Tengfei Ma

Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies.

BACKGROUND Previous studies have examined the effect of statin use on the mortality in cancer patients, but the results are inconsistent. A meta-analysis was performed to assess the association with all available studies. METHODS Relevant studies were identified by searching PubMed and EMBASE to April 2015. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. We estimated combined HRs associated with defined increments of statin use, using random-effects meta-analysis and dose-response meta-regression models. RESULTS Thirty-nine cohort studies and two case-control studies involving 990,649 participants were included. The results showed that patients who used statins after diagnosis had a HR of 0.81 (95% CI: 0.72-0.91) for all-cause mortality compared to non-users. Those who used statin after diagnosis (vs. non-users) had a HR of 0.77 (95% CI: 0.66-0.88) for cancer-specific mortality. Prediagnostic exposure to statin was associated with both all-cause mortality (HR=0.79, 95% CI: 0.74-0.85) and cancer-specific mortality (HR=0.69, 95% CI: 0.60-0.79). Stratifying by cancer type, the three largest cancer-type subgroups were colorectal, prostate and breast cancer and all showed a benefit from statin use. HRs per 365 defined daily doses increment were 0.80 (95% CI: 0.69-0.92) for all-cause mortality and 0.77 (95% CI: 0.67-0.89) for cancer-specific mortality. A 1year increment in duration only conferred a borderline decreased risk of death. CONCLUSIONS In conclusion, the average effect of statin use, both postdiagnosis and prediagnosis, is beneficial for overall survival and cancer-specific survival.

Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein

Acquired drug resistance is a major obstacle to chemotherapy of cancers. In this study, we aim to investigate the role of exosomes in drug-resistance transfer between breast cancer cells and detect the probable mechanism. A docetaxel-resistant variant of MCF-7 cell line (MCF-7/DOC) was established and then compared with the drug-sensitive variant (MCF-7/S). Exosomes were expelled from the cell supernatant using ultracentrifugation. Drug resistance was assessed by apoptosis assay and MTT examination. Expressions of P-glycoprotein (P-gp) were analyzed by flow cytometry. Stained exosomes were absorbed by receipt cells. MCF-7/S in the presence of exosomes extracted from the supernatant of MCF-7/DOC (DOC/exo) acquired drug resistance, while MCF-7/S exposed to their own exosomes (S/exo) did not. P-gp expression patterns of exosomes were similar as the originated cells. P-gp expression of MCF-7/S increased after incubation with DOC/exo and was affected by the amount of exosomes. Exosomes are effective in transferring drug resistance as well as P-gp from drug-resistant breast cancer cells to sensitive ones. The delivery of P-gp via exosomes may be a mechanism of exosome-mediated drug resistance transfer.

Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs

Breast cancer (BCa) remains chemo-unresponsive by inevitable progression of resistance to first-line treatment with docetaxel (doc). Emerging studies indicate that exosomes act as mediators of intercellular communication between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development. Such modulatory effects have been related to the constant shuttle of biologically active molecules including microRNAs (miRNAs). Here, we aimed to investigate the relevance of exosome-mediated miRNA delivery in resistance transmission of BCa subpopulations. Using microarray and polymerase chain reaction, we found that exosomes from doc-resistant BCa cells (D/exo) loaded cellular miRNAs. Following D/exo transfer to the fluorescent sensitive cells (GFP-S), some miRNAs were significantly increased in recipient GFP-S. Target gene prediction and pathway analysis revealed the involvement of the top 20 most abundant miRNAs of D/exo in pathways implicated in therapy failure. Coculture assays showed that miRNA-containing D/exo increased the overall resistance of GFP-S to doc exposure. Moreover, D/exo was able to alter gene expression in GFP-S. Our results open up an intriguing possibility that drug-resistant BCa cells may spread chemoresistance to sensitive ones by releasing exosomes and that the effects could be partly attributed to the intercellular transfer of specific miRNAs.

