Phase separation in innate immune response and inflammation-related diseases.

Inflammation induced by nonspecific pathogenic or endogenous danger signals is an essential mechanism of innate immune response. The innate immune responses are rapidly triggered by conserved germline-encoded receptors that recognize broad patterns indicative of danger, with subsequent signal amplification by modular effectors, which have been the subject of intense investigation for many years. Until recently, however, the critical role of intrinsic disorder-driven phase separation in facilitating innate immune responses went largely unappreciated. In this review, we discuss emerging evidences that many innate immune receptors, effectors, and/or interactors function as "all-or-nothing" switch-like hubs to stimulate acute and chronic inflammation. By concentrating or relegating modular signaling components to phase-separated compartments, cells construct flexible and spatiotemporal distributions of key signaling events to ensure rapid and effective immune responses to a myriad of potentially harmful stimuli.

Atmospheric PM2.5 exposure and risk of ischemic heart disease: A systematic review and meta-analysis of observational studies.

Fine particulate matter <2.5 µm in diameter (PM2.5) has been validated to associate with cardiovascular diseases (CVD) incidence and mortality. So far, no study has quantitatively evaluated the relationship between the atmospheric PM2.5 exposure and ischemic heart disease (IHD). We conducted a meta-analysis to illustrate the relationship between PM2.5 and IHD. Published articles were systematically searched (until June 2022) from PubMed, EMBASE, Cochrane Library. A random-effect model was performed to summarize the total relative risks (RRs) and 95% confidence intervals (CIs). Meta-analysis was performed using Stata 12.0 software. A total of 28 studies among 23 cohorts (23.38 million individuals and 256256 IHD cases) were included. With PM2.5 increasing 10 µg/m3, the total RRs of IHD incidence and mortality were 1.07 (95% CI: 0.99-1.17), 1.21 (95% CI: 1.15-1.28), respectively. In sub-analyses, our study revealed that the combined RRs of exposure to PM2.5 on IHD mortality in Asian and European population [1.11 (95% CI: 0.93-1.33); 1.06 (95% CI: 1.02-1.11)] were much lower compared with American and Canadian people [1.27 (95% CI: 1.17-1.37); 1.30 (95% CI: 1.24-1.35)]. Furthermore, study duration, size and some adjustments were related with the total RR. Our findings indicated that exposure of an increase in the concentration of atmospheric PM2.5 may increase the risk of IHD incidence and mortality. Further evidence is needed to confirmed the association.

Prediction of Axillary Lymph Node Metastasis in Invasive Breast Cancer by Sound Touch Elastography.

The aims of this study were to investigate the value of sound touch elastography (STE) in predicting axillary lymph node metastasis (ALNM) in patients with invasive breast cancer (IBC) and to explore whether lysyl oxidase (LOX) is correlated with increasing stiffness and promotion of metastasis in IBC. A total of 142 lesions in 142 patients were assessed by STE. The STE values of IBCs in the two groups were compared and the best cutoff values for diagnosing ALNM determined. Immunohistochemistry was used to detect LOX expression. Collagen fiber and elastic fiber content was determined by Masson and Weigert elastic fiber staining. Correlation analyses were performed to identify the associations of the data. The optimal cutoff values of Emax (maximum stiffness value of the tumor) and Smax (maximum stiffness value of the shell) for predicting ALNM of IBC were 94.58 and 148.78 kPa. Immunohistochemistry and Masson and Weigert elastic fiber staining were performed on 67 samples. LOX expression and collagen volume fraction were significantly higher in the ALNM+ group than in the ALNM- group (p = 0.04 and 0.03), except for elastic fiber content (p = 0.628). Moreover, Emax, Smax and LOX expression were positively correlated with collagen volume fraction (r = 0.624, 0.512, and 0.533, respectively). Emax and Smax were found to be predictors for ALNM of IBC. STE could serve as a non-invasive method for assessing lymph node status before surgery. Overexpression of LOX and increased collagen fiber contributed to the increased stiffness in the lesions and metastases of IBC.

