Elevated expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the development of the multidrug resistance phenotype in patients with advanced non-small-cell lung cancer (NSCLC). Due to the lack of U.S. Food and Drug Administration (FDA)-approved synthetic inhibitors of ABCG2, significant efforts have been invested in discovering bioactive compounds of plant origin that are capable of reversing ABCG2-mediated multidrug resistance in cancer cells. Sophoraflavanone G (SFG), a phytoncide isolated from the plant species Sophora flavescens, is known to possess a wide spectrum of pharmacological activities, including antibacterial, anti-inflammatory, antimalarial, and antiproliferative effects. In the present study, the chemosensitizing effect of SFG in ABCG2-overexpressing NSCLC cells was investigated. Experimental results demonstrate that at subtoxic concentrations SFG significantly reversed ABCG2-mediated multidrug resistance in a concentration-dependent manner. Additional biochemical data and in silico docking analysis of SFG to the inward-open conformation of human ABCG2 indicate that SFG inhibited the drug transport function of ABCG2 by interacting with residues within the transmembrane substrate-binding pocket of ABCG2. Collectively, these findings provide evidence that SFG has the potential to be further tested as an effective inhibitor of ABCG2 to improve the efficacy of therapeutic drugs in patients with advanced NSCLC.
Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.
Abstract Background : Trophinin‑associated protein (TROAP) was known as the tastin, which originally recognized as a cytosolic protein involved in embryo implantation. Increasing studies have revealed that high expression of TROAP is related with poor outcomes in cancers. However, there have been few studies on the correlation of TROAP and pancreatic cancer. This study aimed to explore the prognostic significance of TROAP in pancreatic cancer by mining the data collected from The Cancer Genome Atlas (TCGA) dataset. Methods : Clinical information and the RNA expression data were obtained from the TCGA dataset. The correlations between clinical information and TROAP mRNA expression were performed by chi-square and Fisher exact tests. Univariate Cox analyses were used to filter the potential prognostic factors. The correlations between TROAP expression and clinical characteristics of patients with pancreatic cancer were confirmed by multivariate Cox analyses. Results : Analysis of tumor data showed that high expression of TROAP was correlated with poor outcomes in pancreatic cancer patients. Univariate and multivariate Cox analyses demonstrated that TROAP mRNA expression played an important role in shorting overall survival (OS) and relapse-free survival (RFS), which might serve as the useful biomarker and prognostic factor for pancreatic cancer. Conclusions : TROAP was an independent risk factor for pancreatic cancer. TROAP has the potential to be a biomarker, especially in predicting prognosis.
Abstract The neutrophil-to-lymphocyte ratio is used to reflect body's inflammatory status with prognostic value in different cancers. We aimed to investigate the influence of preoperative NLR in the prognosis of CRLM patients receiving surgery using meta-analysis. Data in Cochrane Library, PubMed, Embase, and Web of Science databases created before October 2022 were recruited. Meta-analysis was carried out with RevMan 5.3 and Stata16 software, and the primary outcome indicators included overall survival (OS), and secondary outcome indicators included disease-free survival (DFS) and relapse-free survival (RFS). The pooled risk ratio (HR) and 95% confidence interval (CI) for each outcome indicator were determined using random-effects models or fixed-effects models. The pooled odds ratio (OR) and corresponding 95% confidence intervals (CI) for NLR and clinicopathological characteristics were determined with a fixed-effects model. 18 papers published between 2008 and 2022 (3184 patients in total) were included. The pooled analysis found that high preoperative NLR was correlated with poor OS (multivariate HR = 1.83, 95% CI = 1.61–2.08, p < 0.01), DFS (multivariate HR = 1.78, 95% CI = 1.16–2.71, p < 0.01) and RFS (multivariate HR = 1.46, 95% CI = 1.15–1.85, p < 0.01), but NLR was not related to clinicopathological features of CRLM patients correlation. In conclusion, NLR is an independent risk factor for poor prognosis in patients with CRLM. More large-scale clinical researches are required in the future to demonstrate the inclusion of preoperative NLR as a prognostic indicator for CRLM patients to guide postoperative adjuvant chemotherapy.
In maize shoot-borne roots dominate the whole root system and play essential roles in water and nutrient acquisition and lodging tolerance. Shoot-borne roots are initiated at shoot nodes, including crown roots from the belowground nodes and brace roots from aboveground nodes. In contrast to crown roots, few genes for brace roots development have been identified. Here, we characterized a maize AP2/ERF transcriptional factor, ZmRAP2.7, to be involved in brace root development. ZmRAP2.7 expressed in all types of roots, and the encoded protein localized in the nuclear with transcriptional activation activity. A maize transposon target mutant RAP2.7-Mu defective in ZmRAP2.7 expression revealed a decreased number of brace roots but not crown roots. Maize Corngrass1 mutant which showed an elevated expression of ZmRAP2.7, however, revealed an increased number of brace roots. The ZmRAP2.7-based association analysis in a maize panel further identified a SNP marker at the fifth exon of gene to be associated with number of brace roots. These results uncovered a function of ZmRAP2.7 in brace root development, and provided the valuable gene and allele for genetic improvement of maize root systems.
