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Background: Glioma is a heterogeneous aggressive tumor. Ropivacaine, a widely used anesthetic, has been shown to repress the progression of multiple cancers, including glioma. In this study, the effects of ropivacaine on cell proliferation, migration, invasion and apoptosis in glioma were revealed., Methods: The expression levels of circSCAF11 and miR-145-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in glioma tissues and cells. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins were determined by Western blot. Oxidative stress was evaluated by the measurement of reactive oxygen species (ROS) and determination of mitochondrial 8-hydroxy-2-deoxyguanosine (8-OHdG) assay in glioma cells. Cell proliferation was determined by cell counting kit-8 (CCK-8) assay and cell colony formation assay. Cell apoptosis and metastasis were detected by flow cytometry analysis and transwell assay, respectively. The binding relationship between circSCAF11 and miR-145-5p was predicted by circular RNA Interactome and identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. In vivo tumor formation assay was performed to reveal the effects between ropivacaine and circSCAF11 overexpression on tumorigenesis in vivo., Results: CircSCAF11 expression was obviously upregulated and miR-145-5p was significantly downregulated in glioma tissues and cells compared with control groups. Ropivacaine treatment upregulated E-cadherin protein expression and repressed the protein expression of Vimentin. Functionally, ropivacaine exposure promoted ROS and 8-OHdG production and cell apoptosis, whereas inhibited cell proliferation, migration and invasion; however, these effects were hindered by circSCAF11 overexpression. Mechanistically, circSCAF11 was a sponge of miR-145-5p. In addition, ropivacaine was revealed to inhibit tumor growth in vivo by regulating circSCAF11 and miR-145-5p expression., Conclusion: Ropivacaine suppressed glioma progression by regulating circSCAF11 and miR-145-5p, which might provide a theoretical foundation in glioma treatment., Competing Interests: The authors declare that they have no financial or non-financial conflicts of interest for this work., (© 2020 Yin et al.)

Increasing circular RNAs (circRNAs) have been reported to act as key players in human malignancies. However, the expression, role, and mechanism of circRNAs in HCC are not well elucidated. In this study, some differentially expressed circRNAs (DECs) between hepatocellular carcinoma (HCC) and normal tissues were identified using three circRNA microarrays (Gene Expression Omnibus [GEO]: GSE78520, GSE94508, and GSE97332). Twenty-one DECs were found to be commonly upregulated in all the three datasets. Among the 21 DECs, hsa_circ_0001955 ranked as the top three most upregulated DECs in GEO: GSE78520, GSE94508, and GSE97332. Moreover, hsa_circ_0001955 expression in HCC cells and tissues was significantly higher than that in corresponding normal controls. Functional experiments revealed that knockdown of hsa_circ_0001955 markedly inhibited proliferation, migration, and invasion of HCC, and its overexpression led to the opposite effects. hsa_circ_0001955 was mainly located in the cytoplasm, in which hsa_circ_0001955 could directly bind to miR-145-5p. miR-145-5p was downregulated in HCC, and its expression was negatively linked to hsa_circ_0001955 expression. Furthermore, we identified that NRAS was a downstream direct target of the hsa_circ_0001955/miR-145-5p axis in HCC. Collectively, our findings demonstrate the oncogenic roles of the hsa_circ_0001955/miR-145-5p/NRAS axis in HCC, which may represent a potential therapeutic target for HCC., (© 2020 The Authors.)