Short-term exposure to ambient air pollution and atrial fibrillation hospitalization: A time-series study in Yancheng, China.

Atrial fibrillation (AF) is an important cardiovascular disease that causes a great burden of disease. However, there is limited evidence of a link between air pollution exposure and AF. This study aimed to explore the short-term association between air pollution and AF. We obtained daily hospitalization of AF in two major hospitals of Yancheng, China from May, 2015 to May, 2020. Generalized additive models with quasi-Poisson regression were used to assess the associations between six criteria air pollutants and AF hospitalization. We explored the lag patterns, and visualized the concentration-response relationships. The robustness of the association was tested by two-pollutant model, and we explored potential effect modification by age, sex and season. A total of 15,171 inpatients from two hospitals were collected in this study with an average daily count of eight patients. We observed consistent and significant associations between six air pollutants and AF on lag 0-4 days. A 10 ug/m3 increase in PM2.5 was associated with 2.81% (95%CI: 1.44%, 4.20%) changes in AF, and the effect estimate was 1.67% (95%CI: 0.77%, 2.59%) for PM10, 4.90% (95%CI: 1.69%, 8.22%) for NO2, 6.81% (95%CI: 0.46%, 13.57%) for SO2, 1.82% (95%CI: 0.60%, 3.06%) for O3; a 0.1 mg/m3 increase in CO was associated with 2.55% (95%CI: 0.91%, 4.21%) increments in AF. Associations of PM2.5 and PM10 were robust after adjusting for SO2, NO2, CO, and O3, but not vice versa. Female patients and those aged less 70 years had larger risk of AF associated with air pollution exposure. The concentration-response curves of the six pollutants were almost linear and increasing with no obvious thresholds. This time-series study in Yancheng demonstrated increased risk of AF and a delayed effect over lag 0-4 days. Our findings suggested need of prevention and protection against these environmental risk factors for AF in health departments.

Plasmonic Heating-Promoted Photothermal Synthesis of α-Cyanoacrylonitriles Over Au/h-BN Catalysts.

Plasmonic nanoparticle-involved materials play an essential role in the field of photothermal conversion. Herein, we report the application of photothermal heterogeneous catalysts consisting of gold nanoparticles decorated on defect-rich h-BN sheets (Au/h-BN) for the photocatalytic synthesis of α-cyanoacrylonitriles under mild conditions. It has been demonstrated the-NH2 groups present in the defect-rich h-BN act as the catalytically active sites, while plasmonic heating from the gold nanoparticles can drive the reaction by providing local heat. Au/h-BN catalyst can work for a broad substrate scope in the synthesis of α-cyanoacrylonitriles, and a plausible -NH2 group-involved reaction mechanism has been proposed. This work may open up new avenues in photothermal catalysis by combining plasmonic materials and catalytic sites in one system.

Low-work-function LaB6 for realizing photodynamic-enhanced photothermal therapy.

There is great potential for photodynamic therapy (PDT)-enhanced photothermal therapy (PTT) to be used for tumor therapy, especially for the single material-mediated process that could greatly simplify the experimental arrangements. This study presents a new cancer phototherapeutic agent consisting of low-work-function lanthanum hexaboride particles, which are excellent light absorbers in the near-infrared (NIR) region. The photothermal effect and reactive oxygen species production were realized by LaB6 under NIR light irradiation. Theoretical calculations based on density functional theory confirmed that the strong NIR light absorption by LaB6 was attributed to the local plasmonic resonance effect and the excellent photodynamic effect derived from the low work function. In vivo treatment of HepG2 tumor-bearing mice revealed that LaB6-mediated phototherapy resulted in excellent tumor inhibitory effects, and no adverse effects on mice were observed. These results indicate that LaB6 is a promising phototherapeutic agent for cancer synergetic phototherapy.

Association between fine particulate matter and heart failure hospitalizations: a time-series analysis in Yancheng, China.

