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Introduction: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. Methods: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. Results: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. Conclusion: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice. Introduction: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. Methods: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. Results: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. Conclusion: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice. [ABSTRACT FROM AUTHOR]

To investigate the function of miR‐454 in ischemic stroke, this study was carried out. Cerebral ischemia/reperfusion (I/R) injury animal model and a SHSY5Y cell culture model of oxygen‐glucose deprivation/reoxygenation (OGD/R) were constructed. The effects of miR‐454 were detected by evaluating the levels of biochemical markers, gene expression, and pathophysiological markers. The results showed that NOX4 level was elevated, while miR‐454 expression was reduced in I/R brain samples and in OGD/R‐treated cells. The miR‐454 agomir declined NOX4 level and reactive oxygen species (ROS) production in rats suffering from I/R. Furthermore, microRNA‐145 (miR‐454) overexpression inhibited NOX4 level and ROS production in cells treated by OGD/R and decreased luciferase activity in cells transfected with NOX4‐wild type (WT) reporter plasmid. Meanwhile, our results proved that the protected effects of miR‐454 on SH‐SY5Y cells treated by OGD/R were reversed by pcDNA‐NOX4 transfection. MiR‐454 protected animals from brain injury induced by cerebral I/R via directly regulating its target gene NOX4, illustrating a curatively potential target for treating ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract Background The aberrant expression of microRNA-454 (miR-454) has been confirmed to be involved in the development of cancers. However, the functional role of miR-454 in the progression of ovarian cancer remains unclear. Methods The expression of miR-454 in ovarian cancer cells and serum of ovarian cancer patients was detected by RT-PCR. CCK8, colony formation, transwell, and flow cytometry assays were conducted to assess the effects of miR-454 on ovarian cancer cell proliferation, migration, invasion, and apoptosis, respectively. Dual-luciferase reporter assay was used to confirm the targeting relationship between miR-454 and E2F6. The expression pattern of E2F6 in ovarian cancer tissues was detected using immunohistochemistry (IHC) assay. The relative expression of related proteins was examined using western blot analysis. Results miR-454 was markedly down-regulated by hypoxia in ovarian cancer cells. Compared with normal samples, the expression of miR-454 was up-regulated in the serum of ovarian cancer patients, and correlated with the clinicopathological stages of ovarian cancer. Next, we found that miR-454 overexpression inhibited the proliferation, migration and invasion of OVCAR3 and SKOV3 cells, as well as promoted apoptosis. In addition, the Akt/mTOR and Wnt/β-catenin signaling pathway were inhibited by miR-454 in ovarian cancer cells. Mechanically, bioinformatic analysis and dual-luciferase reporter assay confirmed that E2F6 was a direct target of miR-454 and negatively regulated by miR-454 in ovarian cancer cells. Moreover, IHC analysis showed that E2F6 was highly expressed in ovarian cancer tissues. Finally, we found that the increasing cell proliferation and migration triggered by E2F6 overexpression were abolished by miR-454 overexpression. Conclusion Taken together, these results highlight the role of miR-454 as a tumor suppressor in ovarian cancer cells by targeting E2F6, indicating that miR-454 may be a potential diagnostic biomarker and therapeutic target for ovarian cancer.