Sorafenib resistance and tumor metastasis account for poor outcome of hepatocellular carcinoma (HCC). Histone deacetylase 11 (HDAC11) has been reported to exert oncogenic effects in several types of human cancer, but its specific functions and detailed mechanisms in HCC are not fully elucidated. Here we identified HDAC11 as a potential oncogene and promising biomarker in HCC by in silico analysis. Histone deacetylase 11 was upregulated in sorafenib-resistant SMMC7721 compared with its parental cell. Knockdown of HDAC11 suppressed proliferation and sorafenib resistance, which may be due to inhibition of drug metabolism cytochrome P450 predicted by gene-set enrichment analysis. Histone deacetylase expression was higher in highly metastatic MHCC97H than lowly metastatic MHCC97L. Downregulation of HDAC11 significantly attenuated the migrated and invaded abilities of HCC cells. Histone deacetylase 11 was directly targeted and suppressed by miR-145-5p. Inhibition of miR-145-5p enhanced sorafenib resistance and metastasis of HCC, and these effects could be attenuated by knockdown of HDAC11. The promoter methylation level of HDAC11 was markedly decreased in HCC tissues compared with normal controls. Administration of 5'-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, facilitated HDAC11 expression in HCC cells. Our data indicate a role of miR-145-5p/HDAC11 axis in regulation of sorafenib resistance and metastasis in HCC., (Copyright © 2020 Wang, Ding, Lou and Lin.)

An increasing number of studies have demonstrated that circular RNAs (circRNAs), as promising therapeutic targets, are essential for diverse human diseases, especially cancer. However, the potential functions and complex mechanisms of most circRNAs in osteosarcoma (OS) are still not fully elucidated. In the present study, we obtained the expression profile of circRNAs from a GEO database (GSE96964) and identified hsa_circ_0000073 as a highly expressed candidate in OS. Overexpression of hsa_circ_0000073 accelerated the proliferation, migration, invasion and MTX resistance of OS cells, and knockdown of hsa_circ_0000073 resulted in the opposite effects. Mechanistically, hsa_circ_0000073 upregulated NRAS expression by targeting miR-145-5p and miR-151-3p in OS cells. In addition, the promotion of OS progression by hsa_circ_000007 was blocked by miR-145-5p and miR-151-3p-mediated NRAS inhibition. In conclusion, hsa_circ_0000073 facilitated the proliferation, migration, invasion and MTX resistance of OS cells through the inhibition of miR-145-5p and miR-151-3p-mediated downregulation of NRAS.

In recent years, circular RNAs (circRNAs) have been increasingly reported to play a crucial role in the proliferation, migration, and invasion of non-small-cell lung cancer (NSCLC) cells. However, the circRNA MET (circMET) oncogenic mechanism that drives NSCLC development and progression remains largely unknown. In this study, the present results demonstrated that circMET expression was significantly higher in NSCLC tissues than in peritumoral tissues using quantitative real-time polymerase chain reaction. Notably, NSCLC patients with a large tumor diameter, poor differentiation and lymphatic metastasis had high RNA levels of circMET. Moreover, high circMET expression served as an independent risk factor for short overall survival (OS) and progression-free survival (PFS) in NSCLC patients. Next, we validated that circMET overexpression can enhance NSCLC cell proliferation, metastasis, and immune evasion in vitro. Mechanistically, our study uncovers that circMET acts as a miR-145-5p sponge to upregulate CXCL3 expression. Collectively, circMET regulates the miR-145-5p/CXCL3 axis and serves as a novel, promising diagnostic and prognostic biomarker in patients with NSCLC.

Background: Screening for colorectal carcinoma (CRC) lacks an efficient, inexpensive and noninvasive approach. The stable presence of serum miRNA is expected to become a new diagnostic marker. Materials & methods: Based on 135 CRC patients and 135 normal controls, this study was conducted in three phases to identify suitable serum miRNA for CRC diagnosis by using quantitative reverse transcription PCR. Bioinformatic assays were used for target genes prediction and functional annotation. Results: Serum expression level of seven miRNAs were significantly different between CRC patients and the normal controls. The final diagnostic panel (area under the curve = 0.893; sensitivity = 81.25%, specificity = 73.33%) consists of miR-203a-3p, miR-145-5p, miR-375-3p and miR-200c-3p. Conclusion: The four-miRNA panel may serve as a novel, noninvasive biomarker for CRC diagnosis and screening.

