Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for human non-small-cell lung cancer (NSCLC) treatment. However, acquired resistance to EGFR-TKIs is the major barrier of treatment success, and new resistance mechanism remains to be elucidated. In this study, we found that elevated NADPH oxidase 4 (NOX4) expression was associated with acquired EGFR-TKIs resistance. Gefitinib is the first-generation FDA-approved EGFR-TKI, and osimertinib is the third-generation FDA-approved EGFR-TKI. We demonstrated that NOX4 knockdown in the EGFR-TKI resistant cells enabled the cells to become sensitive to gefitinib and osimertinib treatment, while forced expression of NOX4 in the sensitive parental cells was sufficient to induce resistance to gefitinib and osimertinib in the cells. To elucidate the mechanism of NOX4 upregulation in increasing TKIs resistance, we found that knockdown of NOX4 significantly down-regulated the expression of transcription factor YY1. YY1 bound directly to the promoter region of IL-8 to transcriptionally activate IL-8 expression. Interestingly, knockdown of NOX4 and IL-8 decreased programmed death ligand 1 (PD-L1) expression, which provide new insight on TKIs resistance and immune escape. We found that patients with higher NOX4 and IL-8 expression levels showed a shorter survival time compared to those with lower NOX4 and IL-8 expression levels in response to the anti-PD-L1 therapy. Knockdown of NOX4, YY1 or IL-8 alone inhibited angiogenesis and tumor growth. Furthermore, the combination of NOX4 inhibitor GKT137831 and gefitinib had synergistic effect to inhibit cell proliferation and tumor growth and to increase cellular apoptosis. These findings demonstrated that NOX4 and YY1 were essential for mediating the acquired EGFR-TKIs resistance. IL-8 and PD-L1 are two downstream targets of NOX4 to regulate TKIs resistance and immunotherapy. These molecules may be used as potential new biomarkers and therapeutic targets for overcoming TKIs resistance in the future.

Apigenin Inhibits IL-6 Transcription and Suppresses Esophageal Carcinogenesis.

Esophagus cancer is the seventh cause of cancer-related deaths globally. In this study, we analyzed interleukin 6 (IL-6) gene expression in human esophagus cancer patients and showed that IL-6 mRNA levels are significantly higher in tumor tissues and negatively correlated with overall survival, suggesting that IL-6 is a potential therapeutic target for esophagus cancer. We further demonstrated that apigenin, a nature flavone product of green plants, inhibited IL-6 transcription and gene expression in human esophagus cancer Eca-109 and Kyse-30 cells. Apigenin significantly and dose-dependently inhibited cell proliferation and promoted apoptosis while stimulating the cleaved PARP (poly ADP-ribose polymerase) (C-PARP) and caspase-8 expression. It suppressed VEGF (Vascular endothelial growth Factor) expression and tumor-induced angiogenesis. Pretreatment of cells with IL-6 could completely reverse apigenin-induced cellular changes. Finally, using a preclinical nude mice model subcutaneously xenografted with Eca-109 cells, we demonstrated the in vivo antitumor activity and mechanisms of apigenin. Taken together, this study revealed for the first time that apigenin is a new IL-6 transcription inhibitor and that inhibiting IL-6 transcription is one of the mechanisms by which apigenin exhibits its anticancer effects. The potential clinical applications of apigenin in treating esophagus cancer warrant further investigations.

Dietary vitamin B intake and the risk of esophageal cancer: a meta-analysis.

BACKGROUND: Several epidemiology studies have explored the association between dietary B vitamins' intake and the risk of esophageal cancer (EC). However, the results remain inconclusive. Thus, we conducted a systematic review with meta-analysis to evaluate such association. METHODS: Literature retrieval was performed using PubMed (Medline), ScienceDirect, and Cochrane Library electronic databases for all studies published from database inception to December 2017. RESULTS: The meta-analysis included 19 studies and showed an overall decreased risk of EC (OR=0.77, 95% CI: 0.68-0.87) in association with multivitamin B (ie, B1, B2, B3, B5, B6, B9, and B12) dietary intake. In a subgroup analysis based on vitamin B subclass, B1, B3, B6, and B9 vitamins were associated with decreased EC risk (vitamin B1: OR=0.68, 95% CI: 0.56-0.82; vitamin B3: OR=0.70, 95% CI: 0.53-0.94; vitamin B6: OR=0.64, 95% CI: 0.49-0.83; and vitamin B9: OR=0.69, 95% CI: 0.55-0.86). By contrast, no association was detected between dietary vitamin B2 and vitamin B5 intake and EC risk (vitamin B2: OR=0.86, 95% CI: 0.64-1.16; vitamin B5: OR=0.49, 95% CI: 0.20-1.20), whereas a potential non-linear dose-response association was found between dietary vitamin B12 intake and EC risk. A statistically significant, inverse association was observed for an increase of 100 µg/day in supplemental vitamin B6 and B9 and EC risk (vitamin B6: OR=0.98, 95% CI: 0.98-0.99; vitamin B9: OR= 0.89; 95% CI: 0.86-0.94). CONCLUSION: These findings support that vitamin B may have an influence on carcinogenesis of the esophagus. Vitamin B1, B3, B6, B9 showed a decreased risk of EC, and vitamin B12 showed an increased risk of EC.

