Oxymatrine inhibits proliferation and migration of breast cancer cells by inhibiting miRNA-188 and upregulating its target gene, PTEN

Purpose: To explore the potential biological functions of oxymatrine on breast cancer (BCa) cells and the underlying molecular mechanism.Methods: Relative levels of microRNA-188 (miRNA-188) and PTEN (gene of phosphate and tension homology deleted on chromosome ten) in BCa cells, MDA-MB-231 and TB549, were determined. The influence of oxymatrine treatment, miRNA-188 and PTEN on proliferative and migratory abilities in BCa cells were assessed by 3-(4,5-imethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), cell counting kit-8 (CCK-8) and Transwell assay, respectively. The binding relationship between miRNA-188 and PTEN was evaluated by dual-luciferase reporter gene assay.Results: Oxymatrine downregulated miRNA-188 and upregulated PTEN in BCa cells. Proliferative and migratory activities in BCa were inhibited by treatment of oxymatrine (p < 0.05). Dual-luciferase reporter gene assay results indicated that PTEN was the target gene of miRNA-188. Furthermore, rescue experiments demonstrated that the regulatory loop, oxymatrine/miRNA-188/PTEN, was involved in the regulation of the migration and proliferation of BCa.Conclusion: Oxymatrine treatment inhibits BCa progression by downregulating miRNA-188, leading to the upregulation of PTEN. The results of the current study may provide new insight into the diagnosis and treatment of BCa.

Carrying G allele in rs786204926 involved in alternative splicing of PTEN is associated with chemosensitivity in breast cancer

Background Chemoresistance is still the main reason for the failure of breast cancer treatment and is the main cause of death of breast cancer patients. Although many studies have shown the association between genetic polymorphisms of PTEN and chemoresistance, the molecular mechanism of breast cancer chemotherapy has not been further studied. This study aims to investigate the potential association between novel PTEN gene polymorphism and breast chemoresistance in Chinese population, and explore whether alternative splicing of the PTEN gene is affected by the gene polymorphism. Methods The study included 234 patients with breast cancer chemotherapy, 157 chemosensitive cases and 77 chemoresistant case. rs786204926, rs701848, rs12402181, rs35770269 were analysed using Sanger sequence and Sequenom MassArray typing technology. Silicon analysis was used to predict whether and how the polymorphism affects alternative splicing. Semi-quantitative RT-PCR and Western blot were further used to validate the silicon analysis. Results It is showed that there was a significant association between rs786204926 polymorphism and breast cancer chemoresistance. Carrying G allele or AG genotype will increase the risk of chemosensitivity in breast cancer. Additionally, Logistic multivariate regression analysis showed that age, lymph node metastasis and rs786204926 genotype are risk factors for breast cancer chemoresistance. Furthermore, Silico analysis showed that carrying G allele or AG genotype in chemosensitivity samples produced a new receptor site of alternative splicing, which increases the possibility of a new mutant PTEN isoform production. Interestingly, further experiments also verify this possibility. Conclusion We speculate that the mechanism of breast cancer chemosensitivity might be caused by a change in alternative splicing caused by the rs786204926 of PTEN gene. Thus, our study might provide theoretical guidance for the individualized treatment of clinical breast cancer patients.

Comprehensive Biological Information Analysis of PTEN Gene in Pan-Cancer

Background: PTEN is a multifunctional tumor suppressor gene mutating at high frequency in a variety of cancers. However, its expression in pan-cancer, correlated genes, survival prognosis, and regulatory pathways are not completely described. Here, we aimed to conduct a comprehensive analysis from the above perspectives in order to provide reference for clinical application. Methods: we studied the expression levels in cancers by using data from TCGA and GTEx database. Obtain expression box plot from UALCAN database. Perform mutation analysis on the cBioportal website. Obtain correlation genes on the GEPIA website. Construct protein network and perform KEGG and GO enrichment analysis on the STRING database. Perform prognostic analysis on the Kaplan-Meier Plotter website. We also performed transcription factor prediction on the PROMO database and performed RNA-RNA association and RNA-protein interaction on the RNAup Web server and RPISeq. The gene 3D structure, protein sequence and conserved domain were obtained in NCBI respectively.Results: PTEN was underexpressed in all cancers we studied. It was closely related to the clinical stage of tumors, suggesting PTEN may involved in cancer development and progression. The mutations of PTEN were present in a variety of cancers, most of which were truncation mutations and missense mutations. Among cancers (KIRC, LUAD, THYM, UCEC, Gastric Cancer, Liver Cancer, Lung Cancer, Breast Cancer), patients with low expression of PTEN had a shorter OS time and poorer OS prognosis. The low expression of PTEN can cause the deterioration of RFS in certain cancers (TGCT, UCEC, LIHC, LUAD, THCA), suggesting that the expression of PTEN was related to the clinical prognosis. Our study identified genes correlated with PTEN and performed GO enrichment analysis on 100 PTEN-related genes obtained from the GEPIA website. Conclusions: The understanding of PTEN gene and the in-depth exploration of its related regulatory pathways may provide insight for the discovery of tumor-specific biomarkers and clinical potential therapeutic targets.