Aim: Exosome-derived microRNAs (miRNAs) are potential diagnostic biomarkers. However, little is known about their effectiveness as diagnostic biomarkers of intracranial aneurysms (IAs). This study aimed to explore miRNA levels in plasma exosomes of patients with IA to identify potential biomarkers that predict the development and progress of IA., Methods: A total of 69 patients with IA and 30 healthy controls (HC) were recruited, among whom 30 had unruptured IA (UA), and 39 had ruptured IA (RA). The miRNA expression profiles of plasma exosomes in 12 IA patients (4 UA and 8 RA) and 4 HC were determined using next-generation sequencing. In addition, significantly differentially expressed miRNAs were further analyzed by Quantitative Real-Time PCR (qRT-PCR) in a validation cohort of 99 subjects., Results: From the sequencing analysis, 181 miRNAs were identified to be differently (p＜0.05) expressed. Of these, 9 miRNAs were up-regulated, and 20 were down-regulated in patients with UA compared with HC. Also, 21 were up-regulated, and 10 were down-regulated in patients with RA compared with HC. In addition, compared with UA, 92 miRNAs were up-regulated in RA, whereas 29 were down-regulated. Furthermore, qRT-PCR analysis confirmed that miR-145-5p and miR-29a-3p were up-regulated in IA samples. To distinguish IA patients from controls, the area under the receiver operating characteristic curve was 0.791 for miR-29a-3p, while that of miRNA-145-5p was 0.773 in terms of discriminating whether the aneurysm was ruptured., Conclusions: Circulating exosomal miRNAs can serve as biomarkers of the development and progression of IA.

Background: Periodontitis is the second most common dental disease worldwide. TNF-α is up-regulated in periodontal disease and induces inflammation and cell apoptosis in gingival epithelial cells (GECs). miRNAs/mRNA axis play an important role in cell progression and inflammation. However, studies on the pathogenesis of periodontitisare still scarce, especially in the regulation mechanism of miRNAs., Methods: The expression and protein level of miR-16-5p, miR-145-5p, BACH2, and caspase 3 were determined by quantitative real time PCR and western blot, respectively. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Dual-luciferase assay was applied to verify miR-16-5p and miR-145-5p target to the 3'UTR of BACH2., Results: TNF-α induced miR-16-5p, miR-145-5p and caspase 3 expression, inhibited cell viability, promoted cell apoptosis in GECs. However, down-regulated miR-16-5p and miR-145-5p can restore the effects of TNF-α on GECs. In addition, dual-luciferase assay determined that BACH2 was a common target of miR-16-5p and miR-145-5p. Knockdown of BACH2 induced GECs apoptosis. Of note, cell apoptosis induced by miR-16-5p mimic, miR-145-5p mimic, and TNF-α was significantly reversed by up-regulating BACH2., Conclusion: miR-16-5p and miR-145-5p mediate apoptosis induced by TNF-α in human gingival epithelial cells by targeting BACH2., Competing Interests: None., (IJCEP Copyright © 2020.)

Objective: To investigate the role of microRNA-145-5p (miR-145-5p) in regulating the proliferation, migration, invasion and apoptosis of human endometrial carcinoma cells., Methods: Human endometrial carcinoma Ishikawa cells were transfected with miR-145-5p mimic, miR-145-5p inhibitor, or their negative controls via liposome (Lipo2000), and the changes in the expression of miR-145-5p was verified by real-time PCR. The effects of overexpression or inhibition of miR-145-5p on the proliferation, migration, invasion and apoptosis of the cells were evaluated using MTT assay, wound healing assay, Transwell assay or flow cytometry. Bioinformatic analysis was performed to predict the target genes of miR-145-5p. The mRNA and protein expression levels of the downstream target of miR-145-5p, namely dual specific phosphatase 6 (DUSP6), were detected using real-time PCR and Western blotting., Results: Transfection of the cells with miR-145-5p mimic significantly suppressed the proliferation of Ishikawa cells, while transfection with miR-145-5p inhibitor obvious enhanced the proliferation of the cells ( P < 0.05). Over-expression of miR-145-5p significantly suppressed the migration and invasion and promoted apoptosis of the cells, and inhibition of miR-145-5p caused the reverse changes ( P < 0.05). Bioinformatic analysis showed that DUSP6 was the potential target gene of miR-145-5p. Over-expression of miR-145-5p significantly lowered while inhibition of miR-145-5p significantly enhanced the expression of DUSP6 protein ( P < 0.05)., Conclusions: Overexpression of miR-145-5p inhibits the proliferation, migration and invasion and promotes apoptosis of endometrial cancer cells possibly by negative regulation of DUSP6 expression.

