Exosome miRNA-203 promotes M1 macrophage polarization and inhibits prostate cancer tumor progression.

Prostate cancer (PCa) is a prevalent malignant neoplasm affecting the male reproductive system globally. However, the diagnostic and therapeutic approaches fall short of meeting the demands posed by PCa. Poor expression of miRNA-203 (miR-203) within PCa tissues and cells implies its potential utility as a diagnostic indicator for PCa. Exosomes (Exo), membranous vesicles released by various cells, are rich reservoirs of miRNAs. However, the presence of miR-203 presents within Exo derived from PCa cells remains unclarified. In this study, Exo was isolated from urine specimens collected from clinical PCa patients and LNCaP cells to detect miR-203 expression. Meanwhile, the impact of overexpressed miR-203 on M0 macrophages (mø) was analyzed. Subsequently, alterations in the proliferative, migratory, and invasive capacities of LNCaP cells were examined within a co-culture system featuring elevated miR-203 levels in both macrophages and LNCaP cells. Furthermore, the repercussions of miR-203 upregulation or inhibition were explored in a murine PCa tumor model. The results revealed that Exo manifested a circular or elliptical morphology, encapsulating a phospholipid bilayer approximately 100 nm in diameter. Notably, Exo readily infiltrated, with both Exo and miR-203-overexpressing Exo prompting macrophage polarization toward the M1 subtype. In the co-culture system, miR-203 exhibited pronounced suppression of LNCaP cell proliferation, migration, and invasion, while concurrently fostering apoptosis as compared with the LNCaP group (Control). In vivo experiments further disclosed that miR-203 greatly inhibited the growth of PCa tumors in nude mice. Markedly heightened expression of M1 macrophage markers such as IL-1ß, IL-6, IL-12, CXCL9, and CXCL10 was observed within the tumor microenvironment following miR-203 intervention, as opposed to the model group. However, the introduction of miR-203 antagomir led to a reversal in tumor growth trends. This investigation indicates the presence of miR-203 within the urine of PCa patients and Exo originating from cells, and that miR-203 exerted antitumor effect by facilitating M1 macrophage polarization. Our study furnishes valuable insights into the potential applicability of miR-203 as a diagnostic biomarker and therapeutic target for PCa.

The regulatory role of MiR-203 in oxidative stress induced cell injury through the CBS/H2S pathway.

Hydrogen Sulfide (H2S) mediates biological effects in a variety of ways. Due to its strong reducing potential, H2S has been recognized to have an important role in oxidative stress induced hypoxia. It has been reported that H2S production and miRNA can mutually regulate each other. H2S is produced by the catalytic activity of cystathionine-ß-synthase (CBS), which is under the regulation of miRNAs. In this study, we used target gene prediction software, and identified miR-203 as a potential regulator of CBS. We verified this finding using an oxygen and glucose deprivation (OGD) hypoxia cell model in SH-SY5Y cells and pMIR-REPORT™ luciferase miRNA expression reporter vector. Furthermore, transfecting SH-SY5Y cells with miRNA agomir (agonist) and antagomir (antagonist) by lipofectamin RNAiMAX, we further validated miR-203 as a direct regulator of CBS. We also found that miR-203 protects from cell injury by regulating lipid peroxidation, cell apoptosis, and mitochondrial membrane potential. These findings suggest that while over-expression of miR-203 can aggravate OGD induced cell injury, inhibition of miR-203 can protect against OGD induced cell injury. Based on our data and that of others, we propose that miR-203 may regulate oxidative stress induced cell injury by regulating CBS expression and adjusting the levels of H2S production.

Interleukin-12 treatment reduces tumor growth and modulates the expression of CASKA and MIR-203 in athymic mice bearing tumors induced by the HGC-27 gastric cancer cell line.

