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MicroRNAs, small endogenous noncoding RNAs, are involved in the regulation of epidermal homeostasis. Among them, miR-203 was the most described and expressed in human epidermis, promoting keratinocyte (KC) differentiation by repressing genes involved in proliferation. To identify other microRNAs involved in this process, the miRNomes of normal human KCs cultured in monolayer (2-dimensional) or in 3-dimensional reconstructed skin were compared. Besides miR-203, miR-141 was one of the most expressed microRNAs in 3-dimensional culture and was overexpressed in 3-dimensional versus 2-dimensional condition, that is, during KC differentiation. Functional experiments revealed that, mostly expressed in the basal layer, miR-141 decreased KC proliferation and clonogenicity while promoting differentiation. Target prediction algorithm coupled with transcriptomic data of KCs overexpressing miR-141 as well as 3' untranslated region luciferase assays highlighted CCND2 mRNA as a direct target of miR-141, leading to its downregulation by miR-141 overexpression. Finally, CCND2 silencing decreased KC proliferation and induced differentiation, revealing that miR-141 action was mediated by CCND2. MiR-141 features were also compared with those of miR-203 in parallel experiments. Although miR-141 displayed functions similar to those of miR-203, it exhibited different localization and targets, suggesting a joint participation of miR-141 and miR-203 in engaging and maintaining KC toward differentiation, respectively., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2) to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR), and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP) — a hepatokine — and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) — one of REG (Regenerating gene) family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA) revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC) into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism.

The polycomb repressive complexes 1 (PRC1) and 2 (PRC2) are two distinct polycomb group (PcG) proteins that maintain the stable silencing of specific sets of genes through chromatin modifications. Although the PRC2 component EZH2 has been known as an epigenetic regulator in promoting the proliferation of neural stem/progenitor cells (NSPCs), the regulatory network that controls this process remains largely unknown. Here we show that miR-203 is repressed by EZH2 in both embryonic and adult NSPCs. MiR-203 negatively regulates the proliferation of NSPCs. One of PRC1 components, Bmi1, is a downstream target of miR-203 in NSPCs. Conditional knockout of Ezh2 results in decreased proliferation ability of both embryonic and adult NSPCs. Meanwhile, ectopic overexpression of BMI1 rescues the proliferation defects exhibited by miR-203 overexpression or EZH2 deficiency in NSPCs. Therefore, this study provides evidence for coordinated function of the EZH2-miR-203-BMI1 regulatory axis that regulates the proliferation of NSPCs.

MiR-203 was identified as a hub of a potential regulatory miRNA network in central nervous system. Overexpressing of miR-203 in the frontal cortex of C57BL/6J wild type mouse induced neurodegeneration by increasing the apoptotic pathway and neuron death. AFF4, a transcription factor, was identified as a new bona fida protein target of miR-203 in CNS. The miRNA:mRNA interaction of miR-203 and AFF4 was verified using Dural-luciferase assay. Down-regulated expression of AFF4 was induced by overexpressing miR-203 both in vitro and in vivo. Open field test, Y maze and Morris water maze test were conducted for the behavioral assessment of the mice with stereotactic injection of lentiviral vector overexpressing miR-203 in the hippocampus. No anxiety-like behavior or impaired cognition was noticed in these mice. Consistent with the results of the behavioral assessment, the electron micrograph and Nissl staining revealed no significant change in the synaptic density and no neuron injuries in the hippocampus of mice overexpressing miR-203, respectively. Our results indicated that instead of promoting neurodegenerative phenotype, a more profound function should be ascribed to miR-203 in regulating neuron behavioral activities and cognition. Neuron-type specific functions of miR-203 are likely to be executed via its various downstream protein interactors., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021. Published by Elsevier B.V.)

