Renal cell carcinoma (RCC) is a high-risk metastasizing tumor with a poor prognosis and poorly understood mechanism. In this study, we demonstrate that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is a novel tumor suppressor that is highly expressed in normal renal tubular epithelial cells, but it is downregulated in human renal cancer. We have identified CCAAT/enhancer-binding proteinβ (C/EBPβ, also called LAP) as a key transcriptional regulator of TMIGD1, whose loss of expression is responsible for downregulation of TMIGD1 in RCC. Transcriptionally active C/EBPβ/LAP physically interacted with and increased TMIGD1 promoter activity and expression of TMIGD1. Re-introduction of TMIGD1 into renal tumor cells significantly inhibited tumor growth and metastatic behaviors such as morphogenic branching and cell migration. Restoring TMIGD1 expression in renal tumor cells stimulated phosphorylation of p38MAK, induced expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in regulation of the cell cycle. The present study identifies TMIGD1 as a novel candidate tumor suppressor gene and provides important insight into pathobiology of RCC that could lead to a better diagnosis and possible novel therapy for RCC.
Background/AimsPediatric immune thrombocytopenia (ITP) is an autoimmune disease; whose etiology is not exactly understood and seems to be highly multifactorial. Long non‐coding RNAs (lncRNAs) are key regulators of different actions, which contribute to the development of many autoimmune diseases. To gain a further understanding, we estimated the relative expression of lncRNAs Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) and tumor necrosis factor‐α (TNF‐α) and heterogeneous nuclear ribonucleoprotein L (hnRNPL) immune‐regulatory lncRNA (THRIL) in pediatric ITP.MethodsIn this case‐control study, analysis of the expression profiles of these lncRNAs in blood samples from children with ITP and healthy controls (HCs) using quantitative real‐time PCR was done. The association of MALAT1 and THRIL with ITP clinical features and their potential usage as non‐invasive circulating biomarkers for ITP diagnosis was also evaluated. The receiver operating characteristic curve was constructed, and an area under the curve was analyzed.ResultsBoth lncRNAs MALAT1 and THRIL were significantly upregulated in ITP patients in comparison to HCs ( p < .0001 and = .001 respectively). In addition, there was a positive significant correlation between the expression level of both biomarkers among patients (r = 0.745, p < .0001). At cutoff points of 1.17 and 1.27 for lncRNAs MALAT1and THRIL, respectively, both biomarkers had an excellent specificity (100% for both) and fair sensitivity (63.6 and 73.3% for lncRNAs MALAT1and THRIL, respectively). Improvement of biomarkers specificity was obtained by evaluation of the combined expression of both biomarkers. Serum lncRNAs MALAT1 and THRIL could be used as potential biomarkers in differentiating childhood ITP patients and HCs.
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