A cascade nanosystem with "Triple-Linkage" effect for enhanced photothermal and activatable metal ion therapy for hepatocellular carcinoma.

Due to the limitations of single-model tumor therapeutic strategies, multimodal combination therapy have become a more favorable option to enhance efficacy by compensating for its deficiencies. However, in nanomaterial-based multimodal therapeutics for tumors, exploiting synergistic interactions and cascade relationships of materials to achieve more effective treatments is still a great challenge. Based on this, we constructed a nanoplatform with a "triple-linkage" effect by cleverly integrating polydopamine (PDA), silver nanoparticles (AgNPs), and glucose oxidase (GOx) to realize enhanced photothermal therapy (PTT) and activatable metal ion therapy (MIT) for hepatocellular carcinoma (HCC) treatment. First, the non-radiative conversion of PDA under light conditions was enhanced by AgNPs, which directly enhanced the photothermal conversion efficiency of PDA. In addition, GOx reduced the synthesis of cellular heat shock proteins by interfering with cellular energy metabolism, thereby enhancing cellular sensitivity to PTT. On the other hand, H2O2, a by-product of GOx-catalyzed glucose, could be used as an activation source to activate non-toxic AgNPs to release cytotoxic Ag+, achieving activatable Ag+-mediated MIT. In conclusion, this nanosystem achieved efficient PTT and MIT for HCC by exploiting the cascade effect among PDA, AgNPs, and GOx, providing a novel idea for the design of multimodal tumor therapeutic systems with cascade regulation.

Polydopamine-Based Resveratrol-Hyaluronidase Nanomedicine Inhibited Pancreatic Cancer Cell Invasive Phenotype in Hyaluronic Acid Enrichment Tumor Sphere Model.

The dense storm microenvironment formed by an excessively cross-linked extracellular matrix, such as hyaluronic acid and collagens, serves as a major barrier that prevents drugs from reaching the deeper tumor. Current traditional two-dimensional (2D) cultures are not capable of modeling this drug delivery barrier in vitro. Thus, tumor spheroids have become increasingly important in cancer research due to their three-dimensional structure. Currently, various methods have been developed to construct tumor spheroids. However, there are still challenges, such as lengthy construction time, complex composition of added growth factors, and high cultivation costs. To address this technical bottleneck, our study combined the GelMA hydrogel system to develop a rapid and high-yield method for tumor spheroids generation. Additionally, we proposed an evaluation scheme to assess the effects of drugs on tumor spheroids. Building on the hyaluronic acid-rich pathological tumor microenvironment, we constructed a resveratrol-loaded nano-drug delivery system with tumor stroma modulation capability and used a three-dimensional (3D) tumor sphere model to simulate in vivo tumor conditions. This process was utilized to completely evaluate the ability of the nano-drug delivery system to enhance the deep penetration of resveratrol in the tumor microenvironment, providing new insights into future oncology drug screening, efficacy assessment, and drug delivery methods.

Metformin suppresses NFE2L1 pathway activation to inhibit gap junction beta protein expression in NSCLC.

OBJECTIVE: Non-small-cell lung cancer (NSCLC) is a deadly form of cancer that exhibits extensive intercellular communication which contributed to chemoradiotherapy resistance. Recent evidence suggests that arrange of key proteins are involved in lung cancer progression, including gap junction proteins (GJPs). METHODS AND RESULTS: In this study, we examined the expression patterns of GJPs in NSCLC, uncovering that both gap junction protein, beta 2 (GJB2) and gap junction protein, beta 2 (GJB3) are increased in LUAD and LUSC. We observed a correlation between the upregulation of GJB2, GJB3 in clinical samples and a worse prognosis in patients with NSCLC. By examining the mechanics, we additionally discovered that nuclear factor erythroid-2-related factor 1 (NFE2L1) had the capability to enhance the expression of connexin26 and connexin 31 in the NSCLC cell line A549. In addition, the use of metformin was discovered to cause significant downregulation of gap junction protein, betas (GJBs) by limiting the presence of NFE2L1 in the cytoplasm. CONCLUSION: This emphasizes the potential of targeting GJBs as a viable treatment approach for NSCLC patients receiving metformin.