BACKGROUND: Heart failure (HF) is a global public health problem of increasing importance. The association between acute exposure to air pollution and HF has been well established in developed countries, but little evidence is available in developing countries where air pollution levels are much higher. OBJECTIVES: To explore the associations between PM2.5 and HF hospitalizations in Yancheng, China. METHODS: In this time-series study, daily HF hospitalizations admitted in three major hospitals in Yancheng from May 1, 2015 to Apr 30, 2020 were collected. We used a generalized additive model with quasi-Poisson regression to investigate the association between PM2.5 and HF hospitalizations. The robustness of the associations was tested using two-pollutant models, and we examined the potential effect modification by age, gender, and season via stratification analyses. Lastly, we pooled the concentration-response curves. RESULTS: A total of 10,466 HF hospitalizations were recorded, with a daily average of 6 cases. We observed the most robust estimates on lag 0 day, and the associated increment in HF was 1.28% (95% CI 0.45%, 2.11%) for a 10-µg/m3 increase of PM2.5. The association remained after adjustment of O3, but not for NO2, CO, and SO2. The PM2.5-HF associations were positive in females, patients aged ≥ 65 years, and in cold season. The C-R relationship curve was generally increasing below 30 µg/m3. CONCLUSION: This study provided evidence on the association of PM2.5 with acute exacerbation of chronic heart failure, which may benefit future prevention strategy and policymaking.

Author Correction: Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Short-term exposure to coarse particulate matter and outpatient visits for cardiopulmonary disease in a Chinese city.

Limited studies have been conducted to evaluate the short-term relationships between exposure to coarse particulate matter (PM2.5-10) and outpatient visits in China. We designed this time-series analysis in a Chinese city Yancheng, to explore the relationship of PM2.5-10 with outpatient visits for cardiopulmonary diseases. The study period was from 2013 to 2015. A typical generalized additive model was used. We explored the lag patterns by building a series of lag of exposure. We also built two-pollutant models to ascertain the independence of PM2.5-10. Stratified analyses were applied to compare the season-specific associations. Finally, we pooled the concentration-response (C-R) curves for PM2.5-10 and outpatient visits. We recorded a daily average of 85 and 43 outpatient visits for cardiovascular and respiratory causes, respectively. PM2.5-10 exposures of lag 05 day yielded the best estimates for both outcomes. Per 10-µg/m3 increase in PM2.5-10, there was a 1.69% (95% confidence interval [CI]: 0.68%-2.72%) increase in outpatient visits for respiratory causes, and a 0.85% (95% CI: 0.13%-1.57%) increase for cardiovascular causes. The association kept robust after adjusting for PM2.5 and O3, and there were larger associations in warm seasons. The C-R curves had a larger slope for respiratory diseases in relatively lower concentrations (<30 µg/m3), and PM2.5-10 was positively associated with cardiovascular diseases in higher concentrations (>30 µg/m3). This study indicated significant associations of PM2.5-10 with cardiopulmonary outpatient visit. Such results may be used for health risk assessment and policy making for particulate air pollution control.

Association between ambient temperature and daily emergency hospitalizations for acute coronary syndrome in Yancheng, China.

Acute coronary syndrome (ACS) is a major public health concern worldwide. Few studies have directly evaluated the associations between ambient temperature and ACS incidence. To explore the association between ambient temperature and ACS emergency hospitalizations in the area of subtropical monsoon climate, data on ACS emergency hospitalizations were collected from two highest-ranking hospitals in the central urban area of Yancheng, China, from January 1, 2013, to December 31, 2018. We applied the time-series method to investigate the potentially lagged and non-linear effects of ambient temperature on ACS using the generalized linear model combined with the distributed lag non-linear model after adjusting for time trend, day of the week, holiday, and relative humidity. We identified a total of 5303 cases of ACS emergency hospitalizations during the study period. The exposure-response curves between ambient temperature and ACS hospitalizations were inverse "J-shaped." The effects of extreme low temperature on ACS hospitalizations occurred on the present day and lasted for 3 days, followed by the harvesting effect. The effects of extreme high temperature occurred on the present day and lasted for 5 days. The cumulative relative risks of ACS were 2.14 [95% confident interval (CI): 1.32 to 3.47] for extremely low temperature and 1.66 (95% CI: 1.33 to 2.06) for extremely high temperature over the lag of 0-5 days, compared with the reference temperature (25.0 °C). Both low and high temperatures were significantly associated with higher risks of emergency hospital admissions for ACS in Yancheng, China.

