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Simple Summary: This review aims to explore the role of the microRNA-204 (miR-204), a tumor suppressor gene, in the development of breast cancer, focusing on how it influences the hallmarks of cancer. By understanding the impact of miR-204 on these hallmarks, this review seeks to shed light on its potential as a molecular target for breast cancer therapy. microRNA-204-5p (miR-204) is a small noncoding RNA with diverse regulatory roles in breast cancer (BC) development and progression. miR-204 is implicated in the instauration of fundamental traits acquired during the multistep development of BC, known as the hallmarks of cancer. It may act as a potent tumor suppressor by inhibiting key cellular processes like angiogenesis, vasculogenic mimicry, invasion, migration, and metastasis. It achieves this by targeting multiple master genes involved in these processes, including HIF-1α, β-catenin, VEGFA, TGFBR2, FAK, FOXA1, among others. Additionally, miR-204 modulates signaling pathways like PI3K/AKT and interacts with HOTAIR and DSCAM-AS1 lncRNAs, further influencing tumor progression. Beyond its direct effects on tumor cells, miR-204 shapes the tumor microenvironment by regulating immune cell infiltration, suppressing pro-tumorigenic cytokine production, and potentially influencing immunotherapy response. Moreover, miR-204 plays a crucial role in metabolic reprogramming by directly suppressing metabolic genes within tumor cells, indirectly affecting metabolism through exosome signaling, and remodeling metabolic flux within the tumor microenvironment. This review aims to present an update on the current knowledge regarding the role of miR-204 in the hallmarks of BC. In conclusion, miR-204 is a potential therapeutic target and prognostic marker in BC, emphasizing the need for further research to fully elucidate its complex roles in orchestrating aggressive BC behavior. [ABSTRACT FROM AUTHOR]

Abstract Background Pulmonary arterial hypertension is most of the time diagnosed late in the course of the disease and necessitates right cardiac catheterization which is an invasive and costly tool. MicroRNAs have a role in the pathogenesis of pulmonary hypertension, systemic sclerosis, and schistosomiasis and their dosages are easy and non-expensive. Therefore, determining their levels in the blood may be helpful in detecting PAH and differentiating its idiopathic form from those caused by systemic sclerosis and schistosomiasis. Purpose of the study To evaluate the role of microRNA (miR) 204 and miR-210 in the diagnosis of PAH and to distinguish between idiopathic PAH (IPAH), systemic sclerosis-associated PAH (SSc-PAH), and schistosomiasis-associated PAH (Sch-PAH) and to identify patients who may benefit from simple non-expensive and non-invasive methods in diagnosis of PAH. Methods Sixty patients with PAH and 30 subjects as control were enrolled in the study. PAH was diagnosed by right heart catheterization, echocardiography, and laboratory tests. Blood samples were taken from all patients for measuring miR-204 and miR-210. Results MiR-204 was downregulated in PAH and there was a highly significant difference between PAH and control (p = 0.003) with cut-off predictive value ≤ 0.15 µM and 70% sensitivity, 85% specificity with AUC (0.749). However, miR-204 failed to distinguish between IPAH, SSc-PAH, and Sch-PAH. MiR-210 was upregulated in PAH with a highly significant difference between PAH and control (p

Objective: To explore the function and possible molecular mechanism of miR-204 and SOX4 in cutaneous squamous cell carcinoma (CSCC). Methods: A total of 70 patients with CSCC who were diagnosed and underwent surgical treatment in the dermatology department of the Second Affiliated Hospital of Air Force Military Medical University from May 2019 to March 2022 were selected. CSCC tissues and corresponding paracancer tissues of the patients were collected, and the mRNA levels of miR-204 and SOX4 in the tissue samples were detected by qRT-PCR. The protein level of SOX4 in tissue samples were detected by Western blot and immunohistochemical staining. The CSCC cell line SCL-1 was divided into control group, miR-NC group, miR-204 group, miR-204+pcDNA group and miR-204+SOX4 group. miR-NC, miR-204 mimics, miR-204 mimics and pcDNA3.1 empty vector, miR-204 mimics and pcDNA3.1+SOX4 vector were transfected into miR-NC group, miR-204 group, miR-204+pcDNA group and miR-204+SOX4 group by Lipofectamine 