Down-regulation of miRNA-452 is associated with adriamycin-resistance in breast cancer cells.

Adriamycin (ADR) is an important chemotherapeutic agent frequently used in treatment of breast cancer. However, resistance to ADR results in treatment failure in many patients. Recent studies have indicated that microRNAs (miRNAs) may play an important role in such drug-resistance. In the present study, microRNA-452 (miR-452) was found to be significantly down-regulated in adriamycin-resistant MCF-7 cells (MCF-7/ADR) compared with the parental MCF-7 cells by miRNA microarray and real-time quantitative PCR (RT-qPCR). MiR-452 mimics and inhibitors partially changed the adriamycin-resistance of breast cancer cells, as also confirmed by apoptosis assay. In exploring the potential mechanisms of miR-452 in the adriamycin-resistance of breast cancer cells, bioinformatics analysis, RT-qPCR and Western blotting showed that dysregulation of miR-452 played an important role in the acquired adriamycin-resistance of breast cancer, maybe at least in part via targeting insulin-like growth factor-1 receptor (IGF-1R).

Role of miR-155 in drug resistance of breast cancer

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expressions at posttranscriptional level. Growing evidence points to their significant role in the acquisition of drug resistance in cancers. Studies show that miRNAs are often aberrantly expressed in human cancer cells which are associated with tumorigenesis, metastasis, invasiveness, and drug resistance. Breast cancer is the leading cause of cancer-induced death in women. Over the last decades, increasing attention has been paid to the effects of miRNAs on the development of breast cancer drug resistance. Among them, miR-155 takes part in a sequence of bioprocesses that contribute to the development of such drug resistance, including repression of FOXO3a, enhancement of epithelial-to-mesenchymal transition (EMT) and mitogen-activated protein kinase (MAPK) signaling, reduction of RhoA, and affecting the length of telomeres. In this review, we discuss the role of miR-155 in the acquisition of breast cancer drug resistance. This will provide a new way in antiresistance treatment of drug-resistant breast cancer.

MicroRNA-3646 Contributes to Docetaxel Resistance in Human Breast Cancer Cells by GSK-3β/β-Catenin Signaling Pathway

Acquisition of resistance to docetaxel (Doc) is one of the most important problems in treatment of breast cancer patients, but the underlying mechanisms are still not fully understood. In present study, Doc-resistant MDA-MB-231 and MCF-7 breast cancer cell lines (MDA-MB-231/Doc and MCF-7/Doc) were successfully established in vitro by gradually increasing Doc concentration on the basis of parental MDA-MB-231 and MCF-7 cell lines (MDA-MB-231/S and MCF-7/S). The potential miRNAs relevant to the Doc resistance were screened by miRNA microarray. We selected 5 upregulated miRNAs (has-miR-3646, has-miR-3658, has-miR-4438, has-miR-1246, and has-miR-574-3p) from the results of microarray for RT-qPCR validation. The results showed that expression level of miR-3646 in MDA-MB-231/Doc cells was significantly higher than in MDA-MB-231/S cells. Compared to MCF-7/S cells, miR-3646 expression was up-regulated in MCF-7/Doc cells. Further studies revealed that transfection of miR-3646 mimics into MDA-MB-231/S or MCF-7/S cells remarkably increased their drug resistance, in contrast, transfection of miR-3646 inhibitors into MDA-MB-231/Doc or MCF-7/Doc cells resulted in significant reduction of the drug resistance. By the pathway enrichment analyses for miR-3646, we found that GSK-3β/β-catenin signaling pathway was a significant pathway, in which GSK-3β was an essential member. RT-qPCR and Western blot results demonstrated that miR-3646 could regulate GSK-3β mRNA and protein expressions. Furthermore, a marked increase of both nuclear and cytoplasmic β-catenin expressions (with phosphorylated-β-catenin decrease) was observed in MDA-MB-231/Doc cells compared with MDA-MB-231/S cells, and their expression were positively related to miR-3646 and negatively correlated with GSK-3β. Taken together, our results suggest that miR-3646-mediated Doc resistance of breast cancer cells maybe, at least in part, through suppressing expression of GSK-3β and resultantly activating GSK-3β/β-catenin signaling pathway.