Association of fine particulate matter on acute exacerbation of chronic obstructive pulmonary disease in Yancheng, China.

BACKGROUND: Epidemiological evidence on the association between short-term exposure to fine particulate matter (PM2.5) air pollution and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is limited in China. OBJECTIVES: To explore the associations between PM2.5 and AECOPD in Yancheng, China from 2015 to 2017. METHODS: In this time-series study, we used a generalized linear model with quasi-Poisson regression to investigate the association between PM2.5 and AECOPD admitted in two major hospitals in Yancheng. We tested the robustness of the associations using two-pollutant models and examined the potential effect modification by age, gender and season via stratification analyses. Lastly, we fitted the concentration-response curves. RESULTS: We identified a total of 4761 AECOPD inpatients during the study period. The average daily-mean PM2.5 concentration was 45.2 µg/m3. Each 10 µg/m3 increase in PM2.5 concentration on the concurrent day of the onset of AECOPD was associated with a 1.05% (95% confidence interval: 0.14%, 1.96%) increase in AECOPD. The association was robust to the adjustment of ozone, but not to sulfur dioxide, nitrogen dioxide, and carbon monoxide. The association was larger in females, elderly patients, and was restricted within the cold season, but all between-group differences were insignificant. The concentration-response relationship curves were generally linear but flatted at concentrations over 40 µg/m3. CONCLUSIONS: This study demonstrated a higher risk of AECOPD associated with present-day PM2.5 exposure in a Chinese city. We further provided important information on lag patterns, susceptible subgroups, sensitive seasons, as well as the characteristics of the concentration-response relationship curves.

Association between ambient particulate matter air pollution and ST-elevation myocardial infarction: A case-crossover study in a Chinese city.

BACKGROUND: Abundant epidemiological studies have revealed that short-term exposure to ambient air pollution increased the incidence of ischemic heart diseases. However, few investigations have explored the association between air pollution and ST-elevation myocardial infarction (STEMI), one major subtype of such events. METHODS: We conducted a time-stratified case-crossover study in two major hospitals of Yancheng, a city in East China, from January 2015 to February 2018. We used conditional logistic regression models to explore the association between hourly concentrations of air pollutants and STEMI hospitalizations. We explored potential effect modification in susceptible subgroups by age, gender, smoking status, and comorbidities. Two-pollutant models were fitted to test the robustness of the association. RESULTS: We identified a total of 347 STEMI patients. In single-pollutant models, each 10 µg/m3 increase in concentrations of fine and inhalable particulate matter (PM) (lag 13-24 h) was associated with increments of 5.27% [95% confidence interval (CI): 1.09%, 9.46%] and 3.86% (95%CI: 0.83%, 6.88%) in STEMI hospitalizations, respectively. We observed slightly larger associations of STEMI hospitalization with PM in patients who were older than 65, female, non-smoker, and with comorbidities (hypertension, diabetes or hyperlipidemia). The associations were generally robust to adjustment of criteria gaseous pollutants except for carbon monoxide. CONCLUSION: This is the first study in China that suggested acute exposure to elevated PM concentrations may trigger STEMI. Patients with cardiometabolic comorbidities were slightly more susceptible to air pollution.

Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line.

