Elevated hsa‐miR‐590‐3p expression down‐regulates HMGB2 expression and contributes to the severity of IgA nephropathy

Peripheral blood mononuclear cells (PBMCs) play important roles in the pathogenesis of IgA nephropathy (IgAN). Our study aimed to provide a deep understanding of IgAN and focused on the dysregulation of hsa‐miR‐590‐3p and its target gene HMGB2 in PBMCs. Three gene expression profile datasets (GSE14795, GSE73953 and GSE25590) were downloaded from the GEO database. The DEGs (differentially expressed genes)‐miRNA network that was associated with IgAN was constructed by Cytoscape, and HMGB2 and hsa‐miR‐590‐3p were selected for further exploration. The dual‐luciferase reporter system was utilized to verify their interaction. Then, the expression levels of HMGB2 and hsa‐miR‐590‐3p in PBMCs were detected by qPCR in another cohort, and the correlation of their expression levels with the clinical pathological manifestations and serum Gd‐IgA1(galactose‐deficient IgA1) levels was also investigated. HMGB2 was identified as the target gene of hsa‐miR‐590‐3p. Furtherly, the elderly patients had higher HMGB2 expression levels than the expression levels of the younger patients. As the serum creatinine, serum BUN levels increased, the expression of HMGB2 decreased; Besides, the HMGB2 expression was positively correlated with serum complement 3(C3) levels, and it also had a negative correlation with the diastolic blood pressure, but not reach statistical significance. What is more, both hsa‐miR‐590‐3p and HMGB2 expression had a slight correlation tendency with serum Gd‐IgA1 levels in the whole population. In conclusion, HMGB2, the target gene of hsa‐miR‐590‐3p, was identified to correlate with the severity of IgAN, and this provides more clues for the pathogenesis of IgAN.     

Hsa_circ_0128846 promotes tumorigenesis of colorectal cancer by sponging hsa‐miR‐1184 and releasing AJUBA and inactivating Hippo/YAP signalling

Hsa_circ_0128846 was found to be the most significantly up‐regulated circRNA in our bioinformatics analysis. However, the role of hsa_circ_0128846 in colorectal cancer has not been explored. We thus aim to explore the influence and mechanism of hsa_circ_0128846 in colorectal cancer by sponging its downstream miRNA target miR‐1184. We collected 40 colorectal cancer patients’ tumour tissues to analyse the expression of hsa_circ_0128846, miR‐1184 and AJUBA using qRT‐PCR and Western blot where needed. Then, we constructed stably transfected SW480 and HCT116 cells to study the influence of hsa_circ_0128846, miR‐1184 and AJUBA on colorectal cancer cell phenotypes. To obtain reliable results, a plethora of experiments including RNA immunoprecipitation assay, flow cytometry, EdU incorporation assay, wound healing migration assay, transwell invasion assay and live imaging of nude mice xenograft assay were performed. The binding relationship between hsa_circ_0128846, miR‐1184 and AJUBA mRNA in colorectal cancer was validated by reported gene assay. In colorectal cancer tissues, circ_0128846 and AJUBA were both significantly up‐regulated, while miR‐1184 was significantly down‐regulated compared with healthy tissues. Meanwhile, hsa_circ_0128846 can absorb miR‐1184 to promote the progression of CRC in vivo and SW480 and HCT116 cell phenotypes in vitro. The knockdown of AJUBA, a downstream target of miR‐1184, reversed the effect of miR‐1184 in CRC cells via enhancing the phosphorylation of the Hippo/YAP signalling pathway proteins MST1, LATS1 and YAP. This study revealed that hsa_circ_0128846 contributed to the development of CRC by decreasing the expression of miR‐1184, thereby increasing AJUBA expression and inactivating Hippo/YAP signalling.     

Linc00511 acts as a competing endogenous RNA to regulate VEGFA expression through sponging hsa‐miR‐29b‐3p in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Long non‐coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in PDAC are poorly understood. Here, we identify a fundamental role for a novel lincRNA, linc00511, in the progression of PDAC. Linc00511 levels in PDAC tissue specimens and cell lines were examined by quantitative real‐time PCR. Corresponding adjacent non‐neoplastic tissues were used as controls. The function of linc00511 in PDAC cell lines was determined by RNA interference approach in vitro and in vivo. Fluorescence in situ hybridization (FISH) was used to characterize linc00511 expression in PDAC cells. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were obtained from bioinformatic analysis, luciferase assays and RIP assays. The association between the linc00511/hsa‐miR29b‐3p axis and VEGFA was verified by Western blotting assay. Immunohistochemistry was performed to evaluate the expression of VEGFA in PDAC samples. The aberrant up‐regulation of linc00511 was detected in PDAC cell lines and patient specimens compared with controls. An increase in linc00511 expression indicates the adverse clinical pathological characteristics and poor prognosis. Functionally, linc00511 depletion in PDAC cells decreased proliferation, migration, invasion and endothelial tube formation. Mechanistically, linc00511 could up‐regulate VEGFA via its competing endogenous RNA (ceRNA) activity on hsa‐miR‐29b‐3p. In summary, our results define an important axis controlling proliferation, invasion and tumour angiogenesis in PDAC. Linc00511 is a novel lncRNA that plays a significant regulatory role in the pathogenesis and progression of PDAC. Thus, Linc00511 represents a new prognostic biomarker to predict clinical outcome of PDAC patients after surgery and may serve as a potential therapeutic target for PDAC treatment.     

