Zhiwei Chen

The effect of CYP1A1 polymorphisms on the risk of lung cancer: a global meta-analysis based on 71 case–control studies

The cytochrome P450 1A1 (CYP1A1) is a phase I enzyme involved in many oxidative reactions that has attracted considerable attention as a candidate gene for lung cancer susceptibility based on its function as a key factor required for bioactivation of carcinogenic polycyclic aromatic hydrocarbons and catechol oestrogen formation. In the past decade, the relationship between CYP1A1 and lung cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 71 studies involving a total of 30 368 subjects for the MspI and Ile-Val polymorphism of the CYP1A1 gene to evaluate the effect of CYP1A1 on genetic susceptibility for lung cancer. In a combined analysis, the summary per-allele odds ratios for lung cancer of the MspI and Ile-Val polymorphism were 1.19 [95% confidence interval (CI): 1.11-1.28] and 1.20 (95% CI: 1.08-1.33), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity, significantly increased risks were found for the MspI and Ile-Val polymorphism among East Asians in almost all genetic models. However, only marginal significant associations were detected for the MspI polymorphism among Caucasians and other population, while no significant associations were observed for the Ile-Val polymorphism in Caucasians and other population. This meta-analysis demonstrated that the MspI and Ile-Val polymorphism of CYP1A1 is a risk factor associated with increased lung cancer susceptibility, but these associations vary in different ethnic populations.

The synergistic effect of EGFR tyrosine kinase inhibitor gefitinib in combination with aromatase inhibitor anastrozole in non-small cell lung cancer cell lines.

BACKGROUNDnSeveral studies implicated that lung cancer progression was governed by the interaction between estrogen receptor (ER) and epidermal growth factor receptor (EGFR) signaling pathways. Combined targeting of EGFR and ER may have the synergistic effect in lung cancer treatment. The aim of this study was to explore the potential utility of inhibiting these two pathways with combination of anastrozole and gefitinib in non-small cell lung cancer (NSCLC) cell lines.nnnMATERIALS AND METHODSnThe expression levels of ER (ER-α and ER-β) in lung cancer cell lines (A549, H460, SPC-A-1, H1299) and normal bronchus epithelial cell BEAS-2B were detected using real-time PCR and Western blot. Immunocytochemistry was used to locate ER-α and ER-β in cell line with highest ER expression levels. The cells were treated with anastrozole or gefitinib alone or in combination. The cell proliferation inhibition was detected by the CCK8 assay, cell cycle and apoptosis effects were detected by flow cytometry; the expression levels of phosphorylated-EGFR (p-EGFR), ERK, phosphorylated-ERK (p-ERK), AKT and phosphorylated-AKT (p-AKT) were detected by Western blot.nnnRESULTSnAmong these cell lines the expression levels of ER in A549 cells were highest. In A549 cell line, ER-α was mainly localized in the cytoplasm, whereas ER-β was mainly localized in the cytoplasm and to a lesser degree in the nucleus. The combination of two drugs increased the proliferation inhibition rates for 24h, 48 h, 72 h to 37.66 ± 1.02%, 63.41 ± 2.02%, 70.50 ± 0.86%, respectively, which was closely associated with elevation of the G0/G1 phase fraction (P<0.05). Apoptosis rates of A549 cells treated with anastrozole, gefitinib alone or in combination were 10.72 ± 1.12%, 17.40±1.28%, 23.02 ± 2.32%, respectively (P<0.05). The synergistic effects of the combination therapy were accompanied by reduction of p-EGFR, p-ERK and p-AKT expression compared with individual treatment.nnnCONCLUSIONSnThe results of this study suggest that the combination of anastrozole and gefitinib compared with either drug alone can maximally inhibit cell proliferation, induce apoptosis, and affect downstream signaling pathways. Our study supports functional interaction between the ER and the EGFR pathways in lung cancer and provides a clinically exploitable strategy for non-small cell lung cancer patients.

Clinical analysis of postoperative venous thromboembolism risk factors in lung cancer patients

The objective of this study is to explore clinical risk factors for venous thromboembolism (VTE) in postoperative lung cancer patients in order to provide a basis for the prevention and treatment of postoperative VTE.

Effect of ubiquitin carboxy-terminal hydrolase 37 on apoptotic in A549 cells.