Revealing a Novel Methylated Integrin Alpha-8 Related to Extracellular Matrix and Anoikis Resistance Using Proteomic Analysis in the Immune Microenvironment of Lung Adenocarcinoma.

Genomic epigenetics of extracellular matrix (ECM) play an important role in lung adenocarcinoma (LUAD). Our study identified a signature of potential prognostic genes associated with ECM and constructed immune risk-related prognosis model in LUAD. We downloaded mRNAs transcriptome data, miRNAs expression data, and clinical patient information for LUAD based on The Cancer Genome Atlas. "Limma, clusterProfiler, ggplot2" R packages and GSEA were used to analyze meaningful genes and explore potential biological function. A competing endogenous RNA network was constructed to reveal the mechanism of ECM-related genes. Combined with clinical LUAD patients' characteristics, univariate and multivariate Cox regression analyses were used to build prognostic immune risk model. Next, we calculated AUC value of ROC curve, and explored survival probability of different risk groups. A total of 2966 mRNAs were differently expressed in LUAD samples and normal samples. Function enrichment analyses proved mRNAs were associated with many tumor pathways, such as cell adhesion, vascular smooth muscle contraction, and cell cycle. There were 18 mRNAs related to ECM receptor signaling pathway, and 7 mRNAs expressions were correlated with EGFR expression, but only 5mRNAs were associated with the long-term prognosis. Based on Integrin alpha-8 (ITGA8) molecule, we identified potential 3 miRNAs from several databases. The promoter of ITGA8 was higher-methylated and lower-expressed in LUAD. And lower-expressed group has poor prognosis for patients. 66 immunomodulators related to ITGA8 were performed to construct immune correlation prediction model (p < 0.05). Comprehensive analyses of ITGA8 revealed it combined focal adhesion kinase to activate PI3K/AKT signaling pathway to influence the occurrence and development of LUAD. A novel immune prognostic model about ITGA8 was constructed and verified in LUAD patients. Combined with non-coding genes and genomic epigenetics, identification of potential biomarkers provided new light on therapeutic strategy for clinical patients.

The association between chronic obstructive pulmonary disease and autoimmune diseases: a bidirectional Mendelian randomization study.

Objective: Observational studies have reported that chronic obstructive pulmonary disease (COPD) is often accompanied by autoimmune diseases, but the causal relationships between them remain uncertain. In this Mendelian study, we aimed to investigate the potential causal relationship between COPD and four common autoimmune diseases. Methods: We conducted an analysis of summary data on COPD and autoimmune disease using publicly available genome-wide association studies (GWAS) summary data. We initially employed the inverse- variance weighted method as the primary approach to establish the causal impact of COPD on autoimmune diseases in the sample and conducted additional sensitivity analyses to examine the robustness of the results. Subsequently, we performed reverse Mendelian randomization (MR) analyses for the four autoimmune diseases. Finally, the potential for bidirectional causal relationships was assessed. Results: Our MR analysis revealed no significant causal relationship between COPD and any of the studied autoimmune diseases. However, reverse MR results indicated a significant association between rheumatoid arthritis (RA), osteoarthritis (OA) and the risk of developing COPD, with respective odds ratios (OR) of 377.313 (95% CI, 6.625-21487.932, P = 0.004) for RA and 11.097 (95% CI, 1.583-77.796, P = 0.015) for OA. Sensitivity analyses confirmed the robustness of the results. Conclusion: Our findings support a potential causal relationship between autoimmune diseases and COPD, highlighting the importance of considering comorbidities in clinical management of COPD.

PLK3 promotes the proneural-mesenchymal transition in glioblastoma via transcriptional regulation of C5AR1.

