ABSTRACT
Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease, that eventually lead to hypothyroidism. XBP1s is an endoplasmic reticulum stress related protein and participates in the pathogenesis of several diseases. Nevertheless, the potential role of XBP1s in amiodarone (AMIO)-treated HT patients remains unknown. In this study, AMIO aggravated the endoplasmic reticulum stress responses in HT patients and thyroid epithelial follicular cells. Moreover, MTT assay and flow cytometry analysis revealed that knockdown of XBP1s suppressed AMIO-induced thyroid epithelial follicular cells apoptosis. Mechanically, the Chromatin Immunoprecipitation (ChIP) and luciferase activity assay proved that XBP1s enhanced LINC00842 expression in HT patients and thyroid epithelial follicular cells via binding to LINC00842 promoter. LINC00842 functioned as a miR-214 sponge in HT patients and thyroid epithelial follicular cells. Besides, LINC00842 up-regulated Fas ligand (FASL) expression via inhibition of miR-214. In rescue experiments, overexpression of FASL reversed shXBP1s-induced suppression of cell apoptosis in AMIO-treated thyroid epithelial follicular cells. These findings concluded that AMIO-drove XBP1s aggravated endoplasmic reticulum stress and apoptosis in HT via modulating LINC00842/miR-214/FASL axis, providing a new sight for the therapeutic strategy of AMIO-induced HT.
Subject(s)
Amiodarone , Hashimoto Disease , MicroRNAs , RNA, Long Noncoding , X-Box Binding Protein 1 , Humans , Amiodarone/pharmacology , Amiodarone/therapeutic use , Apoptosis , Endoplasmic Reticulum Stress/genetics , Fas Ligand Protein/metabolism , fas Receptor/metabolism , Hashimoto Disease/metabolism , MicroRNAs/genetics , X-Box Binding Protein 1/genetics , RNA, Long Noncoding/geneticsABSTRACT
INTRODUCTION: Anaplastic thyroid carcinoma (ATC) is a nearly chemo-resistant malignancy with high invasion and mortality. Long non-coding RNAs (lncRNAs) have been demonstrated to be dysregulated and play a crucial role in the development and process of ATC. The present study aimed to explore the mechanism of PVT1 dysregulation in ATC. MATERIAL AND METHODS: The mRNA levels of PVT1 and T-box3 (TBX3), and the protein levels of TBX3 in ATC and paracancerous tissues, and FRO and Nthy-ori 3-1 cells were determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blot, respectively. The transcriptional factor binding site was predicted and validated between TBX3 and PVT1 promoter through the JASPAR website, and ChIP and luciferase analysis. The proliferation, migration, and invasion of FRO cells were assessed by MTT, colony formation, and transwell assays. RESULTS: PVT1 expression was upregulated in ATC, which was positively correlative with the level of transcription factor TBX3. Downregulation of PVT1 inhibited the proliferation, migration, and invasion of FRO cells. Moreover, TBX3 targeting the promoter region of PVT1 promoted the expression level of PVT1 and modulated the downstream signalling axis of PVT1, miR-30a/LOX. Also, interference of PVT1 reversed the stimulative role of overexpression of TBX3 in the progress of FRO cells. CONCLUSION: TBX3 enhanced proliferation, migration, and invasion of ATC cells via activation of PVT1 and modulation of the miR-30a/LOX signalling axis.
Subject(s)
MicroRNAs , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Protein-Lysine 6-Oxidase/metabolism , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Thyroid Carcinoma, Anaplastic/genetics , Thyroid Neoplasms/geneticsABSTRACT
Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure-selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of pK(i)(M1), pK(i)(M2) and p[K(i)(M2)/K(i)(M1)] (pK(i)(M2)-pK(i)(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r(2) (r(cv)(2)), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[K(i)(M2)/K(i)(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).