Background: Emerging evidence reveals the importance of long non-coding RNAs (lncRNAs) in the development and progression of keloid formation. However, the roles and molecular mechanism of lncRNA LINC01116 in the progression of keloid formation remain largely unknown., Methods: The expression levels of LINC01116, microRNA-203 (miR-203) and SMAD family member 5 (SMAD5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration and invasion were detected by Cell counting Kit-8 (CCK-8) assay and transwell assay. Flow cytometry and western blot assay were used to examine cell apoptosis and extracellular matrix (ECM) production. The interaction between miR-203 and LINC01116 or SMAD5 was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays., Results: LINC01116 and SMAD5 were upregulated while miR-203 was downregulated in keloid tissues and keloid fibroblasts. LINC01116 knockdown suppressed the proliferation, migration, invasion, and ECM production but induced apoptosis in keloid fibroblasts through enhancing miR-203 and inhibiting SMAD5. Moreover, SMAD5 was identified as a direct target of miR-203 and miR-203 could directly bind to LINC01116. Besides, LINC01116 regulated SMAD5 expression by targeting miR-203., Conclusion: Downregulation of LINC01116 inhibited the progression of keloid formation by regulating miR-203/SMAD5 axis, which might provide a novel target for keloid therapy., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

Recurrent spontaneous abortion (RSA), defined as two or more consecutive pregnancy losses before 12 weeks of gestation with or without previous live births. Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs that play important roles in gene expression regulation and trophoblasts function during embryo development. This study aimed to evaluate the function mechanism of circRNAs regulating trophoblasts function in the occurrence and progression RSA. Through overexpression and down-regulation of circ-ZUFSP, we investigated the effect of circ-ZUFSP on the function of trophoblasts and found loss of circ-ZUFSP suppressed trophoblasts migration and invasion in vitro. Moreover, loss of circ-ZUFSP regulated trophoblasts migration and invasion via regulation of miR-203. Furthermore, STOX1 was revealed to a target of miR-203, and down-regulation of STOX1 reversed circ-ZUFSP enhanced cell invasion, suggesting that circ-ZUFSP might regulate STOX1 expression through sponging miR-203 in HTR-8/SVneo cells. In addition, low expression of circ-ZUFSP, STOX1 and high expression of miR-203 were testified in placental tissues of RSA mice. Our study demonstrated a molecular mechanism of circ-ZUFSP regulating trophoblasts migration and invasion, which might provide a novel indicator for early diagnosis and potential treatment of RSA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Given the comments of Dr Elisabeth Bik regarding this article “… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated”, the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Circular RNA (CirRNA) is a type of noncoding RNA that has been shown to play a unique role in tumor development and other fields in recent years. In this study, we aimed to explore the biological role of hsa_circ_100290 in acute myeloid leukemia (AML). First, we found that the expression of hsa_circ_100290 was increased in human AML samples and cell lines. Down-regulation of hsa_circ_100290 significantly suppressed cell proliferation of AML cells. Silencing hsa_circ_100290 also dramatically induced cell cycle arrest and apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_100290 and Rab10 were targeted by miR-203. Validation experiments verified that hsa_circ_100290 was co-expressed with Rab10 and was negatively correlated with miR-203 expression. Moreover, rescue experiments demonstrated that miR-203 inhibitor could reverse the role of hsa_circ_100290 knockdown on proliferation and apoptosis in AML cells. Overall, the present study identifies the crucial regulation of hsa_circ_100290 in AML cell proliferation and apoptosis via targeting the miR-203/Rab10 axis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of the progression of human cancers, including colorectal cancer (CRC). The study of genome-wide lncRNA expression patterns in metastatic CRC could provide novel mechanism underlying CRC carcinogenesis. In here, we determined the lncRNA expression profiles correlating to CRC with or without lymph node metastasis (LNM) based on microarray analysis. We found that 2439 lncRNAs and 1654 mRNAs were differentially expressed in metastatic CRC relative to primary CRC. Among these dysregulated lncRNAs, FBXL19-AS1 was the most significantly upregulated lncRNA in metastatic tumors. Functionally, knockdown of FBXL19-AS1 played tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Overexpression of FBXL19-AS1 was markedly correlated with TNM stage and LNM in CRC. Bioinformatics analysis predicted that miR-203 was potentially targeted by FBXL19-AS1, which was confirmed by dual-luciferase reporter assay. Pearson's correlation analysis showed that miR-203 expression was negatively related to FBXL19-AS1 in tumor tissues. Finally, miR-203 inhibition abrogated the effect of FBXL19-AS1 knockdown on the proliferation and invasion of LoVo cells. Our results reveal the cancer-promoting effect of FBXL19-AS1, acting as a molecular sponge in negatively modulating miR-203, which might provide a new insight for understanding of CRC development., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3'UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The LIM and SH3 protein 1 (LASP-1) has been reported to be associated with tumor