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system and due to its poor prognosis, there is an increase in the demand for more effective anticancer therapies. Interleukins are potential anticancer agents which can modulate expression of cancer related genes and have therapeutic effects. Interleukin 12 (IL-12) exhibits potent anti-tumor, anti-angiogenic and anti-metastatic activities and represents the ideal candidate for tumor immunotherapy, due to its ability to activate both innate and adaptive immunities. The aim of this study was to evaluate the effect of IL-12 administration on GC tumor growth induced in the cancer xenograft nude mouse model. Tumor development was analyzed weekly and after 8 weeks, the animals were sacrificed for cytokine analysis (IL-4, TNF-alfa, IL-2, INF-gamma, IL-12, IL-10, TGF-beta) by ELISA. The tumor cells in the implanted areas of the animals that developed solid growth of the tumor (anatomopathological analysis was performed). We have also evaluated CASK and miR203 expression, two related cell invasion factors, in the induced tumors after administration of 6 n/kg IL-12. The development of tumor masses was observed in all groups of animals inoculated with HGC-27 neoplastic cells. In animals treated with 6 n/kg IL-12, there was no tumor development confirmed by anatomopathological analysis. Changes in the levels of pro and anti-inflammatory cytokines were also observed. Our results indicated that miR203 expression was elevated while CASK was downregulated. These results suggest that IL-12 treatment repress the tumor growth by induction of miR203 expression which in turn repress CASK expression.

Bio-diagnostic performances of microRNAs set related to DNA damage response pathway among hepatitis C virus-associated hepatocellular carcinoma patients.

BACKGROUND: Up to date, a well-defined microRNAs (miRNAs) profile involved in hepatocellular carcinoma (HCC) pathogenesis remains indecisive. Thus, employing miRNAs for HCC diagnosis is demanded for early therapeutic interventions. We aimed to evaluate the usage of miRNAs set related to the SuperPath: miRNAs involved in DNA damage response pathway as effective biomarkers for HCV-related HCC diagnosis. RESULTS: The study enrolled 97 patients with HCV-related HCC, 84 with hepatitis C virus (HCV), 97 with liver cirrhosis (LC), and 84 healthy individuals. Serum miRNA-23a, miRNA-203, miRNA-100-5p, and miRNA-16 were quantified using qRT-PCR experiments, AFP and routine LFTs were estimated via standard techniques. Pathway enrichment analysis along with the construction of miRNAs regulatory network were performed. With respect to healthy individuals, miRNA-203, miRNA-100-5p, and miRNA-16 were significantly downregulated in HCC, HCV, and LC groups, while miRNA-23a showed significant upregulation (p < 0.001). miRNAs exhibited significant correlations with AFP, ALT, AST, and albumin. Also, elevated levels of miRNA-23a were recognized in patients with multiple focal lesions and/or lesion size > 5 cm. Additionally, the diagnostic performance of miRNA-23a expression level at a selected cut-off value of 3.99 overtakes AFP, while expressions of miR-203, miRNA-100-5p, and miRNA-16 represent poor diagnostic outcomes. CONCLUSIONS: Keeping in mind the individual variability and high level of heterogeneity in HCC, our data revealed the diagnostic value of miRNA-23a expression in HCV-related HCC patients. Further extra in silico HCC-specific microRNAs sets are demanded in diagnosis.

Potential therapeutic role of microvesicles derived from mesenchymal stem cells and platelet-rich plasma in murine burn wound healing: scar regulation and antioxidant mechanism.

BACKGROUND: Microvesicles (MVs) derived from mesenchymal stem cells exhibited an emerging promising therapy in many animal model diseases. Post-burn scars represent one of the significant challenges in wound healing processes. The present study investigated the possible role of MVs derived from mesenchymal stem cells vs. platelet-rich plasma (PRP) in murine burn wound healing. MATERIALS AND METHODS: Wistar rats (n = 40) were assigned into four equal groups (control, burn, burn + PRP, burn + MVs). Small-sized burns were induced, morphologically followed for 3 weeks, then rats were sacrificed and skin lesions were analysed biochemically and immunohistochemically. RESULTS: Both MVs and PRP modulated the burn healing process with better results in the MVs group than in PRP. MVs significantly (p < 0.05) accelerated burn wound size healing and dramatically modulated tissue interleukin (IL)-10, IL-6, and hyaluronidase. Both MVs and PRP significantly downregulated gene expression of miRNA203 and alpha smooth muscle actin and immunoblotting analysis of matrix metalloproteinases 3 and transforming growth factor beta compared with the burn group. The immune-staining intensity of tumour necrosis factor alpha was dramatically reversed in the MVs group compared with the burn group, whereas that of connective tissue growth factor, collagen I and III was significantly reduced in both groups. The antioxidant Nrf2 immune-staining intensity had been dramatically enhanced particularly in MVs. CONCLUSIONS: Microvesicles derived from mesenchymal stem cells and PRP may improve burn wound healing via regulating scar formation and antioxidant mechanism.