BACKGROUND: Accumulating evidence suggests that polo-like kinase 3 (PLK3) plays an essential role in tumor cells and induces cell proliferation and may have implications for the prognosis of various cancers. We sought to define the role of PLK3-dependent proneural-mesenchymal transition (PMT) in the glioblastoma (GBM) therapy. METHODS AND RESULTS: We analyzed the expression data for PLK3 by using the TCGA database. PLK3 expression in GBM cell lines was determined by qRT-PCR and Western blotting. PLK3 levels were modulated using Lentivirus infection, and the effects on symptoms, tumor volume, and survival in mice intracranial xenograft models were determined. Irradiation (IR) was performed to induce PMT. PLK3 expression was significantly elevated in mesenchymal subtype GBM and promoted tumor proliferation in GBM. Additionally enriched PLK3 expression could be associated with poor prognosis in GBM patients compared with those who have lower PLK3 expression. Mechanically, PLK3-dependent PMT induced radioresistance in GBM cells via transcriptional regulation of complement C5a receptor 1 (C5AR1). In therapeutic experiments conducted in vitro, targeting PLK3 by using small molecule inhibitor decreased tumor growth and radioresistance of GBM cells both in vitro and in vivo. CONCLUSIONS: PLK3-C5AR1 axis induced PMT thus enhanced radioresistance in GBM and could become a novel potential therapeutic target for GBM.

Comprehensive analyses of genome-wide methylation and RNA epigenetics identify prognostic biomarkers, regulating the tumor immune microenvironment in lung adenocarcinoma.

The aim of our study was to identify a signature of immune-regulated molecules and reveal its prognostic role in lung adenocarcinoma (LUAD). We downloaded RNA-Sequencing data and DNA methylation data from the Gene Expression Omnibus (GEO) database. GEO2R was used to analyze differentially expressed mRNAs (DEmRNAs). we used "factoextra" R package to do the principal component analysis (PCA) of DEmRNAs. "Limma" R package was used to identify DEmRNAs, differentially expressed miRNAs (DEmiRNAs), differentially expressed lncRNAs (DElncRNAs) from The Cancer Genome Atlas (TCGA) database. Three R packages "org.Hs.eg.db", "clusterProfiler", "ggplot2″ were used to show enrichment results. Considering about methylation and mutation data, TEK and SOX17 mediated cancer signaling pathways. Through tumor-immune system interactions database (TISIDB) and Tumor Immune Estimation Resource (TIMER), higher methylated and lower expressed TEK may act as a prognostic marker, regulating the tumor immunity in LUAD. Through four databases (MEXPRESS, DNMIVD, MethSurv, Firehose), we further verified the methylation (P = 2.33e-23) and mutation about TEK. A signature of immune-associated TEK to predict survival of LUAD patients was validated. Prognostic, methylation, immune microenvironment analysis showed new light on potential novel therapeutic targets in LUAD.

Transmembrane protein 88 inhibits transforming growth factor-ß1-induced-extracellular matrix accumulation and epithelial-mesenchymal transition program in human pleural mesothelial cells through modulating TGF-ß1/Smad pathway.

Pleural fibrosis is an irreversible pathological process occurred in the development of several lung diseases. TMEM88 is a member of transmembrane (TMEM) family and has been found to be involved in the regulation of fibrogenesis. However, the role of TMEM88 in pleural fibrosis remains unknown. In this study, we aimed to explore the role of TMEM88 in pleural fibrosis in vitro using transforming growth factor-ß1 (TGF-ß1)-induced human pleural mesothelial cell line MeT-5A cells. Our results showed that the expression levels of TMEM88 were downregulated in pleural fibrosis tissues and TGF-ß1-treated Met-5A cells. Overexpression of TMEM88 inhibited the proliferation of Met-5A cells under TGF-ß1 stimulation. In addition, TMEM88 overexpression prevented TGF-ß1-induced extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) in Met-5A cells with decreased expression levels of Col I and fibronectin, increased levels of cytokeratin-8 and E-cadherin, as well as decreased levels of vimentin and α-SMA. Furthermore, overexpression of TMEM88 inhibited the expression of TGF-ß receptor I (TßRI) and TßRII and suppressed the phosphorylation of Smad2 and Smad3 in Met-5A cells. In conclusion, these results indicated that TMEM88 exhibited an anti-fibrotic activity in pleural fibrosis via inhibiting the activation of TGF-ß1/Smad signaling pathway.

PDK4 promotes tumorigenesis and cisplatin resistance in lung adenocarcinoma via transcriptional regulation of EPAS1.

The use of cisplatin for the treatment of non-small cell lung cancer has long been constrained by the rapid acquisition of tumor cell chemoresistance. In the present study, we sought to better elucidate the molecular mechanisms underlying this resistance phenotype. To that end, we assessed gene expression patterns in cisplatin-resistant lung adenocarcinoma cells, revealing pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) to be the most up-regulated kinase in resistant cells. We further found PDK4 upregulation to be directly linked with the acquisition of chemoresistance, driving enhanced tumor cell growth in vitro and in vivo. In clinical samples, we also found that PDK4 upregulation was detectable in patients with lung adenocarcinoma and that it was correlated with a poorer prognosis for these patients. From a mechanistic perspective, we further determined that PDK4 was able to promote lung adenocarcinoma cell growth and cisplatin resistance at least in part via regulating endothelial PAS domain-containing protein 1 (EPAS1) expression, thus highlighting PDK4 as a potentially viable therapeutic target in efforts to treat lung adenocarcinoma patients that have become resistant to cisplatin.

Pentraxin 3 (PTX-3) Levels in Bronchoalveolar Lavage Fluid as a Lung Cancer Biomarker.

In this study, we investigated the utility of pentraxin 3 (PTX-3) in bronchoalveolar lavage fluid (BALF) as lung cancer (LCa) diagnostic. A total of 89 LCa patients and 84 non-LCa patients who received bronchoscopy in the First Affiliated Hospital of Xi'an Jiaotong University from December 2014 to February 2015 were enrolled. LCa was subdivided according to pathological type (scale, gland, and small cell lung cancer). BALF samples were obtained during bronchoscopy and PTX-3 levels assayed by ELISA. t-tests, Mann-Whitney, and Kruskal-Wallis tests were performed for the comparison of PTX-3 levels between the different groups. Correlation analysis and receiver operating characteristic (ROC) analysis were used to analyze clinical data. The levels of PTX-3 increased in the LCa groups. PTX-3 levels were higher in the small cell lung cancer (SCLC) compared to non-small-cell lung cancer (NSCLC) groups. In LCa patients, obstructive pneumonia could upregulate the expression of PTX-3 in BALF. The area under the ROC curve of PTX-3 in BALF during LCa diagnosis, SCLC, and LCa with obstructive pneumonia was 0.949 (p ≤ 0.001), 0.672 (p < 0.05), and 0.838 (p < 0.01), respectively. In conclusion, PTX-3 in BALF has a potential value as an LCa biomarker, particularly in cases of SCLC and LCa with obstructive pneumonia.

MicroRNA-147b suppresses the proliferation and invasion of non-small-cell lung cancer cells through downregulation of Wnt/ß-catenin signalling via targeting of RPS15A.

Deregulation of microRNAs (miRNAs) leads to malignant growth and aggressive invasion during cancer occurrence and progression. miR-147b has emerged as one of the cancer-related miRNAs that are dysregulated in multiple cancers. Yet, the relevance of miR-147b in non-small-cell lung cancer (NSCLC) remains unclear. In the present study, we aimed to report the biological function and signalling pathways mediated by miR-147b in NSCLC. Our results demonstrate that miR-147b expression is significantly downregulated in NSCLC tissues and cell lines. Overexpression of miR-147b decreased the proliferative ability, colony-forming capability, and invasive potential of NSCLC cells. Notably, our study identified ribosomal protein S15A (RPS15A), an oncogene in NSCLC, as a target gene of miR-147b. Our results showed that miR-147b negatively modulates RPS15A expression in NSCLC cells. An inverse correlation between miR-147b and RPS15A was evidenced in NSCLC specimens. Moreover, miR-147b overexpression downregulated the activation of Wnt/ß-catenin signalling via targeting of RPS15A. Overexpression of RPS15A partially reversed the miR-147b-mediated antitumour effect in NSCLC cells. Collectively, these findings reveal that miR-147b restricts the proliferation and invasion of NSCLC cells by inhibiting RPS15A-induced Wnt/ß-catenin signalling and suggest that the miR-147b/RPS15A/Wnt/ß-catenin axis is an important regulatory mechanism for malignant progression of NSCLC.

PDK2 induces cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3.

Recurrence of lung adenocarcinoma has become one of the most frequent causes of major cancer incidence and mortality worldwide according to its frequently gained resistance to chemotherapies. In this study, we identified a poorly-studied kinase pyruvate dehydrogenase kinase isoform 2 (PDK2) as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Additionally, PDK2-dependent Cisplatin-resistance promotes tumour growth of lung adenocarcinoma both in vitro and in vivo. Clinically, PDK2 expression was up-regulated in lung adenocarcinoma and was correlated to the poor prognosis of lung cancer patients. Mechanically, PDK2 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of cyclin and CBS domain divalent metal cation transport mediator 3 (CNNM3), indicating that PDK2-CNNM3 signalling axis could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

HOXA4-Dependent Transcriptional Activation of AXL Promotes Cisplatin- Resistance in Lung Adenocarcinoma Cells.

BACKGROUND: Lung cancer is one of the most leading causes of cancer-related deaths in adults worldwide. Non-Small Cell Lung Cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most lethal subtype of lung cancer with a 5-year survival of less than 13%. In this study, we identified a poorly-studied kinase PDK4 as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. METHODS: In vitro cell viability assay and in vivo tumor xenograft assay were used in the detection of cell proliferation. RNA isolation, quantitative Real-Time PCR, Western blot analysis, immunohistochemistry were used to investigate the expression of RNA and protein. Lentivirus infection was used to regulate gene expression. Luciferase assays were used to monitor EPAS1 promoter activity. RESULTS: In vivo PDK4 expression was elevated in a Cisplatin-resistant population of lung adenocarcinoma cells, PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma in vivo and in vitro, clinically PDK4 expression was associated with poor prognosis in lung adenocarcinoma patients, mechanically PDK4 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of endothelial PAS domain-containing protein 1 (EPAS1). CONCLUSION: PDK4 is the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma and PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma mainly through transcriptional regulation of EPAS1. Enriched PDK4 expression was correlated with the poor prognosis of lung cancer patients, indicating that PDK4 could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

Loss of Beclin1 Expression and Nrf2 Overexpression are Associated with Poor Survival of Patients with Non-Small Cell Lung Cancer.

BACKGROUND: Nrf2 pathway and autophagy are abnormally activated in response to cellular stress in various types of human cancers. In this study, we selected Beclin1 as an enter point to discuss the relationship between Nrf2 pathway and autophagy, and defined their associations with clinic pathological features and survival of the patients. METHOD: NSCLC specimens were processed for immunohistochemical and qRT-PCR to analyses the expression of Beclin1 and Nrf2. Kaplan-Meier method and log-rank test were used in the survival data. RESULTS: Beclin1 protein level was found to be significantly associated with more advanced TNM stage (P = 0.035), lymph node metastasis (P = 0.017) and distant metastasis (P = 0.005). The expression of Nrf2 protein was associated with larger tumor size (P = 0.032), more advanced TNM stage (P = 0.011), lymph node metastasis (P = 0.045) and distant metastasis (P = 0.013). Beside there was a strong inverse relationship between Beclin1 and Nrf2 expression in the NSCLC tissues. Distant metastasis, Beclin1, Nrf2, and Beclin1-/Nrf2+ expression was conformed to be independent prognostic factors of patients. CONCLUSION: Both Nrf2 overexpression and Beclin1 lower-expression are independent indicators of a poor prognosis in NSCLC patients.

Combination treatment of FTY720 and cisplatin exhibits enhanced antitumour effects on cisplatin-resistant non-small lung cancer cells.

A major common medical treatment for lung carcinoma is cisplatin (DDP)-based therapy. However, the development or existence of chemoresistance frequently blocks its effectiveness. Currently, autophagy is recognised as a potential anticancer strategy, although there is controversy over its role in the development of cancer. In lung carcinoma, no studies of autophagy induced by FTY720, a sphingosine 1-phosphate analog and a novel immunosuppressant drug, have been published, while apoptosis has been shown to be induced by FTY720 in several cancer cell lines. We evaluated the effects of FTY720 on autophagy in A549 cells and studied the related mechanisms of cell autophagy and apoptosis in non-small cell lung carcinoma, including both DDP-resistant and -sensitive cells. The results revealed that FTY720 inhibited the growth and induced apoptosis in the A549/DDP cells in a time- and dose-dependent manner and the combination of FTY720 and DDP further enhanced apoptosis in these cells as determined by CCK-8 assay, western blotting and flow cytometry. Compared with the sensitive cell line A549, DDP-resistant A549/DDP cells showed a substantial increase in baseline autophagy as determined by increased LC puncta, and expression of LC3-I, LC3-II and Atg7 expression. DDP-induced apoptotic cell death was enhanced by the blockade of either siRNA-mediated knockdown of Atg7 genetic expression or a pharmacological inhibitor (3-MA). Moreover, the combination of FTY720 and DDP showed enhanced antitumour activity in vivo in lung cancer-bearing mice. Immunohistochemistry showed that the mice with lung carcinoma treated with FTY720 and DDP showed decreased expression of Atg7 and Ki67. Compared with monotherapy in vivo and in vitro, FTY720 in combination with DDP inhibited A549 cell growth more effectively. and these findings also show the influence of FTY720 in the induction of autophagy. Overall, the results indicated that FTY720 in combination with a DDP-based regime could enhance the effectiveness of lung carcinoma treatment.

S100A4 amplifies TGF-ß-induced epithelial-mesenchymal transition in a pleural mesothelial cell line.

Pleural fibrosis can dramatically lower the quality of life. Numerous studies have reported that epithelial-mesenchymal transition (EMT) regulated by transforming growth factor-ß (TGF-ß) is involved in fibrosis. However, the molecular mechanism is inadequately understood. Fibroblast-specific protein-1 (S100A4) is a target of TGF-ß signaling. In our previous study, we have reported that S100A4 is highly expressed in pleural fibrosis. Thus, we suggest that S100A4 took part in the TGF-ß-induced EMT in pleural fibrosis. In this study, we determined the expression of S100A4 and EMT-related markers in Met-5A cells (pleural mesothelial cells) treated with TGF-ß or TGF-ß inhibitor by real-time PCR and western blot. In order to explore the role of S100A4, we used siRNA to knock down the expression of S100A4 in cell model. We found that the expression of epithelial cell marker was decreased and the mesenchymal cell marker increased with S100A4 upregulation after treatment with TGF-ß. Moreover, the changes of EMT-related event were restricted when the expression of S100A4 was knocked down. Conversely, S100A4 can partially rescue the EMT-related expression changes induced by TGF-ß inhibitor. These findings suggest that S100A4 expression is induced by the TGF-ß pathway, and silencing S100A4 expression can inhibit the process of TGF-ß-induced EMT.

Combined Evaluation of Expression of CXCR4 and Nrf2 as Prognostic Factor for Patients with Gastric Carcinoma.