Background: LncRNA cancer susceptibility candidate 9 (CASC9) is up-regulated in various cancers. In this study, we explored the role of CASC9 in colon cancer (CC)., Methods: The level of CASC9 in CC tissues, adjacent normal tissues, intestinal epithelial cells (HIEC) and CC cell lines was evaluated by qRT-PCR. HCT116 and SW480 CC cells were transfected with siCASC9. The cell growth and cell proliferation makers (Ki-67 and PCNA) were detected by CCK-8, colony formation and western blotting, respectively. The cell apoptosis and cell cycle were determined by flow cytometry. MicroRNA sponged by CASC9 was predicted by starBase and verified by dual-luciferase reporter assay. Further analyses were performed to investigate the role of CASC9 sponging the microRNA in CC cells by transfection or co-transfection of siCASC9 and miR-145-5p inhibitor., Results: LncRNA CASC9 was high-expressed in CC cells and tissues, especially in CC at advanced TNM stages. In HCT116 and SW480 cells, knockdown of CASC9 suppressed cell proliferation, promoted cell apoptosis and arrested cell cycle at G0/G1 phase. Furthermore, CASC9 was observed to sponge and regulate the expression of miR-145-5p, which was down-regulated in CC tissues. Moreover, increased cell proliferation and decreased cell apoptosis and arrested cell cycle caused by miR-145-5p inhibitor were abrogated by the knockdown of CASC9., Conclusions: LncRNA CASC9 is an oncogene in CC cells through sponging miR-145-5p. The findings in the current study provide a new understanding on CASC9 in CC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.10.33). The authors have no conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

Laryngocarcinoma is the most common head and neck cancer and has a high incidence and mortality, causing about 83 000 deaths per year worldwide. Our research aimed to investigate the possible role of long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) in laryngocarcinoma development. The messenger RNA (mRNA) levels of TUG1 in tumor tissues and control (plasma) samples of laryngocarcinoma patients as well as in laryngocarcinoma cells were detected. The influences of TUG1 suppression on cell biological processes (viability, apoptosis, migration, and invasion) and cytoskeleton rearrangement in laryngocarcinoma cells were tested. Moreover, we investigated the regulatory interaction between TUG1 and miR-145-5p, and identified the target gene of miR-145-5p. The association between TUG1 and the protein expressions of RhoA/rho associated coiled-coil containing protein kinase (ROCK)/matrix metalloproteinases (MMPs) pathway-associated factors were detected. TUG1 was found to be highly expressed in tumor tissues and plasma samples of laryngocarcinoma patients as well as in laryngocarcinoma cells. Suppression of TUG1 decreased laryngocarcinoma cell viability, increased apoptosis, and suppression migration, invasion, and cytoskeleton rearrangement. Moreover, TUG1 negatively regulated miR-145-5p. TUG1 regulated tumor growth (viability and apoptosis) and metastasis through miR-145-5p. Furthermore, ROCK1 was targeted by miR-145-5p, and miR-145-5p/ROCK1 partner was involved in the process of tumor growth and metastasis. Finally, we found that TUG1 functioned on laryngocarcinoma by activating RhoA/ROCK/MMPs pathway. Our study reveals that lncRNA TUG1 is upregulated in laryngocarcinoma and may be involved in the process of laryngocarcinoma through miR-145-5p downregulation and activating the RhoA/ROCK/MMPs signals., (© 2019 Wiley Periodicals, Inc.)

