Significant progress has been made in the diagnosis and treatment of the drugresistant and highly recurrent refractory T cell acute lymphoblastic leukemia (T-ALL). Primary tumor cell-derived induced pluripotent stem cells (iPSCs) have become very useful tumor models for cancer research including drug sensitivity tests. In the present study, we investigated the mechanism underlying drug resistance in T-ALL using the T-ALL-derived iPSCs (T-iPSCs) model. T-ALL cells were transformed using iPSC reprogramming factors (Sox-2, Klf4, Oct4, and Myc) via nonintegrating Sendai virus. T-iPSCs with the Notch1 mutation were then identified through genomic sequencing. Furthermore, T-iPSCs resistant to 80 μM LY411575, a γsecretase and Notch signal inhibitor, were also established. We found a significant difference in the expression of drug resistance-related genes between the drug-resistant T-iPSCs and drug-sensitive groups. Among the 27 genes, six most differently expressed genes (DEGs) based on Log 2 FC >5 were identified. Knockdown analyses using RNA interference (RNAi) revealed that MAEL is the most important gene associated with drug resistance in T-ALL cells. Also, MAEL knockdown downregulated expression of MRP and LRP in drug-resistant T-iPSCs. Interestingly, this phenomenon partially restored the sensitivity of the cells to LY411575. Furthermore, overexpression of the MAEL gene enhanced drug resistance against LY411575. Conclusively, MAEL promotes LY411575 resistance in T-ALL cells increasing the expression of MRP and LRP genes.
Vitamin D is widely considered to have a regulatory effect on the immune system. Some clinical investigations have shown that the demand for vitamin D increases with age. Calcitriol is the biologically active form of vitamin D. However, its effect on human natural killer (NK) cells remains unclear. Therefore, in this study, we investigated the anti-aging and immunomodulatory effects of calcitriol on NK cells using a series of immunological methods to explore its important role in innate immunity. We found that calcitriol reversed the expression of aging-related biomarkers in NK cells and inhibited their expansion by maintaining these cells in the G1 phase, without any apoptosis and exhaustion. Calcitriol repressed the release of inflammation-related cytokines, such as interleukin-5 (IL-5), interleukin-13 (IL-13), interferon-gamma (IFN-γ), and tumor necrosis factoralpha (TNF-α). The degranulation of NK cells was downregulated by calcitriol when these cells were co-cultured with K562 tumor cells. We also found that calcitriol upregulated the agingrelated sirtuin 1-protein/kinase R-like endoplasmic reticulum kinase (SIRT1/pERK) pathway and SIRT1-deltaExon8 (SIRT1-∆Exon8) expression by activating the vitamin D receptor (VDR). Moreover, calcitriol could be a potential negative regulator of NK cell apoptosis and mitochondrial inactivation which caused by oxidative stress. Thus, calcitriol exhibits anti-aging effects on human NK cells in vitro by activating the SIRT1-PERK axis and resisting oxidative senescence.
BackgroundCholangiocarcinoma (CCA), including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, is a highly aggressive malignancy originating from bile duct. The prognosis of CCA is very poor, and the biomarker study is unsatisfactory compared with other common cancers.Materials and methodsIn our study, we investigated the expression of dual-specificity phosphatase 11(DUSP11) in eight pairs of iCCAs, pCCAs, and dCCAs, and their corresponding tumor-adjacent tissues, as well as their tumor-adjacent tissues with qPCR. Moreover, we investigated the expression of DUSP11 in 174 cases of CCAs with immunohistochemistry, including 74 iCCAs, 64 pCCAs, and 36 dCCAs. We classified these patients into subsets with low and high expressions of DUSP11, and evaluated the correlations between the DUSP11 subsets and clinicopathological factors. With univariate and multivariate analyses, we assessed the correlation between DUSP11 and the overall survival (OS) rates in these CCA patients.ResultsIn all the CCA subtypes, DUSP11 was elevated in CCAs compared with their paired adjacent tissues. In iCCA, pCCA, and dCCA, the percentages of DUSP11 high expression were 44.59%, 53.85%, and 55.56%, respectively. In iCCA, high DUSP11 expression was significantly associated with an advanced T stage and a poor prognosis. However, the prognostic value of DUSP11 in pCCA and dCCA was not significant. To decrease the statistical error caused by the small sample size of the dCCA cohort, we merged pCCA and dCCA into extracellular CCA (eCCA). In the 101 cases of eCCA, DUSP11 expression was also not significantly associated with the prognosis.ConclusionsDUSP11 expression was associated with tumor infiltration and the OS rate in iCCA, but not in pCCA and dCCA. DUSP11 was an independent biomarker of iCCA indicating a poor prognosis. Our results suggested that a high expression of DUSP11 was a post-operational risk factor, and detecting DUSP11 could guide the individual treatment for patients with CCA.
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