2000TM transfection reagents, respectively. And control group cells were not transfected. The targeting relationship between miR-204 and SOX4 was analyzed by dual luciferase reporter gene experiment. SCL-1 cell proliferation was detected by CCK-8 assay, cell cloning was detected by clonogenesis assay, cell apoptosis was detected by flow cytometry assay, and cell migration and invasion were detected by Transwell assay. The protein expression levels of SOX4, E-cadherin, N-cadherin and Vimentin were detected by Western blot. Results: The expression of miR-204 was low in CSCC, and the expression of SOX4 mRNA and protein was high. The online analysis results of TargetScan software showed that binding sites existed at 5' of miR-204 and 3' of SOX4. Compared with the control group or the NC group, the relative proliferation activity, number of clone formation, migration and invasion of SCL-1 cells in miR-204 group were decreased (P<0.05), and the apoptosis rate was increased (P<0.05). The protein levels of SOX4, N-cadherin and Vimentin in SCL-1 cells were decreased (P<0.05), while the protein level of E-cadherin was increased(P<0.05). Compared with miR-204 group or miR-204+pcDNA group, the relative proliferation activity, number of clone formation, migration and invasion of SCL-1 cells in miR-204+SOX4 group were increased (P<0.05), and the apoptosis rate was decreased (P<0.05). The protein levels of SOX4, N-cadherin and Vimentin in SCL-1 cells were increased(P<0.05), while the protein level of E-cadherin was decreased(P<0.05). Conclusion: miR-204 inhibits the proliferation, migration, invasion and epithelial mesenchymal transformation of CSCC cells by targeting SOX4, and promotes cell apoptosis, thus alleviating the development of CSCC. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the phenotype and genotype of a Chinese family with autosomal‐dominant retinitis pigmentosa (RP) accompanied by iris coloboma. Methods: The proband, a 34‐year‐old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full‐field electroretinography (ffERG). Genetic analyses were conducted through whole‐exome sequencing (WES) to screen for variations. Results: Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR‐204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. Conclusions: In this third independent and the first Asian family, the existence of a miR‐204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR‐204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal‐dominant pattern, including in Chinese patients, miR‐204 aberrations should be considered. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension is most of the time diagnosed late in the course of the disease and necessitates right cardiac catheterization which is an invasive and costly tool. MicroRNAs have a role in the pathogenesis of pulmonary hypertension, systemic sclerosis, and schistosomiasis and their dosages are easy and non-expensive. Therefore, determining their levels in the blood may be helpful in detecting PAH and differentiating its idiopathic form from those caused by systemic sclerosis and schistosomiasis. Purpose of the study: To evaluate the role of microRNA (miR) 204 and miR-210 in the diagnosis of PAH and to distinguish between idiopathic PAH (IPAH), systemic sclerosis-associated PAH (SSc-PAH), and schistosomiasis-associated PAH (Sch-PAH) and to identify patients who may benefit from simple non-expensive and non-invasive methods in diagnosis of PAH. Methods: Sixty patients with PAH and 30 subjects as control were enrolled in the study. PAH was diagnosed by right heart catheterization, echocardiography, and laboratory tests. Blood samples were taken from all patients for measuring miR-204 and miR-210. Results: MiR-204 was downregulated in PAH and there was a highly significant difference between PAH and control (p = 0.003) with cut-off predictive value ≤ 0.15 µM and 70% sensitivity, 85% specificity with AUC (0.749). However, miR-204 failed to distinguish between IPAH, SSc-PAH, and Sch-PAH. MiR-210 was upregulated in PAH with a highly significant difference between PAH and control (p < 0.001) with cut-off predictive value ≥ 1.16 µM and 93.33% sensitivity, 85% specificity with AUC (0.917). MiiR-210 showed a significant difference between SSc-PAH and idiopathic PAH (P = 0.012) and between SSc-PAH and Sch-PAH (P = 0.035). Conclusions: MiR-204 and miR-210 are useful non-invasive and non-expensive markers for the diagnosis of PAH, miR-210 is an excellent predictor in the diagnosis of PAH and also miR-210 might be used to distinguish SSc-PAH from idiopathic PAH and Sch-PAH. [ABSTRACT FROM AUTHOR]