MicroRNA-145-5p downregulation has been shown to play important roles in the oncogenesis and progression of many cancer types including glioblastoma (GBM). However, the potential role of serum miR-145-5p in the diagnosis and prognosis of glioblastoma (GBM) remains poorly known. This study was designed to explore the clinical significance of serum miR-145-5p in patients with GBM. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was carried out to measure the serum levels of miR-145-5p in 117 GBM patients, 52 grade I/II glioma patients and 50 healthy volunteers. The associations between serum miR-145-5p level and the clinical variables as well as prognosis were analyzed. The bioinformatic analysis of the downstream targets of miR-145-5p was also performed. Compared to grade I/II glioma patients and healthy controls, serum miR-145-5p levels were significantly decreased in GBM patients. In addition, the receiver operating characteristic (ROC) analysis demonstrated that serum miR-145-5p might be a reliable diagnostic marker of GBM with an AUC of 0.895, combing with 84.6% sensitivity and 78.0% specificity. Low serum miR-145-5p level had significant correlation with aggressive clinicopathological parameters. Moreover, the Kaplan-Meier curve revealed that patients in the high serum miR-145-5p group survived significantly longer than those in the low serum miR-145-5p group. Multivariate analysis confirmed that serum miR-145-5p expression was an independent prognostic indicator for overall survival. The bioinformatic analysis revealed that many downstream genes and pathways that miR-145-5p regulated were closely associated with the initiation and development of cancer. Taken together, decreased serum miR-145-5p is a promising diagnostic and prognostic biomarker for GBM., Competing Interests: None., (IJCEP Copyright © 2019.)

Acute lung injury (ALI) is a disease with high incidence and no effective therapeutic treatments. miR- 145-5p has been reported to be aberrantly expressed in lung injury tissues, suggesting a potential role in the progression and development of ALI. To validate this hypothesis and explore the underlying mechanism, a mouse model of ALI was established using lipopolysaccharide (LPS). Hematoxylin and eosin (Hand E) staining verified the successful establishment of mouse model with ALI. Levels of interleukin (IL)-1β, IL- 6, tumor necrosis factor α (TNF-α) and myeloperoxidase (MPO) were detected by both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Mouse type II alveolar epithelial cells (AT II) were isolated and treated with LPS. miR-145-5p was significantly down-regulated both in mice with acute lung injury and LPS-induced AT II cells. Dual luciferase assays confirmed miR-145-5p could target and regulate Toll Like Receptor 4 (TLR4). Further analysis showed that miR-145-5p overexpression decreased the expression levels of IL-1β, IL-6 and TNF-α in LPS-induced AT II cells. miR-145-5p overexpression also blocked the LPS-induced activation of nuclear factor kappa B (NF-κB) pathway and reactive oxygen species (ROS) accumulation in AT II cells. Finally, in ALI mouse model, miR-145-5p overexpression alleviated lung tissue injury, decreased the expression levels of IL-1β, IL-6 and TNF-α and reduced MPO activity. In conclusion, miR-145-5p participated in the progression and development of ALI by decreasing the production of pro-inflammatory cytokines, inhibiting NF-κB pathway and suppressing ROS accumulation, shedding light on miR-145-5p as a potential therapeutic target for the treatment of ALI., (Copyright 2019 Biolife Sas. www.biolifesas.org.)