BACKGROUND/AIMS: Sonodynamic therapy (SDT) is expected to be a new method to solve the clinical problems caused by advanced metastasis in patients with lung cancer. The use of ultrasound has the advantage of being noninvasive, with deep-penetration properties. This study explored the anti-tumor effect of SDT with a new sonosensitizer, sinoporphyrin sodium (DVDMS), on the human small cell lung cancer H446 cell line in vitro and in vivo. METHODS: Absorption of DVDMS was detected by a fluorescence spectrophotometer, and DVDMS toxicity was determined using a Cell Counting Kit-8. Mitochondrial membrane potential (MMP) was assessed using the JC-1 fluorescent probe. Cell apoptosis was measured by flow cytometry, and apoptosis-related proteins were detected by western blotting. The expression of cytokines was measured using an enzyme-linked immunosorbent assay and quantitative real-time PCR. To verify the in vitro results, we detected tumor volumes and weight changes in a xenograft nude mouse model after DVDMS-SDT. Hematoxylin and eosin staining was used to observe changes to the tumor, heart, liver, spleen, lung, and kidney of the mice, and immunohistochemistry was used to examine changes in the expression of tumor CD34 and receptor-interacting protein kinase-3 (RIP3), while terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to observe apoptosis in tumor tissues. RESULTS: DVDMS-SDT-treated H446 cells increased the rate of cellular apoptosis and the levels of reactive oxygen species (ROS), cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and caspase-10, and decreased the levels of MMP, RIP3, B-cell lymphoma 2, vascular endothelial growth factor, and tumor necrosis factor-α. The sonotoxic effect was mediated by ROS and was reduced by a ROS scavenger (N-acetyl-L-cysteine). In the in vivo mouse xenograft model, DVDMS-SDT showed efficient anti-cancer effects with no visible side effects. CONCLUSION: DVDMS-SDT induced apoptosis in H446 cells, in part by targeting mitochondria through the mitochondria-mediated apoptosis signaling pathway, and the extrinsic apoptosis pathway was also shown to be involved. Both apoptosis and changes in RIP3 expression were closely related to the generation of ROS. DVDMS-SDT will be advantageous for the management of small cell lung cancer due to its noninvasive characteristics.

IL-17 induces macrophages to M2-like phenotype via NF-κB.

BACKGROUND: Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-κB) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-κB activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan-Meier method. RESULTS: The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-ß), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkBα and nuclear localization of p65 (a subunit of NF-κB). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-ß, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression. CONCLUSION: IL-17 stimulated macrophages to M2-like phenotypes via NF-κB activation. IL-17 may be a potential therapeutic target for NSCLC.

Cancer/testis antigens (CTAs) expression in resected lung cancer.

BACKGROUND: Increasing evidence shows cancer/testis antigens (CTAs) play a key role in oncogenesis. Our pre-study finds that MAGEA1, MAGEA10, MAGEB2, KK-LC-1, and CTAG1A/B have high expression frequencies at the protein level. We aim to explore their prognostic role and correlations with clinical characteristics in resected lung cancer at the mRNA level. METHODS: Thirty-eight surgical lung cancer samples were included. Validation study was performed based on The Cancer Genome Atlas database. The prognostic roles of CTAs were evaluated by Kaplan-Meier and multivariate analysis. RESULTS: High expression of MAGEA1 (16.7% vs 65.0%, P=0.004), MAGEA10 (61.1% vs 95.0%, P=0.016), MAGEB2 (55.6% vs 95.0%, P=0.007), and KK-LC-1 (16.7% vs 55.0%, P=0.020) was closely correlated with lymph node metastasis at diagnosis. Patients with TNM stage II or III had a higher expression of MAGEA10 (57.1% vs 91.7%, P=0.034) and KK-LC-1 (14.3% vs 50.0%, P=0.039) compared with patients in TNM stage I. High CTAG1A/B expression showed unfavorable prognosis in all cases (P<0.05). Subgroup analysis showed high CTAG1A/B expression was a negative prognostic factor of survival (P=0.031) in patients with TNM stage II or III. Although no statistical significance was reached, high CTAG1A/B also showed a similar prognostic trend in lung adenocarcinoma (ADC) and squamous cell carcinoma. The Cancer Genome Atlas database showed the negative prognostic role of CTAG1A/B was mainly induced by CTAG1B (NY-ESO-1, P=0.047) and high CTAG1B expression (hazard ratio =2.733, 95% CI: 1.348-5.541, P=0.005) was an independent negative prognostic factor of lung ADC. CONCLUSION: CTAs represent potential candidate targets for immunotherapy and their expression was closely correlated with tumor stage. High CTAG1B expression was an independent negative prognostic factor of lung ADC.

