Wang Lv

Esculetin induces apoptosis in human gastric cancer cells through a cyclophilin D-mediated mitochondrial permeability transition pore associated with ROS

Esculetin is a coumarin derivative from natural plants that has been commonly used as a folk medicine and has been reported to have beneficial pharmacological and biochemical activities; however, the mechanism by which esculetin prevents human gastric cancer cell growth is still largely unknown. In this study, we investigated the effect of esculetin on human gastric cancer cells and explored the cell death mechanism. Our data indicated that esculetin inhibited the growth of human gastric cancer cells in a dose- and time-dependent manner and apoptosis was the main cause of decreased cell viability in esculetin-treated cells. Additionally, esculetin treatment increased the activity of caspase-9 and caspase-3, and resulted in the appearance of the PARP cleavage product; and esculetin-induced cell death and apoptosis was decreased by pretreatment with CsA and NAC, but not BA; these results demonstrate that esculetin induced apoptosis via the caspase-dependent mitochondrial pathway in human gastric cancer cells in which cyclophilin D mediated the cytotoxic action by triggering the opening of the mitochondrial permeability transition pore; and the generation of ROS not only was a consequence of mitochondrial dysfunction, but also triggered esculetin-induced apoptosis. These results reveal a novel mechanism of esculetin on gastric cancer cells and suggest that esculetin could be a novel agent in the treatment of gastric cancer.

Clinical Nomogram for Predicting Survival of Esophageal Cancer Patients after Esophagectomy.

The aim of this study was to construct an effective clinical nomogram for predicting the survival of esophageal cancer patients after esophagectomy. We identified esophageal cancer patients (n = 4,281) who underwent esophagectomy between 1988 and 2007 from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Clinically significant parameters for survival were used to construct a nomogram based on Cox regression analyses. The model was validated using bootstrap resampling and a Chinese cohort (n = 145). A total of 4,109 patients from the SEER database were included for analysis. The multivariate analyses showed that the factors of age, race, histology, tumor site, tumor size, grade and depth of invasion, and the numbers of metastases and retrieved nodes were independent prognostic factors. All of these factors were selected into the nomogram. The nomogram showed a clear prognostic superiority over the seventh AJCC-TNM classification (C-index: SEER cohort, 0.716 vs 0.693, respectively; P < 0.01; Chinese cohort, 0.699 vs 0.680, respectively; P < 0.01). Calibration of the nomogram predicted the probabilities of 3- and 5-year survival, which corresponded closely with the actual survival rates. This novel prognostic model may improve clinicians’ abilities to predict individualized survival and to make treatment recommendations.

Video-assisted thoracoscopic surgery versus open thoracotomy in pulmonary metastasectomy: a meta-analysis of observational studies.

BACKGROUND Pulmonary metastasectomy via a traditional open thoracotomy is effective for the treatment of patients with pulmonary metastases. However, whether video-assisted thoracoscopic surgery (VATS) achieves similar clinical effects in terms of survival rates remains unclear. We conducted this meta-analytic study to compare VATS with open thoracotomy for pulmonary metastasectomy. METHODS Relevant studies were identified by searching PubMed from inception to December 2014. The overall and recurrence-free survival rates were measured in terms of hazard ratios (HRs) with VATS and open thoracotomy as the main outcomes. RESULTS Eight studies were included in our meta-analysis, which included 337 patients in the VATS group and 485 patients in the open thoracotomy group. The overall survival rate in the VATS group was statistically significantly higher than that in the open thoracotomy group [HR, 0.69; 95% confidence interval (CI), 0.55-0.87; P = 0.002]. The VATS group still had a higher overall survival rate after exclusion of the one low-quality study (HR, 0.78; 95% CI, 0.59-1.03), but the result was not statistically significant (P = 0.075). No difference in the recurrence-free survival rate was found between the two groups (HR, 0.86; 95% CI, 0.69-1.08). The subgroup analysis showed no difference between the two groups in either the overall survival rate (HR, 0.72; 95% CI, 0.50-1.04) or the recurrence-free survival rate (HR, 0.79; 95% CI, 0.59-1.08) in patients with metastases from colorectal cancer. CONCLUSIONS VATS is an alternative surgical approach for pulmonary metastasectomy in patients with resectable pulmonary metastases. Further large prospective studies are needed to identify the indications for VATS in patients with pulmonary metastases.

Association between the TERT Genetic Polymorphism rs2853676 and Cancer Risk: Meta-Analysis of 76 108 Cases and 134 215 Controls

Background Several recent studies have identified that the TERT genetic polymorphism rs2853676 is associated with cancer risk, but presented inconsistent results. We investigated these inconclusive results by performing a meta-analysis to systematically evaluate the association. Methods We conducted a search in PubMed, Google Scholar and ISI Web of Science to select studies on the association between TERT rs2853676 and cancer risk. We conducted a stratified analysis using cancer type, ethnicity and source of controls. We calculated the odds ratios (OR) and 95% confidence intervals (CI). Article quality, heterogeneity, sensitivity, publication bias and statistical power were also assessed. Results 26 articles covering 76 108 cases and 134 215 controls met our inclusion criteria. A significant association between TERT rs2853676 allele A and cancer susceptibility was demonstrated under a per-allele risk analysis (OR = 1.08, 95% CI = 1.04-1.13). Stratification analysis revealed an increased cancer risk in subgroups of glioma, lung cancer and ovarian cancer. No significant increase was found in melanoma, breast cancer, pancreatic cancer and colorectal cancer. In a subgroup analysis of lung cancer, a statistically significant increase was only observed in adenocarcinoma. Moreover, a stratified analysis performed for ethnic groups revealed that the significant increase was only observed in Caucasians, whereas a non-significant increase was found in Asians. Conclusions This meta-analysis suggests that the TERT genetic polymorphism rs2853676 is associated with increased risk of glioma, lung adenocarcinoma and ovarian cancer among Caucasians. Further functional studies are warranted to validate this association and investigate further.