development and progression. However, the expression and potential function of LASP-1 in human non-small cell lung cancer (NSCLC) remains undefined. Thus, this study aims to determine the relationship of LASP-1 expression with the progression and prognosis of NSCLC. Expression of LASP-1 was evaluated in NSCLC tissues and cell lines by real-time PCR, immunohistochemistry and Western blot analysis. The relationship between LASP-1 expression and clinicopathological characteristics was analyzed. The effects of LASP-1 on cell proliferation, migration and invasion were investigated in NSCLC cell lines in vitro and in vivo. Luciferase assay was used to determine whether LASP-1 could be regulated by miR-203. We found that LASP-1 was overexpressed in NSCLC and its expression level was closely correlated with tumor size, advanced TNM stage, lymph node metastasis as well as survival time and could be recognized as an independent prognostic factor of patients. LASP-1 could promote proliferation, migration and invasion of NSCLC cells in vitro and in vivo. Moreover, LASP-1 was proved to be a direct target gene for miR-203. Our results suggest that LASP-1, mediated by miR-203, has crucial functions in the proliferation, migration and invasion of NSCLC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Elevated cytoplasmic polyadenylation element-binding 4 (CPEB4) is aberrantly expressed in several malignant cancers. However, its expression pattern, clinical significance, and biological function in colorectal cancer are still unknown. In this study, we demonstrated that CPEB4 is abundantly overexpressed in colorectal cancers and has the potential to be used for predicting clinical outcomes of colorectal cancer patients. We suppressed CPEB4 expression by small interfering RNA (siRNA) in SW480 and LOVO cells to clarify the role of CPEB4 on the cell apoptosis and proliferation in vitro. Further study revealed that knockdown of CPEB4 decreased the expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL), but enhanced the expression of B-cell lymphoma-2-associated X (Bax). In addition, we indicated that CPEB4 is a novel target of miR-203, a tumor suppressive microRNA. Notably, restoration of CPEB4 in SW480 cells inhibited miR-203-induced apoptosis signaling pathway, which in turn enhanced cell proliferation and suppressed cell apoptosis. Taken together, our findings imply that posttranscriptional deregulation of CPEB4 contributes to the inhibited cell proliferation and the enhanced cell apoptosis in colorectal cancer, and directly targeting CPEB4 by miR-203 might be a novel strategy in colorectal cancer treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Metastasis is the major problem in malignant melanoma, posing a therapeutic challenge to clinicians. The investigation of the underlying mechanism driving this progress remains a large unmet need. In this study, we revealed a miR-203-BMI1 axis that regulated melanoma metastasis. We found significantly deregulation of miR-203 and up-regulation of BMI1 in melanoma, particularly in metastatic melanoma. An inverse correlation between the levels of miR-203 and BMI1 was further observed in melanoma tissues and cell lines. We also identified BMI1 as a downstream target gene of miR-203, which bound to the 3'UTR of BMI1. Overexpression of miR-203 was associated with decreased BMI1 expression and impaired cell invasion and tumor sphere formation activities. Re-expression of BMI1 markedly rescued miR-203-mediated suppression of these events. Taken together, our results demonstrated that miR-203 regulated melanoma invasive and proliferative abilities in part by targeting BMI1, providing new insights into potential mechanisms of melanoma metastasis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Damage of the zebrafish retina triggers a spontaneous regeneration response that is initiated by Müller Glia (MG) dedifferentiation and asymmetric cell division to produce multipotent progenitor cells. Subsequent expansion of the progenitor pool by proliferation is critical for retina regeneration. Pax6b expression in the progenitor cells is necessary for their proliferation, but exact regulation of its expression is unclear. Here, we show that miR-203 is downregulated during regeneration in proliferating progenitor cells. Elevated miR-203 levels inhibit progenitor cell expansion without affecting MG dedifferentiation or progenitor cell generation. Using GFP-reporter assays and gain and loss of function experiments in the retina, we show that miR-203 expression must be suppressed to allow pax6b expression and subsequent progenitor cell proliferation., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Nickel compounds have been found to be carcinogenic based upon epidemiological, animal and cell culture studies. Previous studies suggest that epigenetic mechanisms play a role in Nickel-induced carcinogenesis such as DNA methylation and histone modification. In this study, we investigated the role of microRNAs (miRNAs) in nickel-induced carcinogenesis. The expression of several miRNAs which may function as tumor suppressor genes revealed a strong downregulation of miR-203 in Ni3S2-transformed 16HBE cells (NSTCs). Meanwhile, we observed hypermethylation of CpGs in miR-203 promoter and first exon area, and proved that the hyper-methylated miR-203 was involved in the Nickel-induced tumorigenesis. Moreover, we identified that miR-203 may suppress the tumorigenesis at least in part through negatively regulating its target gene ABL1. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of Nickel-induced cancer., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)