, whereas inhibited neuronal apoptosis and degeneration and the inflammatory response caused by SCI in rats. In addition, IRF5 expression was reduced after B-Exo treatment. IRF5 promoted macrophage polarization towards M1-phenotype and secretion of inflammatory factors. There is a binding relationship between miR-125a and IRF5. Knockdown of miR-125a in B-Exo increased IRF5 expression in spinal cord tissues of SCI rats and attenuated the neuroprotective effect of B-Exo against SCI. CONCLUSION: Exosomal miR-125a derived from BMMSC exerts neuroprotective effects by targeting and negatively regulating IRF5 expression in SCI rats.

Asunto(s)

Exosomas/metabolismo , Factores Reguladores del Interferón/metabolismo , Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Apoptosis/fisiología , Polaridad Celular/fisiología , Regulación hacia Abajo , Factores Reguladores del Interferón/genética , MicroARNs/genética , Actividad Motora/fisiología , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/genética

RESUMEN

BACKGROUND AND AIM: Periodontitis is a chronic inflammatory disease inducing the absorption of alveolar bone and leading to tooth loss. Human amnion-derived mesenchymal stem cells (HAMSCs) have been used for studying inflammatory processes. This study aimed to explore the role of long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL) in HAMSC-driven osteogenesis in lipopolysaccharide (LPS)-induced human bone marrow mesenchymal stem cells (HBMSCs). METHODS: The cells were incubated with a co-culture system. Reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity were used to detect the oxidative stress level. Flow cytometry was performed to determine cell proliferation. The alkaline phosphatase (ALP) activity, Alizarin red assay, cell transfection, and rat mandibular defect model were used to evaluate the osteogenic differentiation. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis, dual-luciferase reporter assay, and immunofluorescence staining were used to evaluate the molecular mechanisms. RESULTS: This study showed that HAMSCs promoted the osteogenesis of LPS-induced HBMSCs, while the ANRIL level in HBMSCs decreased during co-culture. ANRIL had no significant influence on the proliferation of LPS-induced HBMSCs. However, its overexpression inhibited the HAMSC-driven osteogenesis in vivo and in vitro, whereas its knockdown reversed these effects. Mechanistically, this study found that downregulating ANRIL led to the overexpression of microRNA-125a (miR-125a), and further contributed to the competitive binding of miR-125a and adenomatous polyposis coli (APC), thus significantly activating the Wnt/ß-catenin pathway. CONCLUSION: The study indicated that HAMSCs promoted the osteogenic differentiation of LPS-induced HBMSCs via the ANRIL/miR-125a/APC axis, and offered a novel approach for periodontitis therapy.

Asunto(s)

Poliposis Adenomatosa del Colon , Células Madre Mesenquimatosas , MicroARNs , Amnios , Animales , Células de la Médula Ósea , Diferenciación Celular , Células Cultivadas , Humanos , Lipopolisacáridos/farmacología , Osteogénesis/genética , Ratas

RESUMEN

OBJECTIVE: In chronic lymphocytic leukemia (CLL), lack of expression or dysregulation of some special miRs disrupts apoptosis of malignant cells; thereby miR expression can enhance cell proliferation, disease progression and decrease patient survival. RESULTS: 30 CLL patients and 20 healthy individuals participated in the study. RNA was extracted to evaluate the expression of miR-125, miR-223, BCL-2 and signal transducer and transcription 3 activator (STAT3) genes; quantitative Real Time- PCR (Q-RT-PCR) was performed. MiR-125a and miR-223 expression decreased in the patients compared to the control group (P-Value:0.001). BCL-2 and STAT3 which are the target genes of these two miRs, showed increased expression, in the patients compared to the control subjects (P-Value: 0.001 and P-Value: 0.64 respectively). A significant reverse relationship was found between miR-125a and BCl-2 expression and WBC count. Significantly, miR-223 expression was associated with smoking in patients (P-Value: 0.007). Also, these miRs may have regulatory effects by controlling white blood cell (WBC) production based on the inverse correlation with WBC count and hemoglobin (Hb) concentration. Finally, miR-223 can be used as a prognostic factor in CLL patients; miR-125a may be useful for evaluating the therapeutic approaches based on the inverse link with BCl-2.

Asunto(s)

Leucemia Linfocítica Crónica de Células B , MicroARNs , Estudios de Casos y Controles , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucocitos/metabolismo , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transductores