Selected patients can benefit more from the management of etoposide and platinum-based chemotherapy and thoracic irradiation-a retrospective analysis of 707 small cell lung cancer patients.

The management of small cell lung cancer (SCLC) has reached a plateau. Etoposide and platinum-based chemotherapy plus thoracic irradiation remain the standard treatment strategy for SCLC. Our study aims to assess the potential prognostic factors of patients treated with etoposide and platinum-based chemotherapy and explore which group of patients can benefit more from standard treatment strategies. On univariate analysis, age>65 years, male patients, KPS (Karnofsky Performance Status)≤80 points, positive smoking history, anemia, lymphocyte counts≤1.65×109/L, neutrophil to lymphocyte ratio (NLR)>3.18, lymphocyte to monocyte ratio (LMR)≤2.615, lactate dehydrogenase (LDH)>216.5 U/L, alkaline phosphatase (ALP)>119.5 U/L, absence of surgery, absence of thoracic irradiation, chemotherapy cycles<4, metastatic sites≥2 and extensive disease were correlated with a poor prognosis. Gender, KPS, chemotherapy cycles, thoracic irradiation, metastatic sites, LDH and tumor stage held statistical significance on multivariate analysis (p<0.05). High LDH was closely correlated with extensive disease, metastatic sites≥2, anemia, low LMR, high NLR and ALP levels. Subgroup analysis showed patients with male gender, KPS≤80 points, LDH≤216.5U/L, extensive disease and metastatic sites<2 could benefit more from ≥4 chemotherapy cycles. Patients with male gender, KPS>80 points, LDH≤216.5U/L, limited disease and metastatic sites<2 could benefit more from thoracic irradiation (p<0.05 on uni- and multivariate analysis). In conclusion, female patients, KPS>80 points, chemotherapy cycles≥4, thoracic irradiation, metastatic sites<2, LDH≤216.5U/L and limited disease were independent positive prognostic factors for SCLC patients treated with etoposide and platinum-based chemotherapy. Selected patients can benefit more from the management of ≥4 cycles of chemotherapy and thoracic irradiation.

Interleukin-22 promotes lung cancer cell proliferation and migration via the IL-22R1/STAT3 and IL-22R1/AKT signaling pathways.

Lung cancer continues to be an enormous burden on current health care systems throughout the world, with more than a million deaths every year. Previous studies have shown that interleukin-22 (IL-22) promotes survival and resistance to chemotherapy in human lung cancer cells. However, the association of IL-22 expression with recurrence of lung cancer is still unclear. In this study, we found that expression of IL-22 was upregulated in tumor tissues and serum from patients with recurrent non-small cell lung cancer (NSCLC) as compared to primary NSCLC samples. Treatment with IL-22 promoted cell proliferation and enhanced migration and invasion in A549 and H125 cell lines. Furthermore, we revealed that phosphorylation of STAT3 and AKT was highly induced by treatment with IL-22 via IL-22R1. IL-22R1 was also consistently overexpressed in recurrent NSCLC tissues. Finally, we found that siRNA-mediated depletion of IL-22R1 completely abrogated the effects of IL-22 treatment on cell proliferation and migration activity in NSCLC cell lines. Our findings indicate that IL-22 and IL-22R1 may be novel therapeutic targets for treatment of advanced NSCLC.

Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.