A functional variant in SLC1A3 influences ADHD risk by disrupting a hsa‐miR‐3171 binding site: A two‐stage association study

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and adolescents with high heritability. Evidence is accumulating that SLC1A3 may play a role in ADHD etiology. Therefore, a two‐stage case‐control study was conducted on 752 cases and 774 controls to explore the role of SLC1A3 in ADHD. Bioinformatic annotations and functional experiments were applied to reveal the potential biological mechanisms. Finally, SLC1A3 rs1049522 showed significant association with ADHD risk in two stages with CA genotype vs AA genotype, odds ratio (OR) = 0.694 (95% confidence interval, CI = 0.570‐0.844) and dominant model, OR = 0.749 (95% CI = 0.621‐0.904) in the combined stage. Besides, rs1049522 was found to be related to ADHD hyperactive/impulsive symptom, and rs1049522‐C showed increased SLC1A3 mRNA expression in the cerebellar cortex. Dual‐luciferase reporter assay further indicated that rs1049522‐C allele enhanced SLC1A3 expression by disrupting the hsa‐miR‐3171 binding site. In conclusion, SLC1A3 variant rs1049522 was implicated in ADHD susceptibility in a Chinese Han population probably by enhancing the SLC1A3 expression in a miRNA‐mediated manner.     

Circulating microRNAs,miR‐92a,miR‐100 and miR‐143, as non‐invasive biomarkers for bladder cancer diagnosis

The application of microRNAs (miRNAs) as potential biomarkers and therapy targets has been widely investigated in many kinds of cancers. Recent advantages of serum miRNAs open a new realm of possibilities for non‐invasive diagnosis and prognosis of bladder cancer (BC). The aim of our study was to identify plasma miR‐92a, miR‐100 and miR‐143 expression signatures in patients with BC to introduce new markers for establishing BC diagnosis and prognosis. Blood samples were collected from 70 BC patients and 62 controls. An expression of three target miRNAs (miR‐92a, miR‐100 and miR‐143) was measured using quantitative real‐time PCR method. Results were correlated with clinicopathological data and analysed. Plasma levels of miR‐92a, miR‐100 and miR‐143 were significantly lower in BC patients than in control group. Receiver operator characteristic analysis revealed that the sensitivity and specificity values of miR‐92a were 97·1% and 76·7%, respectively, with a cut‐off value of 0·573. The sensitivity and specificity values of miR‐100 were 90% and 66·7%, respectively, with a cut‐off value of 0·644. The sensitivity and specificity values of miR‐143 were 78·6% and 93·3%, respectively, with a cut‐off value of 0·164. This study explores the existence of specific plasma miRNAs as early diagnostic biomarkers for BC in Egyptian patients; and these findings suggest that plasma miR‐92a, miR‐100 and miR‐143 could be promising novel circulating biomarkers in clinical detection of BC. Copyright © 2016 John Wiley & Sons, Ltd.     

Aryl hydrocarbon‐estrogen alpha receptor‐dependent expression of miR‐206, miR‐27b,and miR‐133a suppress cell proliferation and migration in MCF‐7 cells

The underlying functions of miR‐206, miR‐133a, miR‐27b, and miR‐21, and their link to the estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AhR) signaling pathways remain largely unexplored. In this study, we detect the expression of miR‐206, miR‐133a, miR‐27b, and miR‐21 in MCF‐7 through quantificational real‐time polymerase chain reaction assay along with the activation/inhibition of ERα and AhR receptors. Aside from this, cell proliferation and migration as well as AhR‐dependent CYP1A1 enzyme activity were measured. Here, we found that the forced increased expression of miR‐206, miR‐133a, and miR‐27b were closely associated with the suppression of MCF‐7 cell proliferation and migration. The anti‐proliferative‐metastatic effect of miR‐206, miR‐133a, and miR‐27b was probably mediated by targeting the ERα and AhR signaling pathways. Considered together, our study indicated that the overexpression of miR‐206, miR‐133a, and miR‐27b might be potential biomarkers for prognosis and therapeutic strategies in breast cancer.