Serum miRNA-203 as a Novel Biomarker for the Early Prediction of Acute ST-elevation Myocardial Infarction.

Existing markers of myocardial infarction have limited diagnostic value for infarction, so it is necessary to identify new markers of infarction. To study the predictive value of serum miRNA-203 for acute ST-elevation myocardial infarction. Seventy patients with STEMI who were diagnosed in Hefei Second People's Hospital from December 2020 to December 2021 were selected, and 35 patients with transient chest pain who were hospitalized for other diseases in the Cardiology Department of our hospital during the same period were selected as the control group. The sera of the two groups of patients were collected, and a miRNA-203 semiquantitative experiment was performed. The miRNA-203 level in the STEMI group was higher than that in the control group. The AUC area of miRNA-203 in predicting STEMI was 0.912. Logistic regression analysis showed that miRNA-203 and white blood cell counts were independent risk factors for STEMI (P<0.05), and their ORs (95% CI) were 3.913 (1.574-9.728) and 2.13 (1.247-3.641), respectively. The present study reveals that miRNA-203 could be a possible candidate for a novel biomarker in the early prediction of STEMI.

[Investigate the expression of miRNA-203 in papillary thyroid carcinomaand its effect on cell proliferation].

Objective:To investigate the expression of miRNA-203 in papillary thyroid carcinoma（PTC）tissues and its correlation with clinical pathological parameters，explore its effect on cell proliferation of WRO cell. Method:Thirty cases of PTC tissues, paired normal tissues were collected in our hospital during 2013-2016. The expression of miRNA-203 was determined by qRT-PCR，then the relationship of miRNA-203 expression, clinical pathological parameters were analyzed.WRO cells were transfected with miRNA-203 mimics, then cell proliferation, cell cycle and concerned cyclin protein(CyD1,CyB1) were tested by MTT, flow cytometry and western blot. Result:Compared to the paired normal tissues，tumor tissues showed sifnificantly lower expression of miRNA-203. Upregulaion of miRNA-203 in WRO cells effectively reduced cell growth, G2/M arrest. Mechanistically,in the miRNA-203-mimics-treated groups,cell-cycle-related proteins cyclin B1 was up-regulated, while cyclin D1 was down-regulated. Conclusion:miRNA-203 may play an anticarcinogenic effect in PTC. Upregulation of miRNA-203 is highly correlated with cell prolliferation, and maybe miRNA-203 is a potential targert for the treatment of thyroid carcinoma.

MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling.

BACKGROUND: MicroRNAs (miRNAs) have been proved involved in many tumorigenic behaviors including tumor growth. But, the clinical significance and functions of miRNA-203 in gastric cancer (GC) remain elusive. RESULTS: Decreased expression of miRNA-203 was correlated with tumor size, poor prognosis and recurrence in GC patients. Overexpression of miR-203 or knockdown of its target progesterone immunomodulatory binding factor 1 (PIBF1) inhibited GC growth in vitro and in vivo, while miR-203 knockdown promoted GC proliferation. In addition, PIBF1 overexpression attenuated the inhibitory effects of miR-203 on GC growth and enhanced that effect on p-Akt expression. CONCLUSIONS: MiR-203 as a tumor biomarker suppresses GC growth through targeting the PIBF1/Akt signaling, suggesting that it may have the important therapeutic potential for the treatment of GC.

WITHDRAWN: Serum miRNA-203 expression, a potential biomarker for recurrence and prognosis in papillary thyroid carcinoma.

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