BackgroundThe increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML.MethodsFlow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI.ResultsWe found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI-treated group in the AML PDX model.ConclusionsAntioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0948-3) contains supplementary material, which is available to authorized users.
The identification of novel tumour-associated antigens is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we identified a membrane protein MMSA-1 (multiple myeloma special antigen-1) that was specifically expressed in MM and exhibited significantly positive correlation with MM. We then identified HLA-A*0201-restricted MMSA-1 epitopes and tested their cytotoxic T lymphocyte (CTL) response. The MMSA-1 epitope SLSLLTIYV vaccine was shown to induce an obvious CTL response in vitro. To improve the immunotherapy, we constructed a multi-epitope peptide vaccine by combining epitopes derived from MMSA-1 and Dickkopf-1 (DKK1). The effector T cells induced by multi-epitope peptide vaccine-loaded dendritic cells lysed U266 cells more effectively than MMSA-1/DKK1 single-epitope vaccine. In myeloma-bearing severe combined immunodeficient mice, the multi-epitope vaccine improved the survival rate significantly compared with single-epitope vaccine. Consistently, multi-epitope vaccine decreased the tumour volume greatly and alleviated bone destruction. The frequencies of CD4 and CD8 T cells was significantly increased in mouse blood induced by the multi-epitope vaccine, indicating that it inhibits myeloma growth by changing T cell subsets and alleviating immune paralysis. This study identified a novel peptide from MMSA-1 and the multi-epitope vaccine will be used to establish appropriate individualized therapy for MM.
Reactive oxygen species (ROS) plays a key role in carcinogenesis by aberrantly inducing signaling networks that initiatiate tumorigenesis and stimulate tumor progression. MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate approximately 30% of the genes in a cell via degradation or translational inhibition of their target mRNAs. However, the effects of ROS on miRNAs expression and the role of miRNAs in ROS-mediated injury on carcinogenesis are uncertain. Using UV spectrophotometry and enzyme-linked immunosorbent assay (ELISA), we examined tissues from human gastric cancers and tissues adjascent to gastric cancer and normal gastric tissues and found that total anti-oxidation competence (T-AOC), superoxide dismutase (SOD) and catalase (CAT) concentrations were lower in gastric cancer patients compared to the control subjects, while the concentrations of DNA oxidative damage product 8-oxo-deoxyguanosine (8-OHdG) was higher. To determine the potential role of miRNA in gastric carcinogenesis, real-time quantitative polymerase chain reaction (QPCR) analysis was performed. We found that human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) mRNA and miR-21 expression were significantly upregulated in gastric cancer tissues than in the adjacent normal gastric tissues. Furthermore, the expression of programmed cell death 4 protein (PDCD4) in gastric cancer tissues was significantly lower than in adjacent normal gastric tissues. The expression of miR-21 and PDCD4 was highly correlated with the degree of differentiation, tumor staging, local lymphatic node metastasis and remote metastasis. Expression of miR-21 was negatively correlated with T-AOC, SOD and CAT, but positively correlated with 8-OHdG and hOGG1mRNA. In addition, the relative expression of PDCD4 was negatively correlated with miR-21. These results suggest that the defensive balance of oxidation and antioxidant system in patients with GC was impaired, resulting in enhanced oxidative tissue injury, which may directly contribute to gastric carcinogenesis. Thus we conclude that ROS promotes gastric carcinogenesis via upregulating miR-21 expression which in turn down-regulates the expression of PDCD4 in gastric cancer cells.
Background. The mechanisms of crosstalk between depression and gastric cancer (GC) remain ill defined. Given that reactive oxygen species (ROS) is involved in the pathophysiology of both GC and depression, we try to explore the activities of ROS in the development of GC and GC-related depression. Methods. 110 patients with newly diagnosed GC were recruited in our study. The clinical characteristics of these patients were recorded. Inflammation and oxidative stress markers were detected by ELISA. The depression status of patients with GC was assessed during follow-up. The association between ROS, ABL1, and inflammation factors was evaluated in H2O2-treated GC cell lines and The Cancer Genome Atlas (TCGA) database. The effect of ABL1 on inflammation was detected with Imatinib/Nilotinib-treated GC cell lines. A chronic mild stress- (CMS-) induced patient-derived xenograft (PDX) mice model was established to assess the crosstalk between depression and GC. Results. Depression was correlated with poor prognosis of patients with GC. GC patients with depression were under a high level of oxidative status as well as dysregulated inflammation. In the CMS-induced GC PDX mice model, CMS could facilitate the development of GC. Additionally, tumor bearing could induce depressive-like behaviors of mice. With the treatment of ROS, the activities of ABL1 and inflammatory signaling were enhanced both in vitro and in vivo, and blocking the activities of ABL1 inhibited inflammatory signaling. Conclusions. ROS-activated ABL1 mediates inflammation through regulating NF-κB1 and STAT3, which subsequently leads to the development of GC and GC-related depression.
Our previous studies have indicated that long noncoding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4‐IT1) was highly expressed in hepatocellular carcinoma (HCC). However, it still remained unclear how SPRY4‐IT1 worked in tumorgenesis in HCC. In this study, we tested the overexpression of SPRY4‐IT1 in HCC tissues and cells through a quantitative real‐time polymerase chain reaction. Statistical analyses showed that the upregulation had an association with the tumor node metastasis stage, thrombin time, and alkaline phosphatase. Furthermore, SPRY4‐IT1 could be involved in cell proliferation, metastasis, and the epithelial‐to‐mesenchymal transition (EMT) process in HCC in vitro and in vivo. RNA‐sequencing and transcriptome analysis were carried out to explore the mechanism of SPRY4‐IT1 in HCC. With SPRY4‐IT1 being knocked down or overexpressed, the level of proteins in the tumor necrosis factor (TNF) signaling pathway changed. We detected the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a SPRY4‐IT1 interacting protein through RNA pull‐down assay and liquid chromatography–mass spectrometry, then verified through RNA immunoprecipitation. Downregulation of HNRNPL induced the change of proteins observed on SPRY4‐IT1 downregulation revealing the SPRY4‐IT1: HNRNPL complex in the TNF signaling pathway and EMT process in HCC. In general, our experimental data and analysis demonstrated the role of SPRY4‐IT1 in promoting progress and metastasis of HCC by the TNF signaling pathway.
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