Glutathione S-transferase M1 polymorphism and esophageal cancer risk: An updated meta-analysis based on 37 studies.

AIM: To evaluate the relationship between glutathione S-transferase M1 (GSTM1) polymorphism and susceptibility to esophageal cancer (EC). METHODS: A comprehensive search of the United States National Library of Medicine PubMed database and the Elsevier, Springer, and China National Knowledge Infrastructure databases for all relevant studies was conducted using combinations of the following terms: "glutathione S-transferase M1", "GSTM1", "polymorphism", and "EC" (until November 1, 2014). The statistical analysis was performed using the SAS software (v.9.1.3; SAS Institute, Cary, NC, United States) and the Review Manager software (v.5.0; Oxford, England); crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between the GSTM1 null genotype and the risk of EC. RESULTS: A total of 37 studies involving 2236 EC cases and 3243 controls were included in this meta-analysis. We observed that the GSTM1 null genotype was a significant risk factor for EC in most populations (OR = 1.33, 95%CI: 1.12-1.57, P heterogeneity < 0.000001, and I (2) = 77.0%), particularly in the Asian population (OR = 1.53, 95%CI: 1.26-1.86, P heterogeneity < 0.000001, and I (2) = 77.0%), but not in the Caucasian population (OR = 1.02, 95%CI: 0.87-1.19, P heterogeneity = 0.97, and I (2) = 0%). CONCLUSION: The GSTM1 null polymorphism may be associated with an increased risk for EC in Asian but not Caucasian populations.

MicroRNA-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility: a meta-analysis based on East Asian population.

OBJECTIVE: The relationship between microRNA (miR-146a) rs2910164G/C polymorphism and gastrointestinal cancer susceptibility is not consistent with each other of the published articles. The aim of this meta-analysis was to acquire a more precise effect of the association between the miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer. MATERIALS AND METHODS: Through searching of the MedLine, Embase, China National Knowledge Infrastructure, and Wanfang databases. Case-control or cohort studies about the relationship between miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility were screened and included in this meta-analysis. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer risk by statistical software STATA-11.0. RESULTS: Ten studies including 6473 gastrointestinal cancer patients and 7923 controls were identified and included in this meta-analysis. For recessive genetic model (CC vs. CG + GG), people with CG or GG is associated with the susceptibility of gastrointestinal cancer compared with genotype of CC (R = 0.73, 5% confidence interval [CI]: 0.55-0.97, [P = 0.03]); But for dominant model (CC + CG vs. GG) and homozygous model (CC vs. GG), no association of the miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility were found (dominant: Odds ratio [OR] =0.94, 95% CI: 0.82-1.03, [P = 0.37]; homozygous: OR = 0.85, 95% CI: 0.71-1.03, [P = 0.10]). Sub-group analysis, for homozygous model, people with GG genotype had increased risk of developing colorectal cancer (OR = 0.77, 95% CI: 0.64-0.93, [P = 0.008]). CONCLUSION: No significant association between miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility was found in this meta-analysis. But for homozygous model, people with GG genotype may have increased risk of developing colorectal cancer.

XPD Lys751Gln polymorphism and esophageal cancer risk: a meta-analysis involving 2288 cases and 4096 controls.

AIM: To evaluate the association between xeroderma pigmentosum group D (XPD), genetic polymorphism Lys751Gln and esophageal cancer risk. METHODS: We searched PubMed up to September 1, 2010 to identify eligible studies. A total of 10 case-control studies including 2288 cases and 4096 controls were included in the meta-analysis. Statistical analysis was performed with Review Manage version 4.2. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. RESULTS: The results suggested that there is no significant association between XPD Lys751Gln polymorphism and esophageal cancer susceptibility in the overall population. However, in subgroup analysis by histology type, a significant association was found between XPD Lys751Gln polymorphism and esophageal adenocarcinoma (for CC vs AA: OR = 1.25, 95% CI = 1.01-1.55, P = 0.05 for heterogeneity). CONCLUSION: Our meta-analysis suggested that XPD Lys751Gln polymorphism may be associated with increased risk of esophageal adenocarcinoma.