Background: The heterogeneity of breast tumors presents a challenge in disease management, necessitating an understanding of the molecular mechanisms driving breast tumorigenesis. Aberrant expression of microRNAs is known to promote tumor growth and progression. Our previous RNA-sequencing dataset revealed the upregulation of miR-362-5p and miR-454-3p in breast tumors. We investigated potential role of miR-362-5p and miR-454-3p in breast cancer using MDAMB231 and MCF7 cell lines. Methods and results: The expression of miR-362-5p and miR-454-3p were altered in MCF7 and MDAMB231 using mimics and inhibitors. The effect on cell viability, cell cycle progression and migration was assessed using Alamar blue assay, flow cytometry and wound healing assay. Further, the expression of potential target genes were measured using real-time PCR. Our results indicated that an increased expression of miR-362-5p promoted cell growth and survival in MCF7, but decreased cell migration. In contrast, miR-362-5p overexpression reduced cancer cell growth, survival and migration in MDAMB231. Overexpression of miR-454-3p was oncogenic in both cell lines but suppressed migration in the aggressive cell line MDAMB231. Conclusion: Two microRNAs, miR-362-5p and miR-454-3p, were evaluated for functional activity in breast cancer cell lines and they showed increased proliferative signals and tumorigenic properties. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers., Methods: This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data., Results: Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations., Conclusion: We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Colon cancer-associated transcript 1 (CCAT1) was identified as an oncogenic long non-coding RNA (lncRNA) in a variety of cancers. However, there was a lack of understanding of the mechanism by which CCAT1 conferred cisplatin (also known as DDP) resistance in ovarian cancer cells. Materials and Methods: Cell viability of A2780, SKOV3, A2780/DDP, and SKOV3/DDP cells upon cisplatin treatment was monitored by MTT assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the expression levels of CCAT1 and miR-454. The effect of sh-CCAT1 on cisplatin response was investigated in xenografts study. Bioinformatic analysis, luciferase reporter assay and qRT-PCR were conducted to validate the direct interaction among CCAT1, miR-454, and survivin. Apoptosis was determined by flow cytometry after dual staining of Annexin-V-FITC/propidium iodide, and the expression of apoptosis-related proteins Bcl-2, Bax and survivin were detected by qRT-PCR and Western blotting. Xenograft study was conducted to monitor in vivo tumor formation. Results: CCAT1 was highly expressed in cisplatin-resistant ovarian cancer cell line A2780/DDP and SKOV3/DDP. Knockdown of CCAT1 restored sensitivity to cisplatin in vitro and in vivo. Our data revealed that silencing of CCAT1 promoted cisplatin-induced apoptosis via modulating the expression of pro- or anti-apoptotic proteins Bax, Bcl-2, and survivin. CCAT1 directly interacted with miR-454, and miR-454 overexpression potentiated cisplatin-induced apoptosis. Survivin was identified as a functional target of miR-454, restoration of survivin attenuated the effect of miR-454 on cisplatin response. In addition, miR-454 inhibitor or overexpression of survivin was found to abolish sh-CCAT1-induced apoptosis upon cisplatin treatment. Conclusion: CCAT1/miR-454/survivin axis conferred cisplatin resistance in ovarian cancer cells. [ABSTRACT FROM AUTHOR]

Background: The aberrant expression of microRNA-454 (miR-454) has been confirmed to be involved in the development of cancers. However, the functional role of miR-454 in the progression of ovarian cancer remains unclear. Methods: The expression of miR-454 in ovarian cancer cells and serum of ovarian cancer patients was detected by RT-PCR. CCK8, colony formation, transwell, and flow cytometry assays were conducted to assess the effects of miR-454 on ovarian cancer cell proliferation, migration, invasion, and apoptosis, respectively. Dual-luciferase reporter assay was used to confirm the targeting relationship between miR-454 and E2F6. The expression pattern of E2F6 in ovarian cancer tissues was detected using immunohistochemistry (IHC) assay. The relative expression of related proteins was examined using western blot analysis. Results: miR-454 was markedly down-regulated by hypoxia in ovarian cancer cells. Compared with normal samples, the expression of miR-454 was up-regulated in the serum of ovarian cancer patients, and correlated with the clinicopathological stages of ovarian cancer. Next, we found that miR-454 overexpression inhibited the proliferation, migration and invasion of OVCAR3 and SKOV3 cells, as well as promoted apoptosis. In addition, the Akt/mTOR and Wnt/β-catenin signaling pathway were inhibited by miR-454 in ovarian cancer cells. Mechanically, bioinformatic analysis and dual-luciferase reporter assay confirmed that E2F6 was a direct target of miR-454 and negatively regulated by miR-454 in ovarian cancer cells. Moreover, IHC analysis showed that E2F6 was highly expressed in ovarian cancer tissues. Finally, we found that the increasing cell proliferation and migration triggered by E2F6 overexpression were abolished by miR-454 overexpression. Conclusion: Taken together, these results highlight the role of miR-454 as a tumor suppressor in ovarian cancer cells by targeting E2F6, indicating that miR-454 may be a potential diagnostic biomarker and therapeutic target for ovarian cancer. [ABSTRACT FROM AUTHOR]