Lovastatin suppresses the aberrant tau phosphorylation from FTDP-17 mutation and okadaic acid-induction in rat primary neurons.

Statins are a class of cholesterol-lowering drugs and have been suggested therapeutic use for neurodegenerative diseases including Alzheimers disease (AD). Our recent studies revealed a neuronal protective effect of lovastatin (LOV) from N-methyl-d-aspartic acid (NMDA) excitotoxicity. The neuroprotective mechanism of statins, however, is far unknown. Here we demonstrated that LOV suppressed the aberrant tau phosphorylation both from frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) mutation and okadaic acid (OA) induction in cultured rat primary neurons. The protective effect of LOV occurred at multiple pathological sites of tau protein, including Tyr181, Tyr231 Ser202/Tyr205, Tyr212/Ser214 and Ser396/Ser404. Further analysis revealed that the potential mechanism of the suppressive effect of LOV resulted from two aspects, activating OA-inhibited protein phosphatase 2A (PP2A) activity and attenuating OA-induced activity of tau kinases CDK5/P25 and CDK2/4, but not glycogen synthase kinase 3β (GSK3β). These findings give new insights into the molecular mechanism of LOV-mediated neuroprotective effect and provide experimental evidence for its therapeutic use in AD.

MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in vinorelbine-resistant breast cancer cells.

Vinorelbine (NVB) is one of the most active cytotoxic agents in breast cancer, especially metastatic breast cancer. However, breast cancer patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, miRNA expression profiles of breast cancer cells MDA-MB-231/S and its NVB-resistant variant MDA-MB-231/NVB cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Bioinformatic analyses were carried out to predict gene targets of the dysregulated miRNAs and to analyze their potential roles in the development of drug resistance. Here, 123 differentially expressed miRNAs were identified in the resistant subline compared to MDA-MB-231/S. Networks of KEGG pathways, Gene Ontology (GO) terms, and protein-protein interaction (PPI) of 17 specific selected dysregulated miRNAs were constructed. The results showed that MAPK, mTOR, Wnt, and TGF-beta signaling pathways and several target genes such as CCND1, GRB2 and NT5E may associate with drug resistance of breast cancer cells to NVB. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to NVB in breast cancer MDA-MB-231 cells. All these analysis results provided us a comprehensive view of the function of differential expression miRNAs related to drug resistance of breast cancer and may be helpful for the further study.

Physical Activity and Risk of Lung Cancer: A Meta-analysis.

Objective:Previous studies concerning the association between physical activity (PA) and risk of lung cancer yielded mixed results. We investigated the association by performing a meta-analysis. Data Sources:Relevant studies were identified by searching PubMed and EMBASE to January 2014. Twelve cohort studies and 6 case–control studies involving 2 468 470 participants and 26 453 cases of lung cancer were selected for meta-analysis. Main Results:We calculated the summary relative risk (RR) and 95% confidence intervals (CIs) using random-effects models. The analyses showed that individuals who participated in any amount of PA had an RR of 0.79 (95% CI, 0.73-0.86) for risk of lung cancer. Those who participated in high PA (vs low PA) had an RR of 0.75 (95% CI, 0.68-0.84). Stratifying by study design (case–control and cohort studies), smoking status (current, former, and never smokers), and gender, similar inverse associations were found for all the subgroups except for never smokers subgroup. Conclusions:Pooled results from observational studies support a protective effect of PA against lung cancer.

Regulation of Spike Timing-Dependent Plasticity of Olfactory Inputs in Mitral Cells in the Rat Olfactory Bulb

The recent history of activity input onto granule cells (GCs) in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON) inputs to mitral cells (MCs). Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs) with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP) was achieved by the regulation of the inter-spike-interval (ISI) of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb.