Resveratrol protects mesangial cells under high glucose by regulating the miR-1231/IGF1/ERK pathway.

Diabetic nephropathy (DN) is one of the complications of diabetes mellitus and the main cause of end-stage renal disease (ESRD), which is a serious threat to human health. In DN, mesangial cells (MCs) are a critical target cell that perform a variety of key functions, and abnormal proliferation of MCs is a common and prominent pathological change in DN. In recent years, the investigation of Chinese medicine interventions for DN has increased significantly in recent years due to the many potential adverse effects and controversies associated with the treatment of DN with Western medicines. In this study, we evaluated the protective effect of resveratrol (RES), an active ingredient known as a natural antioxidant, on HMCs under high glucose and explored its possible mechanism of action. We found that RES inhibited the proliferation of human mesangial cell (HMC) under high glucose and blocked cell cycle progression. In the high glucose environment, RES upregulated miR-1231, reduced IGF1 expression, inhibited the activity of the extracellular signal-regulated kinase (ERK) signaling pathway and reduced levels of the inflammatory factors TNF-α and IL-6. In addition, we found that miR-1231 mimics were synergistically inhibited with RES, whereas miR-1231 inhibitor attenuated the protective effect of RES on HMCs. Thus, our results suggest that the protective effect of RES on HMCs under high glucose is achieved, at least in part, through modulation of the miR-1231/IGF1/ERK pathway. The discovery of this potential mechanism may provide a new molecular therapeutic target for the prevention and treatment of DN, and may also bring new ideas for the clinical research in DN.

Upregulated circ_0002141 facilitates oral squamous cell carcinoma progression via the miR-1231/EGFR axis.

OBJECTIVES: The dysregulation of circular RNAs (circRNAs) is implicated in the progression of various cancers. This study was aimed at expounding the role and mechanism of hsa_circ_0002141 in the OSCC progression. MATERIALS AND METHODS: Circ_0002141 expression was examined in 52 pairs of OSCC tissues and matched adjacent tissue samples by quantitative real-time polymerase chain reaction (qRT-PCR) assay. After circ_0002141 was overexpressed or knocked down in OSCC cell lines, cell counting kit-8 (CCK-8) assay, Transwell assay, flow cytometry, and Western blotting were conducted to detect the changes in the growth, migration, invasion and apoptosis of OSCC cells. Western blot assay, qRT-PCR and dual-luciferase reporter assay were performed to clarify the interplay among circ_0002141, miR-1231, and epidermal growth factor receptor (EGFR). RESULTS: Circ_0002141 expression was significantly upregulated in OSCC tissues and cell lines. Circ_0002141 overexpression markedly promoted the proliferation, migration, and invasion of OSCC cells whereas reduced the apoptotic of OSCC cells. Also, circ_0002141 knockdown suppressed the malignant characteristics of OSCC cells. EGFR was validated as the target of miR-1231. Besides, circ_0002141 could sponge miR-1231 and upregulate EGFR expression in OSCC cells. CONCLUSION: Circ_0002141/miR-1231/EGFR axis is involved in the progression of OSCC.

Rs11655237 polymorphism of LINC00673 affects the prognosis of cervical cancer by interfering with the interaction between LINC00673 and microRNA-1231.

Single-nucleotide polymorphism (SNP) in long noncoding RNAs (lncRNAs) is known to disrupt the binding between lncRNAs and microRNAs. In this paper, we aimed to explore the role of LINC00673 rs11655237 SNP in the survival of cervical cancer (CC). Real-time polymerase chain reaction and western-blot analysis were used to detect expressions of LINC00673 and microRNA-1231 (miR-1231) in CC patients with different rs11655237 SNP genotypes. And the expression of LINC00673, miR-1231, and IFNAR1 was measured in mice and cells treated with exosomes carrying GG, GA, and AA rs11655237 genotypes. Compared with patients carrying the rs11655237 A allele of LINC00673 rs11655237 SNP, patients carrying the G allele showed higher overall survival and higher miR-1231 expression. In addition, the expression of miR-1231 was the highest in patients carrying the GG genotype and the lowest in patients carrying the AA genotype. Furthermore, the exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP reduced tumor growth in mice, while the inhibitory effect of rs11655237 A allele was much stronger than that of the rs11655237 G allele. Additionally, exosome treatment upregulated the expression of LINC000673 and IFNAR1 while downregulating the expression of miR-1231. Interestingly, the A allele of rs11655237 generated a binding site for miR-1231 and subsequently affected the expression of IFNAR1, a target gene of miR-1231 containing a miR-1231 binding site in its 3'-untranslated region. Cells transfected with exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP achieved higher LINC000673 and IFNAR1 expression along with lower miR-1231 expression. Therefore, rs11655237 can be used as a prognostic biomarker for CC.