Background MEX3A is an RNA-binding proteins (RBPs) that promotes the proliferation, invasion, migration and viability of cancer cells. The aim of this study was to explore the clinicopathological characteristics and prognostic significance of MEX3A mRNA expression in liver cancer. Methods RNA-Seq and clinical data were collected from The Cancer Genome Atlas (TCGA). Boxplots were used to represent discrete variables of MEX3A. Chi-square tests were used to analyze the correlation between clinical features and MEX3A expression. Receiver operating characteristic (ROC) curves were used to confirm diagnostic ability. Independent prognostic ability and values were assessed using Kaplan–Meier curves and Cox analysis. Results We acquired MEX3A RNA-Seq from 50 normal liver tissues and 373 liver cancer patients along with clinical data. We found that MEX3A was up-regulated in liver cancer which increased according to histological grade ( p < 0.001). MEX3A showed moderate diagnostic ability for liver cancer (AUC = 0.837). Kaplan–Meier curves and Cox analysis revealed that the high expression of MEX3A was significantly associated with poor survival (OS and RFS) ( p < 0.001). Moreover, MEX3A was identified as an independent prognostic factor of liver cancer ( p < 0.001). Conclusions MEX3A expression shows promise as an independent predictor of liver cancer prognosis.
AIMTo determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression.
Clinical responses to standard cytarabine plus anthracycline regimen in acute myeloid leukemia (AML) are heterogeneous and there is an unmet need for biological predictors of response to this regimen. Here, we applied a pharmacometabolomics approach to identify potential biomarkers associated with response to this regimen in AML patients. Based on clinical response the enrolled 82 patients were subdivided into two groups: complete remission(CR) responders (n=42) and non-responders (n=40). Metabolic profiles of pre-treatment serum from patients were analyzed by ultra-high performance liquid chromatography coupled with mass spectrometry and the metabolic differences between the two groups were investigated by multivariate statistical analysis. A metabolite panel containing dodecanamide and leukotriene B4 dimethylamide (LTB4-DMA) had the power capacity to differentiate the two groups of patients, yielding an area under the receiver operating characteristic of 0.945 (85.2% sensitivity and 88.9% specificity) in the training set and 0.944(84.6% sensitivity and 80.0% specificity) in the test set. The patients with high levels of LTB4-DMA and low amounts of dodecanamide had good sensitivity to chemotherapeutic agents. The possible reasons were that dodecanamide was produced by leukemic cells as a lipolytic factor to fuel their growth with a potential role in drug resistance and LTB4-DMA was a potent leukotriene B4 antagonist that could be applicable in the treatment of AML. These preliminary results demonstrates the feasibility of relating chemotherapy responses with pre-treatment metabolic profiles of AML patients, and pharmacometabolomics may be a useful tool to select patients that are more likely to benefit from cytarabine plus anthracycline chemotherapy.
In glioblastomas, the surface glycoprotein CD133 (prominin-1) indicates the presence of cancer stem cells (CSCs), which are able to initiate tumor growth and are highly resistant to conventional chemo/radiotherapy. However, a number of studies have reported that certain CD133- glioma cells are able to self-renew and retain tumorigenic potential. In addition, the reliability of CD133 as a CSC marker is controversial due to inconsistent findings with regard to the prognostic values and distribution of CD133. Such controversies may be due to the detection limits using currently available anti-CD133 antibodies. In the present study, novel anti-human CD133 monoclonal antibodies (mAbs) were generated using two recombinant extracellular domains of human CD133: CD133 ectodomain 1 (amino acids 171-420) and CD133 ectodomain 2 (amino acids 507-716). One of the antibodies produced against CD133 ectodomain 2, C2E1, detected high expression levels of CD133 protein in glioblastoma U87 cells, in contrast to previous studies which did not detect CD133 expression in these cells. The cells exhibited a cytoplasmic distribution pattern of CD133 and produced a 95 kDa band following western blot analysis. In addition, C2E1 was able to bind the full-length glycosylated CD133 on the cell surface and inhibit the proliferation of tumor cells. Therefore, this antibody may be a valuable tool to study CD133 as a CSC marker and may be significant in future cancer treatments.
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