Proteins destined for degradation by the ubiquitin‐proteasome system are labelled with a 76‐amino acid peptide, ubiquitin, through a series of conjugation steps by the E1, E2 and E3 enzymes respectively. Ubiquitin carboxy‐terminal hydrolase 37 (UCH37) belongs to the UCH proteases family that deubiquitinates ubiquitin‐protein conjugates in the ubiquitin‐proteasome system. However, it is few reports about the relationship between UCH37 and apoptosis. In order to clarify the role of UCH37 on apoptosis, the A549 cells were chosen for this study. We transfected UCH37 siRNA and pcDNA3.1‐UCH37 plasmid into A549 cells, respectively. Using MTT assay, Western blot, Hoechst 33342 staining assay and flow cytometry, we found that silencing of UCH37 in A549 cells induced apoptosis. The ratio of Bax/Bcl‐2 was higher in silencing of UCH37 than that in control group after silencing of UCH37 in A549 cells. Meanwhile, experiments with the A549 cell line disclose that silencing of UCH37 could induce efficiently A549 cell apoptosis through activation of caspase‐9 and caspase‐3. On the other hand, over‐expression of UCH37 led to the opposite effect. Hence, UCH37 might play an important role in apoptotic through altering Bax/Bcl‐2 ratio and enzymatic activities of caspase‐9 and caspase‐3. Copyright

Predictive significance of bone sialoprotein and osteopontin for bone metastases in resected Chinese non-small-cell lung cancer patients: A large cohort retrospective study

BACKGROUNDnBone is one of the most common sites of metastasis in patients with non-small-cell lung cancer (NSCLC). Over-expression of bone sialoprotein (BSP) and osteopontin (OPN) in tumour samples has shown prognostic significance in bone metastasis (BM) of breast and prostate cancer, respectively. However, their importance in BM of NSCLC has not been verified. Therefore, we planned a large cohort retrospective study to investigate the relationship between the expression of these two biomarkers (BSP and OPN) and BM in surgically resected NSCLC patients.nnnMETHODSn180 completely resected NSCLC patients were included in this study. 40 patients subsequently developed BM. Paraffin-embedded primary tumour tissues of patients were supplied to produce a tissue microarray, and immunohistochemistry method was used for evaluation of the expression of BSP and OPN. Different expressions of these two biomarkers among BM group and non-BM group were estimated by chi(2) test. BM-free survival was analyzed by Kaplan-Meier method. The prognostic impact of clinicopathologic variables and biomarker expression was evaluated by Cox proportional hazards model.nnnRESULTSnBSP expression was associated with BM (p=0.007), whereas OPN expression did not reach statistical significance (p=0.245). Univariate analysis showed that expression of BSP (p=0.010) and N staging (p<0.005) was associated with BM-free survival. Multivariate analyses showed BSP expression (HR=3.322, p=0.003), N staging (HR=1.879, p=0.001), and T staging (HR=1.618, p=0.024) were independent prognostic factors for BM.nnnCONCLUSIONSnBSP protein expression in the primary resected NSCLC is strongly associated with BM and could be used to identify high-risk patients. Correlation of OPN protein expression and BM needs further investigation.

Regulation of SIRT2 levels for human non-small cell lung cancer therapy

Seven Sirtuin family members (SIRT1-7), comprising a family of NAD+-dependent protein deacetylases and ADP-ribosyltransferases, are key proteins that regulate multiple physiological processes. SIRT2 was recently reported to play an important role in carcinogenesis. However, its role in non-small cell lung cancer (NSCLC) has not yet been investigated. In this study, we analyzed the expression pattern of SIRT2 in NSCLC tissues from clinical patients and in cell lines, and found that SIRT2 was significantly down-regulated at both the mRNA and protein levels in tumor than non-tumor tissues or cells, which were corroborated by the NSCLC tissue microarray results. Overexpression of SIRT2 in A549 and H1299 cells caused cell proliferation inhibition, cell apoptosis induction and cell cycle arrest. Further analysis showed that SIRT2 overexpression increased the ROS (reactive oxygen species) production and p27 levels. Moreover, up-regulation of SIRT2 in NSCLC cells increased the sensitivity to Cisplatin treatment. Taken together, our results implied that down-regulation of SIRT2 was associated with NSCLC, and regulation of SIRT2 might be an important target for NSCLC therapy.

Establishment of a biomarker model for predicting bone metastasis in resected stage III non-small cell lung cancer

BackgroundThis study was designed to establish a biomarker risk model for predicting bone metastasis in stage III non-small cell lung cancer (NSCLC).MethodsThe model consists of 105 cases of stage III NSCLC, who were treated and followed up. The patients were divided into bone metastasis group (nu2009=u200945) and non-bone metastasis group (other visceral metastasis and those without recurrence) (nu2009=u200960). Tissue microarrays were constructed for immunohistochemical study of 10 molecular markers associated with bone metastasis, based on which a model was established via logistic regression analysis for predicting the risk of bone metastases. The model was prospectively validated in another 40 patients with stage III NSCLC.ResultsThe molecular model for predicting bone metastasis was logit (P)u2009=u2009− 2.538u2009+u20092.808 CXCR4 +1.629 BSP +0.846 OPN-2.939 BMP4. ROC test showed that when Pu2009≥u20090.408, the sensitivity was up to 71% and specificity of 70%. Model validation in the 40 cases in clinical trial (NCT 01124253) demonstrated that the prediction sensitivity of the model was 85.7%, specificity 66.7%, Kappa: 0.618, with a high degree of consistency.ConclusionThe molecular model combining CXCR4, BSP, OPN and BMP4 could help predict the risk of bone metastasis in stage IIIa and IIIb resected NSCLC.