MiR-1231 decrease the risk of cancer-related mortality in patients combined with non-small cell lung cancer and diabetes mellitus.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a deadly human malignancy, and previous studies support the contribution of microRNAs (miRNAs) to cancer assessment. It has been reported that miR-1231 can be used as a biomarker to assess prognosis in different cancers. However, the prognostic value of miR-1231 in NSCLC patients with comorbid diabetes mellitus (DM) remains unclear. The present study evaluated the risk factors for NSCLC with DM and developed a predictive model for it. METHODS: A real-world study was conducted, including data from 108 patients with NSCLC combined with DM from April 1, 2010, to June 1, 2015. MiR-1231 was recorded during hospital admission. Cox-proportional hazards model was applied for survival analysis of risk factors for cancer-related mortality and to create nomograms for prediction. The accuracy of the model was evaluated by C-index and calibration curves. RESULTS: The mortality rate in the high miR-1231 level (≥ 1.775) group was 57.4%. On the basis of univariate analysis, we put factors (P < 0.05) into multivariate regression models, and high miR-1231 levels (P < 0.001, HR = 0.57), surgery (P < 0.001, HR = 0.37) and KPS score > 80 (P = 0.01, HR = 0.47) had a better prognosis and were considered as independent protective factors. These independently relevant factors were used to create nomograms to predict long-term patient survival. Nomogram showed good accuracy in risk estimation with a guide-corrected C-index of 0.691. CONCLUSION: MiR-1231 reduced the risk of cancer-related death in patients with combined NSCLC and DM. Nomogram based on multivariate analysis showed good accuracy in estimating the overall risk of death.

Upregulated circular RNA circ_0025033 promotes papillary thyroid cancer cell proliferation and invasion via sponging miR-1231 and miR-1304.

Recent evidence revealed that circular RNAs (circRNAs) are key regulators for tumorigenesis. However, their roles in papillary thyroid cancer (PTC) is not fully understood. In the current work, the differentially expressed circRNAs between PTC tissues and adjacent noncancerous tissue samples were screened by circRNA microarray. We further selected the highest expressed circRNA (circ_0025033) in tumorous tissues for the study. qRT-PCR was used to measure the level of circ_0025033 in PTC tissue samples and cell lines. Gain/loss of function assays were carried out to determine the effect of circ_0025033 on cell viability, clone-forming, apoptosis, migration and invasion. Dual-luciferase reporter assays were conducted to investigate the mechanisms of circ_0025033 in PTC. The data showed that circ_0025033 aggravated cell proliferation, migration and invasion and inhibited cell apoptosis. Additionally, circ_0025033 could directly sponge miR-1231 and miR-1304 in PTC cells. Furthermore, the oncogenic role of circ_0025033 is dependent on its suppression of miR-1231 and miR-1304. Collectively, this work uncovers a novel signal of circ_0025033/miR-1231/miR-1304 involved in PTC initiation and progression.

Enhanced expression of circular RNA circ-DCAF6 predicts adverse prognosis and promotes cell progression via sponging miR-1231 and miR-1256 in gastric cancer.

Circular RNAs (circRNAs) have been reported as essential regulators in various malignancies, including gastric cancer (GC). Previously, circ-DCAF6 was screened as an elevated circRNA in GC patients' tissue samples compared with the normal tissues. To our knowledge, the role of circ-DCAF6 in human cancers is still needed to reveal. The present project is to evaluate the functions and mechanisms of circ-DCAF6 in GC progression. Upregulation of circ-DCAF6 was determined in GC tissue samples and cells by qRT-PCR. Enhanced level of circ-DCAF6 was linked to deeper tumor invasion, positive lymph node metastasis, and higher TNM stages in GC patients. Multivariate analysis further indicated circ-DCAF6 as an independent prognostic indicator. Functionally, CCK-8, clone forming, flow cytometry and transwell assays verified that circ-DCAF6 played as an oncogene in GC cells. Mechanistically, we found the negative correlation between circ-DCAF6 and miR-1231/-1256 in GC specimens. Moreover, luciferase reporter gene assay illustrated that miR-1231 and miR-1256 could be bound to circ-DCAF6. Rescue experiments revealed that circ-DCAF6 facilitated cell growth and invasion via suppressing the levels of miR-1231 and miR-1256. To sum up, circ-DCAF6 acts as an important role in GC tumor progression, and high circ-DCAF6 level may be a useful biomarker for GC.

MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma.

PURPOSE: MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear. METHODS: We performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model. RESULTS: We found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest. CONCLUSIONS: Taken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.

Human microRNA hsa-miR-1231 suppresses hepatitis B virus replication by targeting core mRNA.

Pathogen-specific miRNA profiles might reveal potential new avenues for therapy. To identify miRNAs directly associated with hepatitis B virus (HBV) in hepatocytes, we performed a miRNA array analysis using urokinase-type plasminogen activator (uPA)-severe combined immunodeficiency (SCID) mice where the livers were highly repopulated with human hepatocytes and human immune cells are absent. Mice were inoculated with HBV-infected patient serum samples. Eight weeks after HBV infection, human hepatocytes were collected from liver tissues, and miRNAs were analysed using the Toray 3D array system. The effect of miRNAs on HBV replication was analysed using HBV-transfected HepG2 cells. Four miRNAs, hsa-miR-486-3p, hsa-miR-1908, hsa-miR-675 and hsa-miR-1231 were upregulated in mouse and human livers with HBV infection. These miRNAs were associated with immune response pathways such as inflammation mediated by chemokine and cytokine signalling. Of these miRNAs, hsa-miR-1231, which showed high homology with HBV core and HBx sequences, was most highly upregulated. In HBV-transfected HepG2 cells, overexpression of hsa-miR-1231 resulted in suppression of HBV replication with HBV core reduction. In conclusion, a novel interaction between hsa-miR-1231 and HBV replication was identified. This interaction might be useful in developing new therapeutic strategies against HBV.

CircKIF4A Is a Prognostic Factor and Modulator of Natural Killer/T-Cell Lymphoma Progression.

Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus normal cell lines. Kaplan-Meier survival analysis was used to assess the effect of circKIF4A on the prognosis of NKTL. The correlation between clinicopathological features and circKIF4A expression was examined using cox regression analysis. Luciferase reporter, RNA immunoprecipitation and immunohistochemistry assays were also used to investigate the mechanisms of circKIF4A in NKTL. Results: Our analyses revealed that circKIF4A is significantly upregulated in NKTL cell lines and that its upregulation correlates with the poor prognosis of NKTL. The silencing of circKIF4A significantly suppressed glucose uptake and lactate production in NKTL cells. Moreover, we showed that circKIF4A, PDK1, and BCL11A bind miR-1231 and that circKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Conclusions: During NKTL progression, circKIF4A regulated PDK1 and BCL11A levels by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL.

Circular RNA hsa_Circ_0005795 mediates cell proliferation of cutaneous basal cell carcinoma via sponging miR-1231.

Growing evidence has revealed that circular RNAs (circRNA) play critical roles in cancer progression. Here, we examined the function of a novel circRNA, Circ_0005795, in basal cell carcinoma (BCC) and explored the possible molecular mechanism. Nodular BCC and adjacent non-tumor tissues derived from 30 patients and 2 BCC cell lines were applied to analyze gene expression. Circ_0005795 loss- and gain-of-function were constructed to investigate BCC progression. Nuclear and cytoplasmic fractionation and luciferase assay were carried out to determine cellular localization and molecular interaction of Circ_0005795. Circ_0005795 expression was significantly elevated in BCC tissues and cells. Knockdown of Circ_0005795 dramatically reduced cell viability, colony formation, and anti-apoptotic protein levels, while increased caspase-3 activity. Circ_0005795 located in cytoplasm, which exerted its tumor-promoting effect through targeting and sponging miR-1231 in BCC cells. In summary, Circ_0005795 works as an oncogene in BCC, which might be used as a promising biomarker and a potential therapeutic target for BCC diagnosis and treatment.

Knockdown of lncRNA ABHD11-AS1 Suppresses the Tumorigenesis of Pancreatic Cancer via Sponging miR-1231.