LncRNA GAS5 Competitively Combined With miR-21 Regulates PTEN and Influences EMT of Peritoneal Mesothelial Cells via Wnt/β-Catenin Signaling Pathway

ObjectiveEpithelial-mesenchymal transition (EMT) is an important factor leading to peritoneal fibrosis (PF) in end-stage renal disease (ESRD) patients. The current research aimed to evaluate the effect of long non-coding RNA growth arrest-specific 5 (lncRNA GAS5) in human peritoneal mesothelial cells (HPMCs) EMT and explore the potential molecular mechanisms.Materials and MethodsHPMCs were cultured under control conditions or with high glucose (HG). The cells were then treated with lncRNA GAS5, lncRNA GAS5 siRNA, with or without miR-21 inhibitor and PTEN transfection. Expression of lncRNA GAS5, miR-21, α-SMA, Vimentin, E-cadherin, phosphatase and tensin homolog deleted on chromosome ten (PTEN), Wnt3a, and β-catenin were measured by real time PCR and Western blotting. Bioinformatics analyses were used to test the specific binding sites between the 3′ UTR of the PTEN gene, miR-21, and lncRNA GAS5. Rescue experiments were performed to confirm the lncRNA GAS5/miR-21/PTEN axis in HPMC EMT.ResultsWe found that HG-induced EMT decreased lncRNA GAS5 and that overexpression of lncRNA GAS5 can attenuate EMT in HPMCs. In addition, lncRNA GAS5 regulated HG-induced EMT through miR-21/PTEN. Cotransfection of miR-21 inhibitors remarkably increased PTEN expression and attenuated EMT in lncRNA GAS5 knockdown HPMCs. Moreover, rescue experiments showed that overexpression of PTEN attenuated the EMT effects of lncRNA GAS5 siRNA in HPMCs. We also confirmed that the Wnt/β-catenin pathway was stimulated in lncRNA GAS5/miR-21/PTEN-mediated EMT.ConclusionOur research showed that lncRNA GAS5 competitively combined with miR-21 to regulate PTEN expression and influence EMT of HPMCs via the Wnt/β-catenin signaling pathway. This study provides novel evidence that lncRNA GAS5 may be a potential therapeutic target for HPMC EMT.

Cowden syndrome and Lhermitte - Duclos disease: A case report and review of the literature

Cowden syndrome (CS) is a rare, autosomal dominant, multisystem disease related to the mutation of Phosphatase and tensin homolog (PTEN) tumour suppressor gene. It is characterized by the occurrence of multiple hamartomas, mucocutaneous lesions, and is associated with a high risk of malignancies. Lhermitte–Duclos Disease (LDD), or dysplastic cerebellar gangliocytoma, is a rare hamartomatous lesion of the cerebellar cortex with a unique “Tiger Stripe” appearance on Magnetic Resonance Imaging (MRI). Since 1991, LDD has been considered pathognomonic and part of CS. In addition, as almost all adult onset LDD cases were associated with PTEN gene mutations, LDD and CS are both included in PTEN Harmartoma Tumour Syndrome (PHTS). In this article, we report a 48-year-old female patient, who presented with a right cerebellar lesion resulting in hydrocephalus. The histology of the cerebellar lesion confirmed the diagnosis of LDD, and her clinical history is highly suggestive of CS. Due to the high incidence of multisystemic malignancies and other disease, it is important for clinicians to be aware of the association between LDD and CS. Affected patients should be evaluated carefully and screened for cancers accordingly, so as to allow early diagnosis and treatment.

Modeling and Simulation of a miRNA Regulatory Network of the PTEN Gene

The PTEN onco-suppressor gene is likely to play an important role in the onset of brain cancer, namely glioblastoma multiforme. Consequently, the PTEN regulatory network, involving microRNAs and competitive endogenous RNAs, becomes a crucial tool for understanding the mechanism related to low levels of expression in cancer patients. This paper introduces a novel model for the regulation of PTEN whose solution is approximated by a high-dimensional system of ordinary differential equations under the assumption that the Law of Mass Action applies. Extensive numerical simulations are presented that mirror parts of the biological subtext that lies behind various alterations. Given the complexity of processes involved in the acquisition of empirical data, initial conditions and reaction rates were inferred from the literature. Despite this, the proposed model is shown to be capable of capturing biologically reasonable behaviors of inter-species interactions, thus representing a positive result, which encourages pursuing the possibility of experimenting on data hopefully provided by omics disciplines.

“Thyroid nodular disease and PTEN mutation in a multicentre series of children with PTEN hamartoma tumor syndrome (PHTS)”

Purpose To report the incidence of 4–12% of differentiated thyroid cancer (DTC) and up to 50% of benign thyroid nodular disease and to describe nodular thyroid disease in a multicentre pediatric population with PTEN mutations. Methods: Retrospective data of pediatric patients with PTEN mutations collected from tertiary Departments of Pediatric Endocrinology of Turin, Milan and Genua, Italy, in the period 2010–2020. Results Seventeen children with PTEN mutations were recruited in the study. Thyroid involvement was present in 12/17 (70.6%) subjects, showing a multinodular struma in 6/17 (35.3%), nodules with benign ultrasound features in 5/17 (29.4%) and a follicular adenoma in 1/17 (6%). No correlation was found between thyroid disease and gender, puberty, vascular manifestations, delayed development, or brain MRI abnormalities, while multiple lipomas were associated with thyroid disease (p = 0.03), as was macrocephaly. Standard Deviation (SD) score head circumference was 4.35 ± 1.35 cm in subjects with thyroid disease, 3 ± 0.43 cm (p = 0.02) in the group without thyroid disease. Thyroid involvement was present in all subjects with mutations in exon 6 (4/4) and exon 8 (3/3) of the PTEN gene (p = 0.02). Conclusion In the presented cohort, benign thyroid disorders were prevalent, with no evidence of DTC. A correlation was found between thyroid lesions and head circumference and the occurrence of multiple lipomas. Future studies in larger cohorts should assess whether risk stratification is needed when recommending surveillance strategies in children or young adolescents with PTEN hamartoma syndrome.