LncRNA‐PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis

Correction to: EMBO Reports (2017) 18: 1837–1853. DOI: 10.15252/embr.201744147 ¦ Published online 8 September 2017The authors contacted the journal after becoming aware of duplications between Figs 3 and 6 and identified additional errors in the process of reanalysing their data. Figure 3B: The authors state that the representative images of the migration and invasion assays of EH‐GB1 cells in the Lv‐Control groups had been incorrectly selected from images belonging to the control groups. The figure is herewith corrected. Figure 6B: The authors state that they had incorrectly displayed representative images for the vector group of SGC‐996, and the vector and PAGBC‐mut (miR‐133b) groups of EH‐GB1. The figure is herewith corrected.In addition, the authors are adding a demarcating line to the PCR product of the 5′‐RACE in Fig EV2B, separating the marker lane, which had been inadvertently omitted. Source data for Fig EV2 were published in the original paper.The source data and replicate data for Figs 3B and 6B are published with this corrigendum.The authors apologize for this oversight and any confusion it may have caused and declare that the conclusions of the study are not affected by these changes.     

Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

Correction to: The EMBO Journal (2021) 40: e104450. DOI 10.15252/embj.2020104450 | Published online 1 December 2020The authors correct Figure 6A of this paper. During the revision process, images from p75^NTR‐expressing mice were inadvertently used in place of p75^NTR knock‐out neurons. The corrected figure, showing lack of p75^NTR labeling in knock‐out neurons, along with their corresponding internalized APP, is shown here. This error only concerns the images used to illustrate the quantitative data. It does not affect the analysis itself nor the conclusions derived from it. The authors apologize for this oversight and agree with this corrigendum; no response could be obtained from KT. Figure 6A. Original Figure 6A. Corrected     

Caspase‐12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein

Correction to: The EMBO Journal (2003) 22: 5435–5445. DOI 10.1093/emboj/cdg537 ¦ Published online 15 October 2003 Figure 7A. Original.Source data are available online for this figure. Figure 7A. Corrected. Source data are available online for this figure. The journal was informed of potential image aberrations in Fig 7A. The authors claim that the loading control in the originally published figure corresponded to a replicate experiment as many Western blots were run in parallel with the same samples to measure levels of ER stress markers. The control panel in Fig 7A is herewith retracted and replaced with the author‐supplied loading control of the experiment shown in Fig 7A.The journal noted that Fig 3 and Appendix Figure 3 were duplicated and that the legend to Appendix Figure 3 did not match the displayed figure. The authors recovered the quantification data for Appendix Figure 3, but not the scanned blots. The authors state that they no longer have access to the laboratory books or primary data and that they cannot definitively say which image was analysed. The authors withdraw Appendix Figure 3.The authors also acknowledge that there are undeclared splice sites in Fig 3, but that they could not locate the source data.The source data for Fig 7A are available with this corrigendum notice.The authors apologize for these errors and agree with this corrigendum; no response could be obtained from MR‐C.     

CircHIPK3 prevents chondrocyte apoptosis and cartilage degradation by sponging miR‐30a‐3p and promoting PON2

Osteoarthritis (OA) is a common joint disease featured by the deterioration of articular cartilage and chondrocyte death. Emerging evidence has indicated that circular RNAs (circRNAs) play an essential role in OA progress. Here, we found that the expression of circHIPK3 was significantly decreased in human and mouse OA cartilage. Knocking down circHIPK3 increased apoptosis and intracellular ROS level in HC‐a chondrocytes. We performed proteomic studies and identified that circHIPK3 regulated chondrocyte apoptosis through the mitochondrial pathway. Results of JC‐1 staining and western blot further confirmed that mitochondrial outer membrane permeabilization was promoted in HC‐a chondrocytes transfected by circHIPK3 siRNA. In terms of mechanism, we showed that PON2 functioned as a potential target of circHIPK3 to regulate chondrocyte apoptosis. Moreover, we revealed that circHIPK3 interacted with miR‐30a‐3p to regulate PON2 expression in chondrocytes. Taken together, our findings suggested that circHIPK3 regulated chondrocyte apoptosis by mitochondrial pathway, and targeting the circHIPK3/miR‐30a‐3p/PON2 axis might be a potential strategy for OA treatment.

The current study revealed the important role of circHIPK3 in regulating chondrocyte apoptosis and maintaining extracellular matrix (ECM) homeostasis. Mechanistically, circHIIPK3 might serve as a sponge of miR‐30a‐3p to regulate PON2 expression. The downregulation of circHIIPK3 resulted in the increased expression of miR‐30a‐3p and decreased expression of PON2, thus leading to mitochondrial pathway apoptosis and ECM destruction.     

Circular RNA hsa_circ_0083756 promotes intervertebral disc degeneration by sponging miR‐558 and regulating TREM1 expression

ObjectivesIntervertebral disc degeneration (IVDD) is a leading cause of low back pain. Circular RNAs (circRNAs) have been demonstrated to exert vital functions in IVDD. However, the role and mechanism of hsa_circ_0083756 in the development of IVDD remain unclear.Materials and methodsRT‐qPCR was performed to detect expressions of hsa_circ_0083756, miR‐558 and TREM1 in nucleus pulposus (NP) tissues and cells. CCK8 assay, flow cytometry, TUNEL assay, RT‐qPCR and WB were used to clarify the roles of hsa_circ_0083756 in NP cells proliferation and extracellular matrix (ECM) formation. Bioinformatics analyses, dual‐luciferase reporter gene experiment, RNA immunoprecipitation (RIP) assay and FISH assay were performed to predict and verify the targeting relationship between hsa_circ_0083756 and miR‐558, as well as that between miR‐558 and TREM1. Ultimately, the effect of hsa_circ_0083756 on IVDD was tested through anterior disc‐puncture IVDD animal model in rats.Resultshsa_circ_0083756 was upregulated in degenerative NP tissues and cells. In vitro loss‐of‐function and gain‐of‐function studies suggested that hsa_circ_0083756 knockdown promoted, whereas hsa_circ_0083756 overexpression inhibited NP cells proliferation and ECM formation. Mechanistically, hsa_circ_0083756 acted as a sponge of miR‐558 and subsequently promoted the expression of TREM1. Furthermore, in vivo study indicated that silencing of hsa_circ_0083756 could alleviate IVDD in rats.Conclusionshsa_circ_0083756 promoted IVDD via targeting the miR‐558/TREM1 axis, and hsa_circ_0083756 may serve as a potential therapeutic target for the treatment of IVDD.     

BH3‐only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α

Correction to: The EMBO Journal (2012) 31: 2322–2335. DOI 10.1038/emboj.2012.84 ¦ Published online 17 April 2012 Figure 4A. Original.Source data are available online for this figure. Figure 4A. Corrected. Source data are available online for this figure. The journal was alerted to the claim that the IRE input panels are identical in Figure 1G. Since the IRE input panels show a high degree of similarity, the source data for both panels are published with this notice for the avoidance of doubt.The HSP90 blot looks very similar in Fig 3F and Fig S4A. The authors confirmed that they had stripped and re‐probed the original HSP90 blot in Fig 3F and Fig S4A. Specifically, the membrane was probed with antibodies to IRE1, and HSP90, and then re‐probed with anti‐PERK antibodies. For that reason, HSP90 was presented in both figures because it is the same experiment. In the source data published with this correction, the authors have marked the original data with contrast boxes and arrows to indicate which blots were presented in the figure. The legends have been updated to state that a control originating from one blot is displayed in both figures.The authors acknowledge that they had removed one set of experimental conditions with wild‐type parental DKO cells when preparing Fig 4A and state that this does not change the conclusions of the figure. The figure is herewith updated with a demarcating line and source data for the full experiment is published with this notice.All authors agree with this corrigendum. The authors apologize for any confusion caused by these errors.     

MiR‐223‐3p inhibits rTp17‐induced inflammasome activation and pyroptosis by targeting NLRP3

The incidence of syphilis caused by Treponema pallidum subsp pallidum (T pallidum) infection is accompanied by inflammatory injuries of vascular endothelial cells. Studies have revealed that T pallidum infection could induce inflammasome activation and pyroptosis in macrophages. MicroRNA‐223‐3p (miR‐223‐3p) was reported to be a negative regulator in inflammatory diseases. The present study aimed to explore whether miR‐223‐3p regulates T pallidum‐induced inflammasome activation and pyroptosis in vascular endothelial cells, and determine the mechanisms which underlie this process. MiR‐223‐3p levels in syphilis and control samples were determined. The biological function of miR‐223‐3p in the NLRP3 inflammasome and pyroptosis was evaluated in T pallidum‐infected human umbilical vein endothelial cells (HUVECs). We observed a dramatic decrease in miR‐223‐3p levels in syphilis patients (n = 20) when compared to healthy controls (n = 20). Moreover, miR‐223‐3p showed a notable inhibitory effect on recombinant Tp17 (rTP17)‐induced caspase‐1 activation, resulting in decrease in IL‐1β production and pyroptosis, which was accompanied by the release of lactate dehydrogenase (LDH) in HUVECs. Additionally, the dual‐luciferase assay confirmed that NLRP3 is a direct target of miR‐223‐3p. Moreover, NLRP3 overexpression or knockdown largely blocked the effects of miR‐223‐3p on T pallidum‐induced inflammasome activation and pyroptosis in HUVECs. Most importantly, a notable negative correlation was observed between miR‐223‐3p and NLRP3, caspase‐1, and IL‐1β, respectively, in the serum of syphilis patients and healthy controls. Taken together, our results reveal that miR‐223‐3p targets NLRP3 to suppress inflammasome activation and pyroptosis in T pallidum‐infected endothelial cells, implying that miR‐223‐3p could be a potential target for syphilis patients.     

METTL3‐mediated maturation of miR‐589‐5p promotes the malignant development of liver cancer

MiR‐589‐5p could promote liver cancer, but the specific mechanisms are largely unknown. This study examined the role and mechanisms of miR‐589‐5p in liver cancer. The expressions of miR‐589‐5p, METTL3 and m6A in liver cancers were determined by RT‐qPCR. The relationship between miR‐589‐5p and METTL3‐mediated m6A methylation was examined by m6A RNA immunoprecipitation. After transfection, the viability, migration, invasion and expressions of METTL3 and miR‐589‐5p in liver cancer cells were detected by CCK‐8, wound‐healing, transwell and RT‐qPCR. After the xenograft tumour was established in mice, the tumour volume was determined and the expressions of METTL3, miR‐589‐5p, MMP‐2, TIMP‐2, E‐cadherin, N‐cadherin and Vimentin in tumour tissue were detected by RT‐qPCR and Western blotting. In vitro study showed that miR‐589‐5p and METTL3 were highly expressed in liver cancer. METTL3 was positively correlated with miR‐589‐5p. METTL3 up‐regulated the expression of miR‐589‐5p and promoted the maturation of miR‐589‐5p. Overexpressed miR‐589‐5p and METTL3 promoted the viability, migration and invasion of liver cancer cells, while the effects of silencing miR‐589‐5p and METTL3 on the cells were the opposite. The effects of METTL3 overexpression and silencing were reversed by miR‐589‐5p inhibitor and mimic, respectively. In vivo study showed that METLL3 silencing inhibited the growth of xenograft tumour and the expressions of METTL3, MMP‐2, N‐cadherin and Vimentin, promoted the expressions of TIMP‐2 and E‐cadherin, while miR‐589‐5p mimic caused the opposite results and further reversed the effects of METLL3 silencing. In summary, this study found that METTL3‐mediated maturation of miR‐589‐5p promoted the malignant development of liver cancer.     

Molecular basis of cross‐species ACE2 interactions with SARS‐CoV‐2‐like viruses of pangolin origin

Correction to: The EMBO Journal (2021) 40: e107786. DOI 10.15252/embj.2021107786 | Published online 8 June 2021The authors would like to add three references to the paper: Starr et al and Zahradník et al also reported that the Q498H or Q498R mutation has enhanced binding affinity to ACE2; and Liu et al reported on the binding of bat coronavirus to ACE2.Starr et al and Zahradník et al have now been cited in the Discussion section, and the following sentence has been corrected from:“According to our data, the SARS‐CoV‐2 RBD with Q498H increases the binding strength to hACE2 by 5‐fold, suggesting the Q498H mutant is more ready to interact with human receptor than the wildtype and highlighting the necessity for more strict control of virus and virus‐infected animals”.to“Here, according to our data and two recently published papers, the SARS‐CoV‐2 RBD with Q498H or Q498R increases the binding strength to hACE2 (Starr et al, 2020; Zahradník et al, 2021), suggesting the mutant with Q498H or Q498R is more ready to interact with human receptor than the wild type and highlighting the necessity for more strict control of virus and virus‐infected animals”.The Liu et al citation has been added to the following sentence:“In another paper published by our group recently, RaTG13 RBD was found to bind to hACE2 with much lower binding affinity than SARS‐CoV‐2 though RaTG13 displays the highest whole‐genome sequence identity (96.2%) with the SARS‐CoV‐2 (Liu et al, 2021)”.Additionally, the authors have added the GISAID accession IDs to the sequence names of the SARS‐CoV‐2 in two human samples (Discussion section). To make identification unambiguous, the sequence names have been updated from “SA‐lsf‐27 and SA‐lsf‐37” to “GISAID accession ID: EPI_ISL_672581 and EPI_ISL_672589”.Lastly, the authors declare in the Materials and Methods section that all experiments employed SARS‐CoV‐2 pseudovirus in cultured cells. These experiments were performed in a BSL‐2‐level laboratory and approved by Science and Technology Conditions Platform Office, Institute of Microbiology, Chinese Academy of Sciences.These changes are herewith incorporated into the paper.     

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP1/IGF2BP1

Correction to: EMBO Reports (2019) 20: e47074. DOI 10.15252/embr.201847074 | Published online 6 May 2019The authors noticed that the control and disease labels had been inverted in their data analysis resulting in publication of incorrect data in Figure 1C. The corrected figure is displayed below. This change affects the conclusions as detailed below. The authors apologize for this error and any confusion it may have caused.In the legend of 1C, change from, “Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows increased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.Open in a separate windowFigure 1CCorrected Open in a separate windowFigure 1COriginal To, "Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows decreased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.In abstract, change from, “Here, we report increased IMP1 expression in patients with Crohn''s disease and ulcerative colitis”.To, “Here, we report increased IMP1 expression in adult patients with Crohn''s disease and ulcerative colitis”.In results, change from, “Consistent with these findings, analysis of published the Pediatric RISK Stratification Study (RISK) cohort of RNA‐sequencing data 38 from pediatric patients with Crohn''s disease (CD) patients revealed that IMP1 is upregulated significantly compared to control patients and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.To, “Contrary to our findings in colon tissue from adults, analysis of published RNA‐sequencing data from the Pediatric RISK Stratification Study (RISK) cohort of ileal tissue from children with Crohn’s disease (CD) 38 revealed that IMP1 is downregulated significantly compared to control patients in the RISK cohort and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.In discussion, change from, “Indeed, we report that IMP1 is upregulated in patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.To “Indeed, we report that IMP1 is upregulated in adult patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.     

Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation

The authors approached the journal to correct a mistake in the data presented in Appendix␣Fig S3D. The authors state that the mouse images in Appendix␣Fig S3D mistakenly displayed images from Fig 2F and Appendix␣Fig S1F. The images in Appendix␣Fig S3D are herewith corrected. The authors state that this change does not affect the conclusions or the statistics. The source data for these panels have been added to the original publication.The authors note that the following sentence needs to be corrected from: Appendix Figure S3D. Original. Appendix Figure S3D. Corrected. “Interestingly, several well‐established accumulation signatures of succinate, malate, hypoxanthine, and xanthine induced by endurance exercise (Lewis et␣al, 2010) were found to be decreased by endurance exercise (Figs 1D and EV1A–D)”.to“Interestingly, several well‐established accumulation signatures of succinate, malate, hypoxanthine, and xanthine induced by endurance exercise (Lewis et␣al, 2010) were found to be decreased by resistance exercise (Figs 1D and EV1A–D)”.Further, the authors requested to amend the legend of Appendix␣Fig S3R to indicate that the same sample for the iWAT group, “WT+2%AKG” treatment, is shown in Fig 3P. The corrected legend reads: “(R‐S). Representative images (R) and quantification (S) of p‐HSL DAB staining from male OXGR1OE^AG mice treated with AKG for 12 weeks (n = 6 per group). The same sample is shown as in Fig 3P ”.The authors regret these errors and any confusion they may have caused. All authors approve of this correction.     

Down‐regulated HDAC3 elevates microRNA‐495‐3p to restrain epithelial‐mesenchymal transition and oncogenicity of melanoma cells via reducing TRAF5

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment.     

Administration of mircoRNA‐135b‐reinforced exosomes derived from MSCs ameliorates glucocorticoid‐induced osteonecrosis of femoral head (ONFH) in rats

Exosomes were found to exert a therapeutic effect in the treatment of osteonecrosis of the femoral head (ONFH), while miR‐135b was shown to play an important role in the development of ONFH. In this study, we investigated the effects of concomitant administration of exosomes and miR‐135b on the treatment of ONFH. A rat mode of ONFH was established. TEM, Western blotting and nanoparticle analysis were used to characterize the exosomes collected from human‐induced pluripotent stem cell–derived mesenchymal stem cells (hiPS‐MSC‐Exos). Micro‐CT was used to observe the trabecular bone structure of the femoral head. Real‐time PCR, Western blot analysis, IHC assay, TUNEL assay, MTT assay and flow cytometry were performed to detect the effect of hiPS‐MSC‐Exos and miR‐135b on cell apoptosis and the expression of PDCD4/caspase‐3/OCN. Moreover, computational analysis and luciferase assay were conducted to identify the regulatory relationship between PDCD4 mRNA and miR‐135b. The hiPS‐MSC‐Exos collected in this study displayed a spheroidal morphology with sizes ranging from 20 to 100 nm and a mean concentration of 1 × 10¹² particles/mL. During the treatment of ONFH, the administration of hiPS‐MSC‐Exos and miR‐135b alleviated the magnitude of bone loss. Furthermore, the treatment of MG‐63 and U‐2 cells with hiPS‐MSC‐Exos and miR‐135b could promote cell proliferation and inhibit cell apoptosis. Moreover, PDCD4 mRNA was identified as a virtual target gene of miR‐135b. HiPS‐MSC‐Exos exerted positive effects during the treatment of ONFH, and the administration of miR‐135b could reinforce the effect of hiPS‐MSC‐Exos by inhibiting the expression of PDCD4.     

miR‐24 and its target gene Prdx6 regulate viability and senescence of myogenic progenitors during aging

Satellite cell‐dependent skeletal muscle regeneration declines during aging. Disruptions within the satellite cells and their niche, together with alterations in the myofibrillar environment, contribute to age‐related dysfunction and defective muscle regeneration. In this study, we demonstrated an age‐related decline in satellite cell viability and myogenic potential and an increase in ROS and cellular senescence. We detected a transient upregulation of miR‐24 in regenerating muscle from adult mice and downregulation of miR‐24 during muscle regeneration in old mice. FACS‐sorted satellite cells were characterized by decreased levels of miR‐24 and a concomitant increase in expression of its target: Prdx6. Using GFP reporter constructs, we demonstrated that miR‐24 directly binds to its predicted site within Prdx6 mRNA. Subtle changes in Prdx6 levels following changes in miR‐24 expression indicate miR‐24 plays a role in fine‐tuning Prdx6 expression. Changes in miR‐24 and Prdx6 levels were associated with altered mitochondrial ROS generation, increase in the DNA damage marker: phosphorylated‐H2Ax and changes in viability, senescence, and myogenic potential of myogenic progenitors from mice and humans. The effects of miR‐24 were more pronounced in myogenic progenitors from old mice, suggesting a context‐dependent role of miR‐24 in these cells, with miR‐24 downregulation likely a part of a compensatory response to declining satellite cell function during aging. We propose that downregulation of miR‐24 and subsequent upregulation of Prdx6 in muscle of old mice following injury are an adaptive response to aging, to maintain satellite cell viability and myogenic potential through regulation of mitochondrial ROS and DNA damage pathways.     

METTL3/N6‐methyladenosine/ miR‐21‐5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF‐κB pathway activation

Renal fibrosis induced by urinary tract obstruction is a common clinical occurrence; however, effective treatment is lacking, and a deeper understanding of the mechanism of renal fibrosis is needed. Previous studies have revealed that miR‐21 impacts liver and lung fibrosis progression by activating the SPRY1/ERK/NF‐kB signalling pathway. However, whether miR‐21 mediates obstructive renal fibrosis through the same signalling pathway has not been determined. Additionally, studies have shown that N6‐methyladenosine (m⁶A) modification‐dependent primary microRNA (pri‐microRNA) processing is essential for maturation of microRNAs, but its role in the maturation of miR‐21 in obstructive renal fibrosis has not yet been investigated in detail. To address these issues, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated for 3, 7 and 14 days to simulate the fibrotic process. In vitro, human renal proximal tubular epithelial (HK‐2) cells were transfected with plasmids containing the corresponding sequence of METTL3, miR‐21‐5p mimic or miR‐21‐5p inhibitor. We found that the levels of miR‐21‐5p and m⁶A modification in the UUO model groups increased significantly, and as predicted, the SPRY1/ERK/NF‐kB pathway was activated by miR‐21‐5p, confirming that miR‐21‐5p plays an important role in obstructive renal fibrosis by enhancing inflammation. METTL3 was found to play a major catalytic role in m⁶A modification in UUO mice and drove obstructive renal fibrosis development by promoting miR‐21‐5p maturation. Our research is the first to demonstrate the role of the METTL3‐m⁶A‐miR‐21‐5p‐SPRY1/ERK/NF‐kB axis in obstructive renal fibrosis and provides a deeper understanding of renal fibrosis.     

MicroRNA‐148a‐3p suppresses epithelial‐to‐mesenchymal transition and stemness properties via Wnt1‐mediated Wnt/β‐catenin pathway in pancreatic cancer

Although miR‐148a‐3p has been reported to function as a tumour suppressor in various cancers, the molecular mechanism of miR‐148a‐3p in regulating epithelial‐to‐mesenchymal transition (EMT) and stemness properties of pancreatic cancer (PC) cells remains to be elucidated. In the present study, we demonstrated that miR‐148a‐3p expression was remarkably down‐regulated in PC tissues and cell lines. Moreover, low expression of miR‐148a‐3p was associated with poorer overall survival (OS) in patients with PC. In vitro, gain‐of‐function and loss‐of‐function experiments showed that miR‐148a‐3p suppressed EMT and stemness properties as well as the proliferation, migration and invasion of PC cells. A dual‐luciferase reporter assay demonstrated that Wnt1 was a direct target of miR‐148a‐3p, and its expression was inversely associated with miR‐148a‐3p in PC tissues. Furthermore, miR‐148a‐3p suppressed the Wnt/β‐catenin pathway via down‐regulation of Wnt1. The effects of ectopic miR‐148a‐3p were rescued by Wnt1 overexpression. These biological functions of miR‐148a‐3p in PC were also confirmed in a nude mouse xenograft model. Taken together, these findings suggest that miR‐148a‐3p suppresses PC cell proliferation, invasion, EMT and stemness properties via inhibiting Wnt1‐mediated Wnt/β‐catenin pathway and could be a potential prognostic biomarker as well as a therapeutic target in PC.