Compelling evidence shows that deregulated microRNAs (miRNAs) are important regulators in the progression of melanoma. miR-145-5p has been suggested to exhibit antitumorigenic activity in melanoma. However, the molecular mechanism underlying the biological activity of miR-145-5p in melanoma remains to be further understood. Herein, quantitative real-time polymerase chain reaction was used to examine the miR-145-5p expression in malignant melanoma tissues and cells. The interaction between miR-145-5p and toll-like receptor 4 (TLR4) was explored by bioinformatics analyses, luciferase reporter assay, and Western blot. The effects of miR-145-5p or combined with TLR4 on cell proliferation, colony formation, migration, and invasion abilities were investigated by (4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, colony formation, wound healing, and transwell assays, respectively. The melanoma xenograft tumor models were established to determine the biological activity of miR-145-5p in melanoma in vivo. In addition, the changes of the nuclear factor kappa B (NF-κB) pathway were analyzed by detecting the NF-κB activity and the NF-κB p65 protein level. We observed that the miR-145-5p expression was underexpressed in melanoma tissues and cells. miR-145-5p suppressed the TLR4 expression by binding to its 3'untranslated region in melanoma cells. Moreover, TLR4 overexpression abolished the inhibition of cell proliferation, colony formation, migration, and invasion abilities induced by miR-145-5p in melanoma cells. Meanwhile, miR-145-5p was confirmed to restrain melanoma tumor growth in vivo by targeting TLR4. Furthermore, miR-145-5p overexpression inactivated the NF-κB pathway in melanoma in vitro and in vivo, which was reversed by TLR4 overexpression. We concluded that miR-145-5p hindered the occurrence and metastasis of melanoma cells in vitro and in vivo by targeting TLR4 via inactivation of the NF-κB pathway., (© 2019 Wiley Periodicals, Inc.)

Long non-coding RNA (LncRNA) BRE-AS1 has recently proven to be a tumor suppressor in lung cancer. The present study aimed to investigate the involvement of lncRNA BRE-AS1 in prostate carcinoma (PC). In the present study we found that plasma BRE-AS1 and miR-145-5p were both down-regulated in PC patients than in healthy controls. Down-regulation of BRE-AS1 and miR-145-5p effectively distinguished early-stage PC patients from healthy controls. A significant and positive correlation between BRE-AS1 and miR-145-5p was only found in PC patients. BRE-AS1 overexpression mediated miR-145-5p up-regulation in PC cells, while miR-145-5p overexpression did not significantly affect BRE-AS1. Overexpression of BRE-AS1 and miR-145-5p led to inhibited proliferation and promoted apoptosis of PC cells. miR-145-5p inhibitor attenuated the effects of BRE-AS1 overexpression on cancer cell behaviors. Therefore, lncRNA BRE-AS1 may regulate cancer cell proliferation and apoptosis in PC by interacting with miR-145-5p., (© 2019 The Author(s).)