Dickkopf-1 autoantibody is a novel serological biomarker for non-small cell lung cancer

Objective:u2002We investigated whether or not there are autoantibodies for DKK1 (Dickkopf-1) in patients with non-small cell lung cancer (NSCLC) and whether this autoantibody can be used for cancer detection. Methods: u2002The levels of DKK1 autoantibodies were determined in 93 NSCLC patients and 87 healthy controls. Results:u2002We found that, in the sera, the presence of autoantibody against DKK1 was highly correlated with NSCLC. High anti-DKK1 autoantibody titres were found in the sera of NSCLC patients, whereas low or negative titres were found in the control group. The ROC curve results showed that autoantibody immunoassay exhibited 62% sensitivity and 84% specificity. The sensitivity for the detection of NSCLC in stage I also reach 64.3%. Furthermore, a combined ELISA assays for both DKK1 and autoantibody DKK1 increased sensitivity and classified 81.7% (76/93) of the NSCLC patients as positive, whereas only 13.8 % (12/87) of healthy volunteers were falsely diagnosed as positive. Conclusions:u2002Our results suggest that the detection of circulating DKK1 autoantibody could potentially serve as a useful non-invasive marker for determining lung cancer status.

Chinese pediatric and adolescent primary tracheobronchial tumors: a hospital-based study

ObjectivesTo investigate the clinical characteristics and treatment outcomes in Chinese pediatric and adolescent patients with primary tracheobronchial tumors by focusing upon the exploration of prognostic factors.MethodsA retrospective review of medical records collected from January 1996 through June 2009 was conducted within a single institution, inclusive of the total 19 treated pediatric and adolescent patients (3 benign tumors, 16 malignant tumors). A parallel comparison of adult cases with tracheobronchial tumor was performed to the pediatric and adolescent cases.ResultsThe chart review of pediatric and adolescent case reports revealed 19 cases with primary tracheobronchial tumors. Final pathologic diagnosis included 14 (73.68%) mucoepidermoid carcinoma (ME), 2 (10.53%) carcinoid tumor, 2 (10.53%) papillomatosis and 1 (5.26%) neurofibroma. Median age upon diagnosis was 12xa0years (range 4–18xa0years). Chest imaging revealed common abnormal radiographic atelectasis (12/19). Patients with localized disease received surgical tumor resection. There were a total of 8 (42.1%) sleeve resections, 4 (21.1%) resection of anatomically related lung parenchyma (1 bilateral lobectomies, 2 lobectomies, 1 pneumonectomy) and 7 local tumor resections. No surgery-related deaths or complications were observed. 16 patients (84.2%) remained disease free with a median follow-up of 70.5xa0months (range 44–168xa0months).ConclusionsOur hospital data indicated a high incidence of ME, presenting the difference in the incidence rates between Chinese and western populations. Sleeve lobectomy provides efficient treatment with excellent prognosis among Chinese pediatric and adolescent patients.

Functional roles of PC‐PLC and Cdc20 in the cell cycle, proliferation, and apoptosis

Phosphatidylcholine‐specific phospholipase C (PC‐PLC) is the major enzyme in the Phosphatidylcholine (PC) cycle and is involved in many long‐term cellular responses such as activation, proliferation, and differentiation events. Cell division cycle 20 homolog (Cdc20) is an essential cell‐cycle regulator required for the completion of mitosis. Our previous studies identified the interaction between PC‐PLC and Cdc20. Through the interaction, Cdc20 could mediate the degradation of PC‐PLC by Cdc20‐mediated ubiquitin proteasome pathway (UPP). In this study, we found that PC‐PLC might not be involved in cancer metastasis. Inhibition of PC‐PLC by D609 could cause cell proliferation inhibition and apoptosis inhibition in CBRH‐7919 cells. Inhibition of PC‐PLC could also influence the cell cycle by arresting the cells in G1 phase, and Cdc20 might be involved in these processes. Taken together, in this report, we provided new evidence for the functional roles of PC‐PLC and Cdc20 in the cell cycle, proliferation, and apoptosis in CBRH‐7919 cells. Copyright