MicroRNA-454 (miR-454), is involved in the progression of various types of cancers. The present study aimed to evaluate the effect of miR-454 on the progression of gastric cancer. SGC-7901 cells overexpressing or silencing miR454 were constructed via transfection and the survival rate of the cells was determined. The relationship between miR-454 and cylindromatosis (CYLD) was explored and the influence of miR-454 on oxaliplatin resistance was investigated in SGC-7901 cells. It was determined that overexpression of miR-454 increased the number of colonies and reduced apoptosis rate of SGC-7901 cells. The CYLD gene was identified as a direct target of miR-454. miR-454 overexpression downregulated the expression of CYLD, leading to an increase in SGC-7901 cell proliferation. Finally, miR-454 was also demonstrated to induce resistance to oxaliplatin in gastric cancer cells. In conclusion, the present in vitro findings suggested that miR-454 might be a novel therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Aberrant miRNAs expression regulates the occurrence and progression of a variety of cancers, including oral squamous cell carcinoma (OSCC). This study aims to illustrate the potential effects of miR-454/nuclear receptor subfamily 3 group C member 2 (NR3C2) on the biological behaviors of OSCC cells.Methods: GEO database was applied to detect and analyze the expression of miR-545 and NR3C2 in OSCC tissues. Two OSCC cell lines including CAL27 and Tca-83 were utilized to determine the function of miR-454/NR3C2 on OSCC cells biological behaviors. miR-454 and NR3C2 expressions were regulated by miR-454 mimic/inhibitor and pcDNA3.1-NR3C2/si-NR3C2, respectively. Cells biological behaviors were evaluated by cell proliferation, colony formation, and transwell assays.Results: The data collected from GEO database indicated that miR-454 expression was upregulated in OSCC tissues; however, the expression of NR3C2 assumed a downward trend. In vitro experiments, the expression trend of miR-454 in OSCC cell lines was consistent with that of the trend in tissues, and the OSCC cells growth and movement abilities significantly decreased after miR-454 depletion. Through co-transfection experiments, we explored that the abilities of OSCC cell proliferation, colony formation, invasion, and migration obviously reduced after miR-454 depletion, but these phenomena were mitigated to some extent after NR3C2 silencing.Conclusion: The study illustrates that miR-454 acts as an active regulator to facilitate OSCC cells growth, colony formation, invasion, and migration by targeting NR3C2, which may afford a novel perspective and possibility for the targeted treatment of OSCC. [ABSTRACT FROM AUTHOR]

Abstract Background Altered microRNAs expression mediates tumor development and progression in many type cancers including triple negative breast cancer (TNBC). Here we detected the effect of miR-454 on cell proliferation, migration and invasion of triple negative breast cancer cells. Results miR-454 promoted the proliferation of TNBC, and enhanced migration and invasion in TNBC cells. Meanwhile, miR-454 improved the survival of TNBC cells after ironizing radiation. miR-454 inhibited radiation-induced apoptosis in TNBC cells by regulation of caspase 3/7 and Bcl-2 expression. Furthermore, PTEN and pAKT levels in TNBC cells were changed after overexpression of miR-454. Conclusions miR-454 played an essential role in tumor development and progression in TNBC, and might be used as a potential biomarker to predict radiotherapy response and prognosis in TNBC.

Triple-negative breast cancer (TNBC) is a one of the subtypes of breast cancer which accounts for approximately 10–20% of all breast cancers. LncRNA XIST (XIST) is reported to be dysfunctional in numerous tumor types and is involved in the key pathways of cancer initiation, progression and metastasis. Thus, in the present study, we explored the detailed molecular mechanism of XIST in TNBC. XIST was down-regulated in TNBC tissues and cell lines. Overexpressed XIST inhibited cell proliferation, epithelial mesenchymal transition (EMT) and induced apoptosis in vitro as well as suppressed TNBC tumor growth in vivo. MicroRNA (miR)-454 was up-regulated in TNBC tissues and cell lines. Knockdown of miR-454 inhibited TNBC progression by suppressing cell proliferation, EMT and inducing cell apoptosis. Moreover, miR-454 was predicted and confirmed to be a target of XIST, and rescue assay indicated that overexpressed miR-454 could reverse XIST restoration mediated-anti-tumor effects on TNBC cells. In conclusion, XIST interacts with miR-454 to inhibit cells proliferation, EMT and induce apoptosis in TNBC, indicating a promising treatment strategy for TNBC patients. [ABSTRACT FROM AUTHOR]