Transforming growth factor β (TGF-β), signaling induced by cigarette smoke (CS), plays an important role in the progression of airway diseases, like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD), and in smokers. Chronic bronchitis is characterized by reduced mucociliary clearance (MCC). Cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in normal MCC. TGF-β and CS (via TGF-β) promote acquired CFTR dysfunction by suppressing CFTR biogenesis and function. Understanding the mechanism by which CS promotes CFTR dysfunction can identify therapeutic leads to reverse CFTR suppression and rescue MCC. TGF-β alters the microRNAome of primary human bronchial epithelium. TGF-β and CS upregulate miR-145-5p expression to suppress CFTR and the CFTR modifier, SLC26A9. miR-145-5p upregulation with a concomitant CFTR and SLC26A9 suppression was validated in CS-exposed mouse models. While miR-145-5p antagonism rescued the effects of TGF-β in bronchial epithelial cells following transfection, an aptamer to block TGF-β signaling rescues CS- and TGF-β-mediated suppression of CFTR biogenesis and function in the absence of any transfection reagent. These results demonstrate that miR-145-5p plays a significant role in acquired CFTR dysfunction by CS, and they validate a clinically feasible strategy for delivery by inhalation to locally modulate TGF-β signaling in the airway and rescue CFTR biogenesis and function., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Laryngeal squamous cell carcinoma (LSCC) is a common form of head and neck cancer with poor prognosis. However, the mechanism underlying the pathogenesis of LSCC remains unclear. Here, we demonstrated increased expression of fascin actin-bundling protein 1 (FSCN1) and decreased expression of microRNA-145-5p (miR-145-5p) in a clinical cohort of LSCC. Luciferase assay revealed that miR-145-5p is a negative regulator of FSCN1. Importantly, low miR-145-5p expression was correlated with TNM (tumor, node, metastasis) status and metastasis. Moreover, cases with low miR-145-5p/high FSCN1 expression showed poor prognosis, and these characteristics together served as independent prognostic indicators of survival. Gain- and loss-of-function studies showed that miR-145-5p overexpression or FSCN1 knockdown inhibited LSCC migration, invasion, and growth by suppressing the epithelial-mesenchymal transition along with inducing cell-cycle arrest and apoptosis. Additionally, hypermethylation of the miR-145-5p promoter suggested that repression of miR-145-5p arises through epigenetic inactivation. LSCC tumor growth in vivo could be inhibited by using miR-145-5p agomir or FSCN1 small interfering RNA (siRNA), which highlights the potential for clinical translation. Collectively, our findings indicate that miR-145-5p plays critical roles in inhibiting the progression of LSCC by suppressing FSCN1. Both miR-145-5p and FSCN1 are important potential prognostic markers and therapeutic targets for LSCC., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Micro-RNAs play critical roles in initiation and progression of hepatocellular carcinoma. However, the biological role of microRNA-145-5p in hepatocellular carcinoma and how it works are still not clearly understood. Expression levels of microRNA-145-5p in hepatocellular carcinoma cell lines were examined by reverse transcription quantitative polymerase chain reaction. Cell counting kit-8, wound-healing assay, and flow cytometry assay were conducted to investigate the role of microRNA-145-5p von proliferation, migration, and apoptosis. Luciferase reporter assay and Western blot were performed to investigate the correlation between microRNA-145-5p and RAB18. We found microRNA-145-5p was downregulated in hepatocellular carcinoma cell lines compared to the normal cell line. Overexpression of microRNA-145-5p inhibited the proliferation and migration but promoted apoptosis of hepatocellular carcinoma cells in vitro. RAB18 was validated a target of microRNA-145-5p and ectopic expression of RAB18 can promote the proliferation and migration but inhibit apoptosis of hepatocellular carcinoma cells. These findings indicate that microRNA-145-5p functions as a novel tumor suppressor through targeting RAB18, suggesting that microRNA-145-5p might be a potential new therapeutic molecule for the treatment of hepatocellular carcinoma.

The hsa-mir-483 gene, located within the IGF2 locus, transcribes for two mature microRNAs, miR-483-5p and miR-483-3p. This gene, whose regulation is mediated by the the CTNNB1/USF1 complex, shows an independent expression from its host gene IGF2. The miR-483-3p affects the Wnt/β-catenin, the TGF-β, and the TP53 signaling pathways by targeting several genes as CTNNB1, SMAD4, IGF1, and BBC3. Accordingly, miR-483-3p is associated with various tissues specific physiological properties as insulin and melanin production, as well as with cellular physiological functions such as wounding, differentiation, proliferation, and survival. Deregulation of miR-483-3p is observed in different types of cancer, and its overexpression can inhibit the pro-apoptotic pathway induced by the TP53 target effectors. As a result, the oncogenic characteristics of miR-483-3p are linked to the effect of some of the most relevant cancer-related genes, TP53 and CTNNB1, as well as to one of the most important cancer hallmark: the aberrant glucose metabolism of tumor cells. In this review, we summarize the recent findings regarding the miR-483-3p, to elucidate its functional role in physiological and pathological contexts, focusing overall on its involvement in cancer and in the TP53 pathway. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common types of tumors and the leading cause of cancer-associated mortality in the world. Additionally, non-small cell lung cancer (NSCLC) accounts for ~80% of all lung cancer cases. Epithelial-mesenchymal transition (EMT) is an important cell biological process, which is associated with cancer migration, metastasis, asthma and fibrosis in the lung. In the present study, it was revealed that miR-145-5p was able to suppress EMT by inactivating the c-Jun N-terminal kinase (JNK) signaling pathway in NSCLC cells. Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) was predicted and confirmed to be a novel target of miR-145-5p. Overexpression of MAP3K1 was able to reverse the inhibition of EMT induced by miR-145-5p via the JNK signaling pathway. Overall, the results revealed that miR-145-5p inhibits EMT via the JNK signaling pathway by targeting MAP3K1 in NSCLC cells.