BACKGROUND: Pancreatic cancer ranks first among the most aggressive malignancies. Long non-coding RNA (LncRNA) ABHD11-AS1 is known to be upregulated in pancreatic cancer. However, the mechanism by which ABHD11-AS1 mediates the tumorigenesis of pancreatic cancer remains unclear. METHODS: Gene and protein expressions in pancreatic cancer cells were detected by qRT-PCR and Western blot, respectively. Cell viability was measured by CCK-8 assay. Cell apoptosis and cycle were tested by flow cytometry. In addition, cell migration and invasion were tested by wound healing and transwell assay, respectively. The correlation between ABHD11-AS1, miR-1231 and cyclin E1 was confirmed by dual-luciferase report and RNA pull-down. Finally, xenograft mice model was established to investigate the role of ABDH-AS1 in pancreatic cancer in vivo. RESULTS: ABHD11-AS1 was found to be negatively correlated with the survival rate of patients with pancreatic cancer. ABHD11-AS1 silencing significantly inhibited the proliferation and induced the apoptosis of pancreatic cancer cells. Additionally, knockdown of ABHD11-AS1 greatly inhibited the migration and invasion of pancreatic cancer cells. Meanwhile, ABHD11-AS1 bound to miR-1231 and cyclin E1 was found to be the target of miR-1231. Moreover, ABHD11-AS1 knockdown-induced G1 arrest in pancreatic cancer cells was reversed by miR-1231 antagomir. Finally, knockdown of ABHD11-AS1 obviously inhibited the tumor growth of pancreatic cancer in vivo. CONCLUSION: ABHD11-AS1 silencing significantly inhibited the tumorigenesis of pancreatic cancer in vitro and in vivo. Thus, ABHD11-AS1 may serve as a potential target for the treatment of pancreatic cancer.

Exosomal miRNA-1231 derived from bone marrow mesenchymal stem cells inhibits the activity of pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant tumor with increased morbidity and mortality, which is difficult to diagnose and cure in the clinic. Through secreting exosomes containing biological molecules, including diverse RNAs and proteins, bone marrow mesenchymal stem cells (BM-MSCs) influence the immunity, inflammation, tumor environment, and cancer metastasis. In this study, low expression of miRNA-1231 (miR-1231) in exosomes derived from the peripheral blood was significantly correlated with the TNM stage of PC, suggesting the potential inhibitory effect of exosomal miR-1231 on PC occurrence and development. The proliferation, migration, invasion, and adhesion to the matrix of PC cells BxPC-3 and PANC-1 were negatively regulated by exosomes derived from the supernatants of BM-MSCs that transfected with miR-1231 oligonucleotides. Simultaneously, tumor growth in vivo was seriously restrained in BALB/C nude mice by tail vein injection with exosomes originated from BM-MSCs that transfected with miR-1231 mimics. The exosomes extracted from BM-MSCs with high level of miR-1231 inhibit the activity of PC, providing the potential application for developing new and efficient medicine for cancer therapy, especially for PC treatment. The exosomal miR-1231 of peripheral blood may also be a potential indicator for PC diagnosis in the future.

miR-1231 exacerbates arrhythmia by targeting calciumchannel gene CACNA2D2 in myocardial infarction.

MicroRNAs (miRNAs) are noncoding single-stranded RNAs of ~22 nucleotides suppressing a wide range of gene expression by direct degradation or translational inhibition of their target mRNAs. Acute myocardial infarction (AMI), a common cardiovascular disease mainly induced by coronary artery occlusion, can lead to the development of heart failure. Several recent findings have indicated that miRNAs might play vital roles in AMI, and some miRNAs have even been proposed as potential candidates for intervening AMI. However, the pathophysiological functions of miRNAs implicated in MI are still largely unidentified. Here, we show that miR-1231 is overexpressed both in human hearts after MI insults and in rat hearts with experimental MI compared with their healthy counterparts. Next, by using predictive strategy and gene expression array, cacna2d2 is identified as the target of miR-1231. In human and rat ischemic hearts, cacna2d2 expression is indeed suppressed by miR-1231. In addition, the inhibition of miR-1231 in vivo ameliorates arrhythmias in rat MI hearts; conversely, the forced overexpression of miR-1231 promotes arrhythmias. Furthermore, cacna2d2 knockdown alone induced arrhythmias in ischemic hearts, despite knockdown of miR-1231. Thus, these results indicate that miR-1231 exacerbates arrhythmia by inhibiting cacna2d2 in ischemic heart, which shed light on the important arrhythmogenic function of miR-1231 in MI and suggest it may serve as a potential antiarrhythmic target.