Abstract Triglycerides account for 99% of milk fat and play a central role in determining dairy product quality. Many factors influence triglyceride synthesis and milk fat secretion. MicroRNAs have been verified to be involved in numerous biological processes, but little is known about their roles in milk fat biosynthesis. In this study, we aim to explore whether miR-454 could regulate triglyceride synthesis in bovine mammary epithelial cells (BMECs) by targeting PPAR-γ. A luciferase reporter assay showed that the predicted target site was correct and that miR-454 and PPAR-γ had a direct interaction. In addition, miR-454 mimics and inhibitors were transfected into BMECs. The results showed that both the mRNA and protein levels of PPAR -γ were negatively correlated with miR-454 expression. Fat droplet accumulation and triglyceride production were also inversely correlated with miR-454 expression. Our results indicate that miR-454 regulates triglyceride synthesis by directly targeting the PPAR-γ 3′ UTR in BMECs, suggesting that miR-454 could potentially be a new factor to elevate dairy product quality. Highlights • PPAR-γ is a target gene of miR-454 in bovine mammary epithelial cells. • miR-454 reduced the mRNA and protein expression levels of PPAR-γ. • miR-454 suppresses lipogenesis in bovine mammary epithelial cells. [ABSTRACT FROM AUTHOR]

As is known, hepatic stellate cells (HSCs) activation contributes to liver cirrhosis. This study aims to find out the acting mechanisms of miR-454 inhibiting the activation and proliferation of hepatic stellate cells. The expression of Col1A1, α-smooth muscle actin (α-SMA) and Wnt10a were determined by western blot, and the miR-454 level was determined by quantitative real-time PCR in this study. We took two objects as experiment subjects, one was liver cirrhosis rats, and the other was transforming growth factor (TGF)-β1-stimulated HSC-T6 cells. After activated with TGF-β1 and transfected with microRNA-454 mimic, separately or successively, the changes on the Col1A1 and α-SMA expression, HSC proliferation, miR-454 level and Wnt10a expression were examined in HSC-T6 cells, respectively. Interaction between miR-454 and Wnt10a was evaluated with dual luciferase reporter assay. MiR-454 expression was down-regulated in tissues of liver cirrhosis rats. TGF-β1 caused the down-regulation of the miR-454 in HSC-T6 cells. MiR-454 inhibited the activation and proliferation of HSC-T6 cells. Wnt10a had a targeting relationship with miR-454. TGF-β1 promoted HSC-T6 activation and proliferation via down-regulating miR-454 expression, which further up-regulated Wnt10a expression. MiR-454 mimic inhibited cirrhosis progression in liver cirrhosis rats. MiR-454 can inhibit the activation and proliferation of HSCs via suppressing the expression of Wnt10a, to restrain liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.