Nurr1 is a member of the nuclear receptor 4 family of orphan nuclear receptors that is decreased in inflammatory responses and leads to neurons death in Parkinson's disease. Abnormal expression of Nurr1 have been attributed to various signaling pathways, but little is known about microRNAs (miRNAs) regulation of Nurr1 in ischemia/reperfusion injury. To investigate the post transcriptional regulatory networks of Nurr1, we used a miRNA screening approach and identified miR-145-5p as a putative regulator of Nurr1. By using computer predictions, we identified and confirmed a miRNA recognition element in the 3'UTR of Nurr1 that was responsible for miR-145-5p-mediated suppression. We next demonstrated that overexpression of Nurr1 inhibited TNF-α expression in microglia by trans-repression and finally attenuated ischemia/reperfusion-induced inflammatory and cytotoxic response of neurons. Results of further in vivo study revealed that anti-miR-145-5p administration brought about increasing expression of Nurr1 and reduction of infarct volume in acute cerebral ischemia. Administration of anti-miR-145-5p promotes neurological outcome of rats post MCAO/R. It might be an effective therapeutic strategy to relieve neurons injury upon ischemia/reperfusion of rats through interrupting the axis signaling of miR-145-5p- Nurr1-TNF-α in acute phase.

MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 ( CCNA2 ), cyclin D1 ( CCND1 ) and cyclin E1 ( CCNE1 ), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2 , MMP7 and MMP13 . Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 ( Sp1 ) and nuclear factor κ B ( NF-κB ) ( p65 ) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB ( p65 ). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB ( p65 ) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway., Competing Interests: The authors declare no conflict of interest.

MicroRNAs have been reported to be involved in various biological processes. Here, we performed a systematic analysis to explore the clinical value and potential molecular mechanism of miR-145-5p in non-small cell lung cancer. First, a meta-analysis was performed with eligible literature, followed by microRNA microarrays in the Gene Expression Omnibus database, to verify the diagnostic and prognostic values of miR-145-5p. A cohort of 125 clinical paired non-small cell lung cancer samples was next used to detect the level of miR-145-5p and to explore the relationship of miR-145-5p with clinicopathological parameters. The Cancer Genome Atlas database was additionally applied to investigate the role of miR-145-5p in non-small cell lung cancer. The potential targets of miR-145-5p were predicted using 12 online prediction databases to explore the prospective molecular mechanism of miR-145-5p in non-small cell lung cancer. The expression of miR-145-5p in non-small cell lung cancer was significantly lower than that in healthy tissues. And miR-145-5p tended to show better diagnostic performance in lung squamous cell carcinoma than in lung adenocarcinoma. Furthermore, the expression of miR-145-5p was closely associated with lymph node metastasis in non-small cell lung cancer. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes were mainly enriched with enzyme-linked receptor protein signaling pathways, SH3 domain binding, cell leading edge, and adherens junction. The protein-protein interaction network showed that eight hub genes (SMAD4, SMAD2, IRS1, FOXO1, ERBB4, NRAS, ACTB, and ACTG1) might be the key target genes of miR-145-5p in non-small cell lung cancer. The information we obtained might offer new perspectives for clinical diagnosis and treatment for non-small cell lung cancer.

In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA (miR)-145-5p (guide-strand) and miR-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that miR-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of miR-145-3p and BC oncogenic pathways and targets regulated by miR-145-5p/miR-145-3p. Ectopic expression of either miR-145-5p or miR-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of miR-145 (miR-145-5p: guide-strand and miR-145-3p: passenger-strand) play pivotal roles in BC cells by regulating UHRF1. The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies., Competing Interests: The authors indicated no potential conflicts of interest.

Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.