Extracellular ATP has been shown to play an important role in invasion and the epithelial‐mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia‐inducible factor (HIF) signaling and upregulate hypoxia‐inducible factor 1/2α (HIF‐1/2α) expression. After knocking down HIF‐1/2α using siRNA, we found that ATP‐driven invasion and EMT were significantly attenuated via HIF2A‐siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF‐2α direct targets, among which lysyl oxidase‐like 2 (LOXL2) and matrix metalloproteinase‐9 (MMP‐9) mediated ATP‐driven invasion, and E‐cadherin and Snail mediated ATP‐driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF‐2α and mediate ATP‐driven HIF‐2α upregulation. Furthermore, we demonstrated that expressions of HIF‐2α and its target proteins could be regulated via ATP by AKT‐PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF‐2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP‐HIF‐2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF‐2α signaling, which may be a potential target for future anti–metastasis therapy.
Highlights d C1QBP stabilizes the MRE11 protein by forming the MRC complex with MRE11/RAD50 d C1QBP inhibits MRE11 exonuclease activity by preventing its binding to DNA d Appropriate C1QBP levels are essential for genomic stability and DNA repair
As an inhibitor of high mobility group protein B1 (HMGB1), ethyl pyruvate (EP) has been associated with various inflammatory diseases. Recent studies have investigated the relationship between EP and cancer. The present study aimed to determine the antitumor efficacy of EP in non-small cell lung cancer (NSCLC) cells and elucidate the underlying mechanism. A549, H520 and PC-9 cells were treated with EP in suitable concentrations. RT-qPCR and western blot analysis were performed to evaluate HMGB1 and RAGE expression levels. MTT and colony formation assays assessed the effect of EP on cell growth. A Transwell assay was used to evaluate invasion and migration potential and flow cytometry was performed to analyze cell apoptosis. Bcl-2 family proteins were identified by western blot analysis. The results demonstrated that an increased EP concentration effectively reduced HMGB1 and RAGE expression, thus inhibiting the HMGB1/RAGE axis. EP decreased level of PCNA and MMP-9 and increased P53 levels. Bcl-2 and Mcl-1 were also decreased, whereas Bax expression was increased. Furthermore, a high concentration of EP (30 mmol/l) significantly inhibited NF-κB and STAT3 activation. In summary, EP inhibited NSCLC cell growth, invasion and migration and induced apoptosis by suppressing the HMGB1/RAGE axis and the NF-κB/STAT3 pathway, thus suggesting that EP may be a valuable therapeutic agent for NSCLC.
Altered expression of claudin-3 (CLDN3), a key cytoskeletal structural protein of the tight junctions in the epithelium, is associated with the development and metastasis of various human cancers. CLDN3 expression has been shown to be significantly associated with the prognosis of lung squamous cell carcinoma (SqCC). This study investigated the role of CLDN3 in inhibiting lung SqCC cell migration and invasion as well as the underlying molecular mechanisms. The CLDN3 levels were assessed between 20 paired lung SqCC tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The ectopic CLDN3 overexpression or knockdown was generated by using a plasmid carrying CLDN3 cDNA or shRNA, respectively. CLDN3 expression was significantly reduced in lung SqCC tissues vs. the adjacent normal tissues. The ectopic CLDN3 overexpression markedly inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of lung cancer H520 cells, whereas CLDN3 knockdown had an inverse effect on SK-MES-1 cells. However, cell viability and plate colony formation assays showed that both CLDN3 knockdown and overexpression did not affect SqCC cell proliferation. Both tissue and cell data revealed that CLDN3 expression was significantly associated with the expression of the EMT biomarkers E-cadherin and Vimentin. Furthermore, CLDN3-modulated EMT and expression of the EMT markers were through regulation of the Wnt/β-catenin signaling pathway. In conclusion, this study identified reduced CLDN3 expression in lung SqCC tissues, which was associated with the progression and metastasis of lung SqCC and was attributed to EMT by activation of the Wnt pathway. Thus, CLDN3 could be further evaluated as a novel biomarker for predicting the prognosis of lung SqCC and as a target for the treatment of lung SqCC in the future.
AIMThe aim of this paper is to clarify the inconsistent findings in the association between antidepressant use and the risk of epithelial ovarian cancer (EOC). METHODSThis study is a meta-analysis of observational studies retrieved from the PubMed, EMBASE, and Web of Science databases prior to August 15, 2017. Two researchers independently screened studies and extracted study characteristics and risk estimates. The odds ratios (OR) and 95% confidence intervals (CI) of EOC risk were summarized using an inverse variance weighted randomeffects model. Heterogeneity between studies was assessed with the I 2 statistic. RESULTSEight case-control studies involving 7878 EOC cases and 73 913 controls were identified. Compared with non-use, use of antidepressants was not significantly associated with EOC risk (summarized OR = 1.10, 95% CI: 0.91-1.32, I 2 = 74.4%). Similar null results were also observed in the use of selective serotonin reuptake inhibitors (OR = 1.04, 95% CI = 0.80-1.35), tricyclic antidepressants (OR = 1.01, 95% CI = 0.79-1.30), and other antidepressant drugs (OR = 0.91, 95% CI = 0.74-1.12). Subgroup analyses of study characteristics, stratified by the type of control subjects, geographic location, exposure assessment, number of cases, and adjustment for potential confounders, showed that the ORs were broadly consistent across strata. The OR per 1 yearincrement of duration was 0.99 (95% CI = 0.94-1.05, I 2 = 40.0%, P = 0.154). Additionally, the OR for the greatest intensity of antidepressant use compared with never use was 0.82 (95% CI = 0.70-0.98, I 2 = 0%, P = 0.489). Furthermore, no evidence of publication bias was detected through Funnel plots as well as Egger's and Begg's tests. CONCLUSIONSThere is no association between antidepressant use and EOC risk. Further prospective studies are warranted to confirm these findings. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2018) 84 649-658 649
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