Abstract MicroRNAs (miRNAs) are emerging as important regulators in the pathogenesis of pre-eclampsia (PE). Recent evidence has reported that miR-454 plays an important role in regulating cell proliferation and invasion. The decreased proliferation and invasion of trophoblast cells contribute to the pathogenesis of PE. However, whether miR-454 is involved in the regulation of trophoblast cell proliferation and invasion remains unknown. In this study, we aimed to investigate the potential role and underlying mechanism of miR-454 in regulating trophoblast cell proliferation and invasion in vitro. We found that miR-454 expression was significantly decreased in placental tissues from PE patients compared to controls. Transfection of miR-454 mimics promoted the proliferation, reduced the apoptosis, and increased invasion of trophoblast cells, while transfection of miR-454 inhibitor showed opposite effects. Bioinformatics analysis showed that activin receptor-like kinase 7 (ALK7) was a potential target gene of miR-454. Dual-luciferase reporter assay showed miR-454 directly targeted the 3′-untranslated region of AKL7. Further experiments showed that miR-454 negatively regulated ALK7 expression. Interestingly, transfection of miR-454 mimics significantly abrogated the inhibitory effect of Nodal on trophoblast cell proliferation and invasion. Moreover, overexpression of ALK7 markedly reversed the promotion effect of miR-454 on trophoblast cell proliferation and invasion. Overall, our results suggest that miR-454 promotes the proliferation and invasion of trophoblast cells by downregulation of ALK7. Our study suggests that miR-454 may play critical roles in the pathogenesis of PE and serve as a potential therapeutic target for treatment of PE. Graphical abstract Image 1 Highlights • miR-454 appears to be decreased in placental tissues from PE patients. • miR-454 may regulate trophoblast cell proliferation and invasion. • miR-454 targets ALK7 3′-UTR and regulates its expression. • miR-454 may regulate Nodal signaling in trophoblast cells via AKL7. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • miR-454 is downregulated in placental tissues from PE patients. • miR-454 promotes the proliferation and invasion of trophoblast cells. • miR-454 targets EPHB4 3'-UTR and regulates its expression. • miR-454 regulates trophoblast cell proliferation and invasion by EPHB4. Abstract Preeclampsia (PE) is a pregnancy-specific disorder representing a major cause for maternal and perinatal morbidity and mortality. The dysfunction of trophoblast cells plays an important role in the pathogenesis of PE. In recent years, microRNAs (miRNAs) have been suggested to play an important role in regulating trophoblast cell biological functions involved in the pathogenesis of PE. Accumulating evidence has showed that miR-454 plays an important role in regulating cell functions. However, whether miR-454 is involved in regulating cell functions of trophoblast cells during PE remains unclear. In this study, we found that miR-454 expression was significantly downregulated in placental tissues from PE patients. in vitro experiments showed that miR-454 overexpression significantly increased proliferation, inhibited apoptosis, and promoted invasion of trophoblast cells, whereas miR-454 inhibition markedly suppressed proliferation, increased apoptosis, and inhibited invasion of trophoblast cells. Interestingly, bioinformatics analysis predicted that ephrin receptor B4 (EPHB4), an important gene for regulating trophoblast cell function in PE, was a potential target gene of miR-454. Dual-luciferase reporter assay showed that miR-454 directly targeted the 3'-untranslated region of EPHB4. Real-time quantitative polymerase chain reaction and Western blot analysis demonstrated that miR-454 negatively regulated EPHB4 expression in trophoblast cells. Moreover, miR-454 expression was found inversely correlated with EPHB4 expression in placental tissues from PE patients. Importantly, EPHB4 overexpression partially reversed the promotion effect of miR-454 overexpression on trophoblast cell proliferation and invasion. Taken together, these findings demonstrate that miR-454 promotes the proliferation and invasion of trophoblast cells by inhibiting EPHB4 expression, and the decreased miR-454 expression may contribute to PE by promoting EPHB4 expression. Our study provides novel insights into understanding the molecular pathogenesis of PE. [ABSTRACT FROM AUTHOR]

Abstract Background In the process of hepatic fibrosis, hepatic stellate cells (HSCs) can be activated by many inflammatory cytokines. The transforming growth factor-β1 (TGF-β1) is one of the main profibrogenic mediators. Recently, some studies have also shown that microRNAs (miRNAs) play essential roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs. Methods The expression of miR-454 in LX-2 cells treated with TGF-β1 and in the fibrotic livers with Schistosoma japonicum infection was detected by qRT-PCR. The role of miR-454 on LX-2 cells was then analyzed by Western blot, flow cytometry and luciferase assay. Results The results showed that the expression of miR-454 was down-regulated in the TGF-β1-treated LX-2 cells and miR-454 could inhibit the activation of HSCs by directly targeting Smad4. However, we found that miR-454 had no effect on cell cycle and cell proliferation in TGF-β1-treated LX-2. Besides these, miR-454 was found to be regulated in the process of Schistosoma japonicum infection. Conclusions All the results suggested that miR-454 could provide a novel therapeutic approach for treating liver fibrosis, especially the liver fibrosis induced by Schistosoma japonicum.