BACKGROUND: CXC Chemokine Receptor 4 (CXCR4) and NFE-related factor 2 (Nrf2) have been observed implicated with cell malignant behavior of human cancers. AIMS: In this study, we detected their expression in gastric carcinoma (GC) tissue specimens and related the result with clinicopathological data and patient survival. METHODS: 120 GC and compared normal tissue specimens were processed to analyse the expression of CXCR4 and Nrf2. We found that the expression of CXCR4 and Nrf2 was dramatically increased in GC tissues when compared to the distant non-cancer tissues (P<0.05). CXCR4 overexpression was associated with the depth of invasion (P= 0.006), Histological grade (P=0.018), TNMstage (P= 0.021), lymph node metastasis (P < 0.001) and distant metastasis (P=0.026), whereas overexpression of Nrf2 protein was significantly associated with tumor size (P=0.045), Histological grade (P=0.026), TNMstage (P= 0.020), lymph node metastases (P < 0.001) and distant metastasis (P=0.008). Furthermore, we observed a significant co-expression of CXCR4 and Nrf2 expression in GC specimens. RESULTS: In the survival part, we found that GC patients with CXCR4+ and Nrf2+ had worse outcomes. The significant prognostic indicators are age, tumor size, histological grade, TNMstage, CXCR4, Nrf2, and coexpression of CXCR4 and Nrf2 in GC patients. Multivariate analysis showed that TNMstage and CXCR4+/Nrf2+ expression were risk factors. Above all we come to the conclusion that the expression of CXCR4 might partly be regulated by the level of Nrf2 and both positive expressions suggest poor prognosis of GC patients.

Nrf2 promotes progression of non-small cell lung cancer through activating autophagy.

The transcription factor, NFE2-related factor 2 (Nrf2) and autophagy have been implicated in the oxidative-stress response during tumor evolution. However, few studies focus on crosstalk between Nrf2 and autophagy in cancer progression of non-small cell lung cancer (NSCLC). Herein, we evaluated the effect of Nrf2 on autophagy in NSCLC and their role in development of NSCLC. Effect of Nrf2 on overal survival (OS) of NSCLC patients were evaluated. Cell biological behaviors in response to Nrf2 were evaluated by MTT, colony formation assay and flow cytometry. Effect of 3-MA (a classical inhibitor of autophagy) on 95D-Nrf2 cells was also analyzed using flow cytometry. After up/down-regulating Nrf2 in NSCLC cell lines, expression of autophagy-related proteins were evaluated with western blot analysis. The results revealed that Nrf2 was an independent prognositc factor negtively associated with OS of NSCLC patients. Elevated Nrf2 expression promotes NSCLC progression, enhancing the escape of tumor cells from apoptosis in vivo and in vitro. Double staining with Annexin V-APC and 7-AAD showed that the proportions of apoptotic cells in 95D-Nrf2 cells were gradually increased after the addition of 3-MA. Importently, Nrf2 induced autophagosome formation and enhanced autophagic activity, which subsequently inhibits NSCLC cell apoptosis. In conclusion, our present study demonstrates that Nrf2 promotes progression of non-small cell lung cancer through activating autophagy. It provides novel insights into Nrf2-mediated of cell proliferation in NSCLC and may facilitate therapeutic development against NSCLC.

SDF-1/CXCR4 promotes epithelial-mesenchymal transition and progression of colorectal cancer by activation of the Wnt/ß-catenin signaling pathway.

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in angiogenesis and are associated with tumor progression. This study aimed to investigate the role of SDF-1/CXCR4-mediated epithelial-mesenchymal transition (EMT) and the progression of colorectal cancer (CRC) as well as the underlying mechanisms. The data showed that expression of CXCR4 and ß-catenin mRNA and protein was significantly higher in CRC tissues than in distant normal tissues. CXCR4 expression was associated with ß-catenin expression in CRC tissues, whereas high CXCR4 expression was strongly associated with low E-cadherin, high N-cadherin, and high vimentin expression, suggesting a cross talk between the SDF-1/CXCR4 axis and Wnt/ß-catenin signaling pathway in CRC. In vitro, SDF-1 induced CXCR4-positive colorectal cancer cell invasion and EMT by activation of the Wnt/ß-catenin signaling pathway. In contrast, SDF-1/CXCR4 axis activation-induced colorectal cancer invasion and EMT was effectively inhibited by the Wnt signaling pathway inhibitor Dickkopf-1. In conclusion, CXCR4-promoted CRC progression and EMT were regulated by the Wnt/ß-catenin signaling pathway. Thus, targeting of the SDF-1/CXCR4 axis could have clinical applications in suppressing CRC progression.