Purpose: To study the regulatory impact of mir-204 on the biological behavior of childhood leukemia cells and to elucidate its mechanism of action. Methods: A total of 112 children with leukemia who were treated in Three Gorges University Yichang Central People's Hospital, Yichang, China from July 2018 to June 2020 were randomly divided into study and control groups (n = 56 each). The expression levels of mir-204 and hepatocyte growth factor (HGF) were determined using real-time polymerase chain chain reaction (RT-PCR) while the cell proliferation potential was determined using the CCK-8 method. Apoptosis and cell cycle progression of each group were evaluated using flow cytometry while changes in cell invasion and migration were assessed by Transwell assay. Luciferase reporter assay was used to determine the binding of mir-204 and HGF to 3'UTR. Results: The expression level of mir-204 in study group was significantly lower than that in control group, while expression level of HGF was significantly higher (p < 0.01) compared to control group. There was no significant change in cell proliferation capacity at 24 h. The expression level of mir-204 was significantly decreased, while the expression level of HGF was significantly increased (p < 0.05). Luciferase activity of wild-type HGF 3'UTR in mir-204 overexpression group was significantly decreased, relative to mir-204 negative control group (p < 0.01). There was no significant difference in luciferase activity in mutant HGF gene between the two groups (p > 0.05). Conclusion: Mir-204 reduces HGF expression level via HGF 3'UTR end, thereby inhibiting cell proliferation, invasion and migration, while promoting apoptosis, blocking cell cycle and regulating biological behavior of childhood leukemia cells. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis. Experimental Approach: ApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects. Key Results: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis. Conclusion and Implications: Macrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects. [ABSTRACT FROM AUTHOR]

Abstract Purpose To characterize the phenotype and genotype of a Chinese family with autosomal‐dominant retinitis pigmentosa (RP) accompanied by iris coloboma. Methods The proband, a 34‐year‐old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full‐field electroretinography (ffERG). Genetic analyses were conducted through whole‐exome sequencing (WES) to screen for variations. Results Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR‐204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. Conclusions In this third independent and the first Asian family, the existence of a miR‐204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR‐204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal‐dominant pattern, including in Chinese patients, miR‐204 aberrations should be considered.

Osimertinib is an effective treatment option for patients with advanced non-small cell lung cancer (NSCLC) with EGFR activation or T790M resistance mutations; however, acquired resistance to osimertinib can still develop. This study explored novel miRNA–mRNA regulatory mechanisms that contribute to osimertinib resistance in lung cancer. We found that miR-204 expression in osimertinib-resistant lung cancer cells was markedly reduced compared to that in osimertinib-sensitive parental cells. miR-204 expression levels in cancer cells isolated from treatment-naive pleural effusions were significantly higher than those in cells with acquired resistance to osimertinib. miR-204 enhanced the sensitivity of lung cancer cells to osimertinib and suppressed spheroid formation, migration, and invasion of lung cancer cells. Increased miR-204 expression in osimertinib-resistant cells reversed resistance to osimertinib and enhanced osimertinib-induced apoptosis by upregulating BIM expression levels and activating caspases. Restoration of CD44 (the direct downstream target gene of miR-204) expression reversed the effects of miR-204 on osimertinib sensitivity, recovered cancer stem cell and mesenchymal markers, and suppressed E-cadherin expression. The study demonstrates that miR-204 reduced cancer stemness and epithelial-to-mesenchymal transition, thus overcoming osimertinib resistance in lung cancer by inhibiting the CD44 signaling pathway.

Vasculogenic mimicry (VM) is an angiogenesis-independent process that potentially contributes to the poor clinical outcome of anti-angiogenesis therapy in multiple malignant cancers, including pancreatic adenocarcinoma (PAAD). Several studies have shown that ginsenoside Rg3, a bioactive component of ginseng, holds considerable potential for cancer treatment. Our previous work has proved that Rg3 can inhibit VM formation in PAAD. However, its underlying mechanism remains unclear. To explore the underlying mechanism by which Rg3 affects VM formation in PAAD. We first investigated the effects of Rg3 on the cellular phenotypes of two PAAD cell lines (SW-1990 and PCI-35), and the expression of EMT- and stemness-related proteins. SW-1990 cells were adopted to construct xenograft models, and the anti-tumor effects of Rg3 in vivo were validated. Subsequently, we isolated the exosomes from the two PAAD cell lines with Rg3 treatment or not, and explored whether Rg3 regulated VM via PAAD cell-derived exosomes. MiRNA sequencing, clinical analysis, and rescue experiments were performed to investigate whether and which miRNA was involved. Subsequently, the target gene of miRNA was predicted using the miRDB website (https://mirdb.org/), and rescue experiments were further conducted to validate those in vitro and in vivo. Rg3 indeed exhibited excellent anti-tumor effects both in vitro and in vivo , with inhibitory effects on EMT and stemness of PAAD cells. More interestingly, Rg3-treated PAAD cell-derived exosomes suppressed the tube-forming ability of HUVEC and PAAD cells, with a decrease in stemness-related protein expression, indicating that Rg3 inhibited both angiogenesis and VM processes. Subsequently, we found that Rg3 induced the up-regulation of miR-204 in PAAD cell-derived exosomes, and miR-204 alone inhibited tube and sphere formation abilities of PAAD cells like exosomes. Specifically, miR-204 down-regulated DVL3 expression, which was involved in regulating cancer cell stemness, and ultimately affected VM. The in vivo experiments further indicated that Rg3-treated SW-1990 cell-derived exosome-inhibited tumor growth, VM formation, and stemness-related protein expression can be abrogated by DVL3 overexpression. Ginsenoside Rg3 increased the PAAD cell-derived exosomal miR-204 levels, which subsequently inhibited its target genes DVL3 expression in the receptor PAAD cells, and the down-regulated DVL3 broke stemness maintenance, ultimately suppressing VM formation of PAAD. Our findings revealed a novel mechanism by which Rg3 exerted its anti-tumor activity in PAAD via inhibiting VM, and provided a promising strategy to make up for the deficiency of anti-angiogenesis therapy in cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Endometritis severely limits the development of the dairy industry. • Up-regulation of miR-204 alleviated LPS induced uterine injury. • miR-204 can enhance the expression of tight junctional proteins. • miR-204 inhibits the activation of Wnt/β-catenin pathway. One of the most common bacterial diseases of the reproductive system in dairy cows is endometritis, which will cause huge economic loss. Here, we investigate the mechanisms of miR-204 on LPS-stimulated endometritis in vitro and in vivo. Experiments displayed that the expression of miR-204 was lower in bovine uterine tissue samples or bovine endometrial epithelial cell line (BEND) that stimulated by LPS. Compared with the negative group, miR-204 treatment significantly suppressed the production of proinflammatory factors and the Wnt/β-catenin pathway activation. Additionally, the result of the dual luciferase assay showed that miR-204 targeted cyclin D2. More importantly, up-regulation of miR-204 alleviated LPS induced uterine injury was confirmed in vivo studies. Molecular experiments indicated that the expression level of tight junctional proteins Claudin3 and cadherin1 were both enchanced by miR-204 treatment. Accordingly, miR-204 may serve as a new measure to prevent and treat endometritis caused by LPS. [ABSTRACT FROM AUTHOR]