MicroRNA-454 (miR-454) is emerging as critical regulator in tumorigenesis; it may function as an oncogene or a tumor suppressor. However, the role of miR-454 in prostate cancer remains unknown. In this study, we aimed to investigate the function and molecular mechanisms of miR-454 in prostate cancer. We found that miR-454 was highly expressed in prostate cancer tissues and cell lines (*p < 0.05), as detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 assay, colony formation assay and cell invasion assay showed that the inhibition of miR-454 significantly suppressed prostate cancer cell proliferation and invasion (*p < 0.05), whereas the overexpression of miR-454 markedly promoted prostate cancer cell proliferation and invasion (*p < 0.05). Bioinformatics analysis showed that N-myc downstream-regulated gene 2 (NDRG2), a well-known tumor suppressor, was identified as a potential target gene of miR-454. Dual-luciferase reporter assay showed that miR-454 directly targeted the 3′-untranslated region of NDRG2. RT-qPCR and western blot showed that miR-454 overexpression significantly decreased NDRG2 expression (*p < 0.05), whereas miR-454 inhibition markedly promoted NDRG2 expression (*p < 0.05). Spearman’s correlation analysis showed that miR-454 expression was inversely correlated with NDRG2 expression in prostate cancer tissues ( r = −0.8932; p < 0.0001). Moreover, miR-454 inhibition significantly suppressed the protein expression of β-catenin (*p < 0.05) and blocked the activation of WNT signaling (*p < 0.05). In addition, small interfering RNA mediated NDRG2 knockdown significantly reversed the antitumor effect of miR-454 inhibition on prostate cancer cell proliferation and invasion (*p < 0.05). Taken together, these results reveal an oncogenic role of miR-454, which promotes prostate cancer cell proliferation and invasion by downregulation of NDRG2. These results also suggest miR-454 as a potential therapeutic target for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose MicroRNA-454 has been proven dysregulated in some human malignancies and correlated with tumor progression. However, its expression and function in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to explore the effects of miR-454 in NSCLC tumorigenesis and development. Methods Using quantitative RT-PCR, we detected miR-454 expression in NSCLC cell lines and primary tumor tissues. The association of miR-454 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-454 on the biological behavior of NSCLC cells were investigated. At last, the potential regulatory function of miR-454 on PTEN expression was confirmed. Results miR-454 was found to be up-regulated in NSCLC tissues and cell lines. High miR-454 expression was closely correlated with lymph node metastasis, advanced TNM stage, and shorter overall survival. Multivariate regression analysis corroborated that miR-454 overexpression was an independent unfavourable prognostic factor for patients with NSCLC. Down-regulation of miR-454 could significantly reduce NSCLC cell proliferation, enhance cell apoptosis, and impair cell invasion and migration in vitro, while up-regulation of miR-454 showed opposite effects. Further, PTEN was confirmed as a direct target of miR-454 by using Luciferase Reporter Assay. Conclusions These findings indicate that miR-454 may act as an oncogene in NSCLC and would serve as a potential therapy target for this disease. [ABSTRACT FROM AUTHOR]

Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI. © 2016 The Author(s) Published by S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It has been well documented that aberrant expression of microRNAs is associated with carcinogenesis of glioblastoma (GBM), however the underlying mechanisms are not clear. In this present study, we aimed to clarify the biological function of miR-454 in GBM. MiR-454 was identified to be significantly down-regulated in GBM primary tumors and cell lines. Overexpression of miR-454 in GBM cells resulted in arresting cells at G 0 /G 1 phase and thus inhibiting cell proliferation. Bioinformatic analysis predicted 3-phosphoinositide-dependent protein kinase-1 (PDK1) as a target of miR-454 which acted as a tumor promoter gene. Increased miR-454 significantly repressed PDK1 expression, and then regulating cell proliferation and cell cycle regulators, down-regulation of Cyclin D1 and p-pRb and p21 was up-regulated. Taken together, our study has revealed miR-454 as a tumor suppressor in GBM. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) regulate gene expression by targeted repression of transcription and translation, and are involved in carcinogenesis. In this study, we demonstrated that the expression of miR-454 was up-regulated in uveal melanoma tissues compared to normal tissues. Ectopic expression of miR-454 resulted in significant promotion of cell proliferation, colony formation, invasion and induction of cell cycle in uveal melanoma cells. Furthermore, we identified PTEN as a direct target of miR-454. Our data revealed that ectopic expression of PTEN restored the effects of miR-454 on cell proliferation and invasion in uveal melanoma cells. These findings support an oncogene role of miR-454 in development of uveal melanoma. [ABSTRACT FROM AUTHOR]

Recent advances in high-throughput screening of human tumors have enabled the identification of numerous tumor markers. However, the clinical utility of these newly identified molecules remains enigmatic until they are well validated in patient samples. Although many long non-coding RNA molecules of clinical importance have been identified in the differential diagnosis of prostate cancer, the consistency of many of them in practice is still controversial. Therefore, short non-coding RNA molecules such as miRNAs are coming to the forefront in the differential diagnosis of the disease because of their stability. Accordingly, in the present study, we aimed to reveal the clinical significance of miR-130a, miR-301a, miR-454 expression levels in formalin fixed paraffin embedded (FFPE) tissue samples of prostate cancer patients. miRNA expression signatures were determined by RT-qPCR method. Notably, we found that miR-301a and miR-454 were significantly upregulated whereas miR-130a were downregulated in cancerous tissues of prostate cancer patients compared to adjacent healthy tissue samples. Moreover, differential expression of these miRNAs was significantly associated with patients' clinicopathological findings, such as Gleason score, lymphovascular invasion, perineural invasion, and extra-prostatic extension. Collectively, our observations indicate that these miRNAs may be of clinical importance in the differential diagnosis of prostate cancer. [ABSTRACT FROM AUTHOR]

Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response. [ABSTRACT FROM AUTHOR]

Renal cell cancer (RCC) is one of the most common malignant tumors of the urinary system. MicroRNA-454 (miR-454) has been reported to play an important role in various cancer progressions, such as hepatocellular carcinoma, breast cancer and glioblastoma. Nevertheless, its effect on RCC still remains unknown. We aimed to investigate the biological function and underlying mechanisms of miR-454 in RCC. The expressions of miR-454 and MECP2 in RCC tissues were assessed using data from TCGA database and our own clinical samples. Functional experiments Cell Counting Kit-8 (CCK-8), colony formation, wound healing and Transwell assays were applied to detect the effects of miR-454 and MECP2 in RCC. The interaction between miR-454 and MECP2 was assessed by western blot and luciferase reporter assays. MiR-454 was upregulated in RCC tissues and cell lines compared with matched adjacent normal tissues and the normal kidney tubular epithelial cell line HK-2. MiR-454 inhibition and methyl-CpG binding protein 2 (MECP2) overexpression could both decrease the proliferative, migrative and invasive abilities of RCC cells. Higher expression of miR-454 predicted a poor overall survival (OS) (HR: 1.8; P < 0.05), while MECP2 level was positively related with RCC OS (HR: 0.55; P < 0.05) and disease-free survival (HR: 0.56; P < 0.05). Mechanistically, we showed that miR-454 could directly target the downstream gene MECP2 . Our findings indicated that miR-454 accelerates RCC progression via suppressing MECP2 expression, which may provide a novel potential target of RCC treatment in the future., Competing Interests: None., (AJTR Copyright © 2020.)

Previous studies showed that miR-454 acted as an oncogene or tumor suppressor in cancer. However, its function in HCC remains unknown. In this study, we found that miR-454 expression was upregulated in HCC cell lines and tissues. Knockdown of miR-454 inhibited HCC cell proliferation and invasion and epithelial mesenchymal transition (EMT), whereas overexpression of miR-454 promoted HCC cell proliferation and invasion and EMT. Furthermore, we identified the CHD5 as a direct target of miR-454. CHD5 was downregulated in HCC tissues and cell lines and the expression level of CHD5 was inversely correlated with the expression of miR-454 in HCC tissues. In addition, knockdown of miR-454 inhibited the growth of HepG2-engrafted tumors in vivo. Taken together, these results indicated that miR-454 functioned as an oncogene in HCC.