DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan–Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients.

Cancer side-population (SP) represents a sub-population of stem-like cancer cells that have an important role in drug resistance due to their high expression of the ATP-binding cassette transporter ABCG2 involved in drug export. Auranofin (AF), a clinical drug of gold complex that is used in treatment of rheumatoid arthritis, has been reported inducing tumor antiproliferation. However, whether AF can impact SP cells remains unclear. Our study showed that AF caused a depletion of SP cells and a downregulation of stem cell markers, and impaired their ability to form tumor colonies in vitro and incidence to develop tumors in vivo of lung cancer cells. Reactive oxygen species (ROS) had an important role in mediating AF-induced depletion of SP cells, which could be reversed by antioxidant NAC. Further study revealed that AF could also cause ATP depletion by inhibition of glycolysis. The depletion of cellular ATP might impair the function of ABCG2 pump, leading to increased drug accumulation within the cells and thus enhancing anticancer activity of chemotherapeutic agents such as adriamycin. Synergistic effect of AF and adriamycin was demonstrated both in vitro and in vivo. Simultaneous increase of ROS and inhibition of glycolysis is a novel strategy to eliminate stem-like cancer cells. Combination of AF with adriamycin seems to be promising to enhance therapeutic effectiveness.

BackgroundCancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s).MethodsBiochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo.ResultsWe show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the β-catenin pathway.ConclusionGlutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by β-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0623-x) contains supplementary material, which is available to authorized users.

IntroductionNicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are frequently deregulated in several human malignancies, including gastric cancer (GC). NOX-derived reactive oxygen species have been reported to contribute to gastric carcinogenesis and cancer progression. However, the expression and prognostic role of individual NOX in GC patients remain elusive.Methods and materialsWe investigated genetic alteration and mRNA expression of NOX family in GC patients via the cBioPortal, Human Protein Atlas, and Oncomine databases. Furthermore, we evaluated prognostic value of distinct NOX in GC patients through “The Kaplan–Meier plotter” database.ResultsOur analysis demonstrated that mRNA deregulation of NOX genes was common alteration in GC patients. Compared with normal tissues, NOX1/2/4 mRNA expression levels in GC tissues were higher, while NOX5 and DUOX1/2 expression levels were lower. Importantly, our results indicated that high mRNA expression of NOX2 was associated with better overall survival whereas NOX4 and DUOX1 were correlated with worse overall survival in all GC patients, particularly in intestinal-type GC patients. In addition, our data also shed light on the diverse roles of individual NOX members in GC patients with different clinicopathological features, including human epidermal growth factor receptor 2 status, clinical stages, pathological grades, and different choices of treatments of GC patients.ConclusionThese findings suggest that individual NOX family genes, especially NOX2/4, and DUOX1, are potential prognostic markers in GC and implicate that the use of NOX inhibitor targeting NOX4 and DUOX1 may be an effective strategy for GC therapy.

The ubiquitin-proteasome pathway is an important protein degradation regulatory system in cells. This pathway is also a reversible process that is strictly regulated, and the regulation of deubiquitinating enzymes (DUBs) represents an important facet of the process. Ovarian tumor-associated proteases domain-containing proteins (OTUDs), as a subfamily within the DUB family, serve an important role in regulatory mechanisms of several biological processes, through the regulation of gene transcription, cell cycle, immune response, inflammation and tumor growth processes, and may be important in the diagnosis of various diseases and constitute novel drug targets. However, the role of OTUDs in non-small-cell lung cancer (NSCLC) has not been fully elucidated. In the present study, the Oncomine database was used to examine gene expression in NSCLC, and the prognostic value of each gene was analyzed by Kaplan-Meier analysis. The results indicated that high mRNA expression levels of OTUD1, OTUD3, OTUD4 and putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 were associated with improved prognosis in all NSCLC and adenocarcinoma, but not in squamous cell carcinoma. By contrast, high expression levels of OTUD2 mRNA were associated with poorer overall survival in patients with NSCLC. These data suggested that these OTUD isozymes may be a potential drug target for NSCLC.

Thrombospondin-2 (THBS2) is a secreted protein overexpressed in numerous cancers and may function as a diagnostic tumor marker. The objective of the present study was to investigate the diagnostic performance of serum THBS2 in early stage non-small-cell lung cancer (NSCLC). Serum THBS2 and Cyfra21-1 level were evaluated in blood samples of 112 patients from NSCLC groups and 51 healthy control (HC) groups. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic significance. Serum THBS2 level was significantly up-regulated in NSCLC patients compared with healthy control subjects (P<0.0001), and the postoperative THBS2 level decreased significantly (P<0.0001). ROC curves analysis demonstrated that THBS2 was a comparable biomarker as Cyfra21-1 to distinguish early stage NSCLC or lung squamous cell carcinoma (SC) from healthy control subjects. And Cyfra21-1 was observed with significantly improved performances by the combination of THBS2 to distinguish early stage NSCLC (P<0.05) as well as SC (P<0.05) from the control subjects. In addition, THBS2 was estimated to perform well in the diagnosis of patients with Cyfra21-1-negative NSCLC (area under the curve [AUC] = 0.73). In summary, the present study suggested that serum THBS2 might be an early diagnostic biomarker for NSCLC.

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