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Beckwith–Wiedemann Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Jirat Chenbhanich, Sirisak Chanprasert, Wisit Cheungpasitporn
The KCNQ1/CDKN1C domain includes at least three important imprinted genes: two maternally coding genes, KCNQ1 and CDKN1C, and one paternally non-coding gene, KCNQ1OT1. KCNQ1 encodes a voltage-gated potassium channel, and its germline mutation implicates in various inherited cardiac arrhythmias such as familial atrial fibrillation and long QT syndrome, including autosomal dominant Romano–Ward syndrome and autosomal recessive Jervell and Lange–Nielsen syndrome. The mutant potassium channel does not appear to involve in the pathogenesis of BWS directly. However, the untranslated transcripts from KCNQ1 allele might indirectly play an undiscovered role in the imprinting process. CDKN1C encodes a cell cycle regulator that inhibits cell proliferation by interacting with cyclin/CDK complexes during the G1 phase of cell cycle. The germline loss-of-function mutation of CDKN1C is associated with an overgrowth syndrome, BWS, whereas its gain-of-function mutation results in growth-retardation syndromes including Silver−Russell syndrome and IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome [12]. ICR2, in contrast to ICR1, is intragenic, locating within the 11th intron of the KCNQ1 gene, and contains the promotor of KCNQ1OT1 gene which encodes an antisense long non-coding RNA. ICR2 is not methylated in the paternal chromosome, and its KCNQ1OT1 transcript subsequently silences all the paternal imprinted genes within the domain, yet the mechanism by which long non-coding RNA silences imprinted genes is not fully understood. ICR2 is methylated on the maternal chromosome, resulting in the silencing of KCNQ1OT1 transcription and the expression of KCNQ1 and CDKN1C. Similar to ICR1, CTCF-binding sites have been identified in ICR2, and it has been postulated that the insulator model may contribute to the differential expression of the KCNQ1/CDKN1C domain as well [13].
Curcumin Suppresses TGF-β2-Induced Proliferation, Migration, and Invasion in Lens Epithelial Cells by Targeting KCNQ1OT1/miR-377-3p/COL1A2 Axis in Posterior Capsule Opacification
Published in Current Eye Research, 2022
Considering that lncRNAs can act as competing endogenous RNAs (ceRNAs) of miRNAs to regulate mRNAs expression, we predicted the possible miRNA targets of KCNQ1OT1 by searching starBase database. miR-377-3p was predicted to be a candidate target of KCNQ1OT1 and their putative binding sites were shown in Figure 3(A). RT-qPCR verified the transfection efficiency of miR-377-3p mimics (Figure 3B). We co-transfected SRA01/04 cells with wild-type or mutant luciferase reporter plasmid (WT/MUT-KCNQ1OT1) and miR-377-3p or miR-NC, and the results showed that miR-377-3p overexpression notably reduced the luciferase activity of WT-KCNQ1OT1 but not that of MUT-KCNQ1OT1 (Figure 3C), suggesting that miR-377-3p directly bind to KCNQ1OT1 in SRA01/04 cells. RIP assay revealed that both miR-377-3p and KCNQ1OT1 were enriched in RNA-induced silencing complex (RISC) when using Ago2 antibody (Figure 3D), indicating the interaction between miR-377-3p and KCNQ1OT1. miR-377-3p expression was markedly decreased in PCO patients relative to normal patients (Figure 3E). miR-377-3p expression in posterior lens capsule samples of PCO patients was negatively correlated with KCNQ1OT1 level (Figure 3F). TGF-β2 treatment reduced miR-377-3p expression in SRA01/04 cells (Figure 3G). The transfection efficiencies of KCNQ1OT1 siRNA and plasmid in TGF-β2-treated SRA01/04 cells were confirmed by RT-qPCR (Figure 3H). KCNQ1OT1 knockdown up-regulated miR-377-3p expression, and KCNQ1OT1 overexpression reduced miR-377-3p level (Figure 3I), suggesting the negative regulatory relationship between KCNQ1OT1 and miR-377-3p in SRA01/04 cells.
Responses of patients with juvenile idiopathic arthritis to methotrexate: a genomic outlook
Published in Expert Review of Clinical Immunology, 2021
Davide Selvestrel, Marianna Lucafò, Letizia Pugnetti, Sofia Pagarin, Valentina Moressa, Serena Pastore, Andrea Taddio, Gabriele Stocco, Giuliana Decorti
Despite the most studied class of ncRNA is miRNA, the long ncRNAs (lncRNA) are also emerging as important mediators in drug-resistance mechanisms [67]. They can promote or inhibit gene transcription, acting as scaffolds for the recruitment of epigenetic regulators or proteins such as transcription factors, and sequestering miRNAs [68]. Several studies have highlighted an altered expression of lncRNAs in peripheral blood cells of patients with RA [69]. To date no association studies considering lncRNAs expression and MTX response in JIA patients have been published, but a number of pre-clinical and clinical studies are exploring their role in MTX activity. Spurlock et al. found that RA patients showed reduced basal levels of lncRNA-p21 and increased basal levels of phosphorylated p65, a marker of NF-κB activation; interestingly, MTX treatment restored lincRNA-p21 levels to normal compared to patients not receiving MTX [70]. In vitro studies showed that reduced levels of lincRNA-p21 increased basal and stimulus-dependent NF-κB activity, and restoration of levels of lincRNA-p21 by MTX treatment decreased NF-κB activity. Further studies are needed to clarify the role of this lncRNA in the MTX mechanism of action. Xian and collaborators demonstrated that the lncRNA KCNQ1OT1 was markedly overexpressed in MTX‐resistant HT29 and Caco2 colon cancer cells and in MTX-resistant colorectal cancer tumor tissues [71]. Silencing of KCNQ1OT1 induced cell cycle arrest and apoptosis in MTX‐resistant cells and prevented MTX‐resistant colorectal tumor growth in nude mice, indicating KCNQ1OT1 as a potential predictive marker and a new therapeutic target. The lncRNA H19 and TUG1, were also found to be important mediators of MTX resistance in HT-29 colon cancer cells [72,73]. Both lncRNAs were significantly upregulated in MTX-resistant cells and their knockdown improved MTX response evaluated by MTT assay. Lastly, another lncRNA involved in MTX effectiveness is LUCAT1 [74]. lncRNA LUCAT1 expression was up-regulated in MTX-resistant MG63 and HOS osteosarcoma cells in comparison to parental cells. In vitro and in vivo, LUCAT1 knockdown suppressed MTX resistance, decreased the invasive cell number and reduced the tumor weight. Although this research is definitely a nascent field in precision medicine of JIA, several candidate ncRNAs could be promising markers of MTX response and deserve in-depth investigation in patients.