The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. However, it remains unclear how IL-17 might contribute to tumor angiogenesis. In our study, IL-17 enhanced the formation of vessel-like tubes in HUVECs both directly (when HUVECs were incubated with IL-17) and indirectly (when HUVECs were incubated in conditioned cell media (CCM) from IL-17-treated cancer cells). Our results from experiments using siRNA-mediated knockdowns of STAT3 and GIV suggest that the effects of IL-17 were mediated by activating STAT3/GIV signaling in NSCLC cells and subsequently up-regulating its downstream target VEGF. Consistent with these findings, immunostaining experiments on human NSCLC tissues indicated that IL-17 and GIV expression were significantly and positively associated with increased tumor vascularity. The clinical significance of IL-17 was authenticated by our finding that the combination of intratumoral IL-17 + cells and GIV expression served as a better prognosticator for survival than either marker alone. Therefore, our finding highlights a novel aspect of STAT3/GIV pathway in the IL-17 promotes tumor angiogenesis of NSCLC.

miR-34c-3p functions as a tumour suppressor by inhibiting eIF4E expression in non-small cell lung cancer.

OBJECTIVES: MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression and mediate diverse physiological processes. In this study, we investigated functions of miRNA miR-34c-3p in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: miR-34c-3p expression was evaluated by qPCR. Cell viability was examined by MTT and proliferation by cell cycle analysis. Cell migration and invasion were tested using Transwells with/without Matrigel coating. Western blot analysis was performed for eIF4E, c-Myc, Cyclin D1, survivin and Mcl-1 protein expression. RESULTS: miR-34c-3p expression was significantly reduced in tissues and serum samples from NSCLC patients and in NSCLC cell lines A549, H460, H23, H157 and H1299. Overexpression of miR-34c-3p in A549 and H157 cells reduced cell proliferation, migration and invasion, whereas transfection with miR-34c-3p inhibitor (miR-34c-3p-in) produced opposite effects. Target analysis using algorithms miRanda, TargetScan and DIANA identified eIF4E as a potential target of miR-34c-3p. Luciferase assay using the eIF4E 3'-UTR reporter carrying a putative miR-34c-3p target sequence revealed eIF4E to be a specific target of miR-34c-3p. Overexpression of miR-34c-3p in NSCLS cell lines led to significant reduction in mRNA and protein levels of eIF4E, whereas inhibition of miR-34c-3p resulted in significant increase in eIf4e protein levels, confirming eIF4E to be a direct target of miR-34c-3p in NSCLS. Overexpression of eIF4E in A549 cells promoted cell proliferation, migration and invasion, which were partially reversed by miR-34c-3p. CONCLUSION: miR-34c-3p directly targeted eIF4E and reduced miR-34c-3p expression in NSCLC, promoting cell cycle progression, proliferation, migration and invasion.

Nonmuscle myosin heavy chain IIA mediates Epstein-Barr virus infection of nasopharyngeal epithelial cells.

EBV causes B lymphomas and undifferentiated nasopharyngeal carcinoma (NPC). Although the mechanisms by which EBV infects B lymphocytes have been extensively studied, investigation of the mechanisms by which EBV infects nasopharyngeal epithelial cells (NPECs) has only recently been enabled by the successful growth of B lymphoma Mo-MLV insertion region 1 homolog (BMI1)-immortalized NPECs in vitro and the discovery that neuropilin 1 expression positively affects EBV glycoprotein B (gB)-mediated infection and tyrosine kinase activations in enhancing EBV infection of BMI1-immortalized NPECs. We have now found that even though EBV infected NPECs grown as a monolayer at extremely low efficiency (<3%), close to 30% of NPECs grown as sphere-like cells (SLCs) were infected by EBV. We also identified nonmuscle myosin heavy chain IIA (NMHC-IIA) as another NPEC protein important for efficient EBV infection. EBV gH/gL specifically interacted with NMHC-IIA both in vitro and in vivo. NMHC-IIA densely aggregated on the surface of NPEC SLCs and colocalized with EBV. EBV infection of NPEC SLCs was significantly reduced by NMHC-IIA siRNA knock-down. NMHC-IIA antisera also efficiently blocked EBV infection. These data indicate that NMHC-IIA is an important factor for EBV NPEC infection.