Clinical Characteristics and Prognostic Significance of TERT Promoter Mutations in Cancer: A Cohort Study and a Meta-Analysis

Background The prevalence of telomerase reverse transcriptase (TERT) promoter mutations (pTERTm) in non-small-cell lung cancer (NSCLC) have been investigated, but the results were inconsistent. In addition, several studies have analysed the role of pTERTm in the etiology of various types of cancers, however, the results also remain inconsistent. Methods The genomic DNA sequence of 103 NSCLC samples were analysed to investigate the frequency of pTERTm in these patients and to establish whether these mutations are associated with their clinical data. Furthermore, a meta-analysis based on previously published articles and our cohort study was performed to investigate the association of pTERTm with patient gender, age at diagnosis, metastasis status, tumour stage and cancer prognosis (5-year overall survival rate). Results In the cohort study, 4 patients had C228T and 2 had C250T, with a total mutation frequency up to 5.8%. Significant difference of clinical data between pTERTm carriers and noncarriers was only found in age at diagnosis. In the meta-analysis, We found that pTERTm carriers in cancer patients are older than noncarriers (Mean difference (MD) = 5.24; 95% confidence interval [CI], 2.00 to 8.48), male patients were more likely to harbour pTERTm (odds Ratios (OR) = 1.38; 95% CI, 1.22 to 1.58), and that pTERTm had a significant association with distant metastasis (OR = 3.78; 95% CI, 2.45 to 5.82), a higher tumour grade in patients with glioma (WHO grade III, IV vs. I, II: OR, 2.41; 95% CI, 1.88 to 3.08) and a higher tumour stage in other types of cancer (III, IV vs. I, II: OR, 2.48; 95% CI, 1.48 to 4.15). pTERTm was also significantly associated with a greater risk of death (hazard ratio = 1.71; 95% CI, 1.41 to 2.08). Conclusions pTERTm are a moderately prevalent genetic event in NSCLC. The current meta-analysis indicates that pTERTm is associated with patient age, gender and distant metastasis. It may serves as an adverse prognostic factor in individuals with cancers.

Wnt3a Expression Is Associated with Epithelial-Mesenchymal Transition and Impacts Prognosis of Lung Adenocarcinoma Patients

Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/β-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E-cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients. Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/β-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities. Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrells C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities. Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients.

Time-to-Progression of NSCLC from Early to Advanced Stages: An Analysis of data from SEER Registry and a Single Institute.

The average time required for cancers to progress through stages can be reflected in the average age of the patients diagnosed at each stage of disease. To estimate the time it takes for non-small-cell lung cancer (NSCLC) to progress through different tumor, node and metastasis (TNM) stages and sizes, we compared the mean adjusted age of 45904 NSCLC patients with different stages and tumor sizes from Surveillance, Epidemiology and End Results (SEER) cancer registry database and our institute. Multiple-linear-regression models for age were generated adjusting for various factors. Caucasian, African-American and Asian patients with stage IA cancers were on average 0.8, 1.0 and 1.38 adjusted years younger, respectively, than those with stage IIIB cancers (p < 0.001). And these with T1a cancers were on average 0.84, 0.92 and 1.21 adjusted years younger, respectively, than patients with T3 cancers (p < 0.001). Patients with tumors measuring larger than 8 cm in diameter were on average 0.85 adjusted years older than these with tumors smaller than 1 cm (p < 0.001), with Caucasian demonstrating the shortest age span (0.79 years, P < 0.001). In conclusion, the time-to-progression of NSCLC from early to advanced stages varied among ethnicities, Caucasian patients demonstrating a more rapid progression nature of tumor than their African-American and Asian counterparts.

Telomerase Cajal body protein 1 depletion inhibits telomerase trafficking to telomeres and induces G1 cell cycle arrest in A549 cells.

Telomerase Cajal body protein 1 (TCAB1) is a telomerase holoenzyme, which is markedly enriched in Cajal bodies (CBs) and facilitates the recruitment of telomerase to CBs in the S phase of the cell cycle. This recruitment is dependent on TCAB1 binding to a telomerase RNA component. The majority of cancer cells are able to grow indefinitely due to telomerase and its mechanism of trafficking to telomeres. In the present study, a certain level of TCAB1 expression in A549 human lung cells was identified and TCAB1 knockdown exhibited a potent antiproliferative effect on these cells, which was coupled with a decrease in the cell density and activity of the cellular enzymes. In addition, TCAB1-depletion was demonstrated to inhibit telomerase trafficking to telomeres in the A549 cells, leading to subsequent G1 cell cycle arrest without inducing apoptotic cell death. Overall, these observations indicated that TCAB1 may be essential for A549 cell proliferation and cell cycle regulation, and may be a potential candidate for the development of a therapeutic target for lung adenocarcinomas.

Prognostic Impact of Lymphadenectomy on Outcomes of Sublobar Resection for Stage IA Non-Small Cell Lung Cancer ≤ 2 cm

Objective To investigate the prognostic impact of lymph node (LN) dissection on sublobar resection for stage IA non–small cell lung cancer (NSCLC) tumors ≤2 cm. Methods All patients who underwent sublobar resection for stage IA NSCLC tumors ≤2 cm were identified from the Surveillance, Epidemiology and End Results database. Patients were classified into no‐LN dissection and LN dissection groups, and the latter was subclassified by the extent of LN dissection (1‐3 regional LNs or ≥4 regional LNs). These groups were compared in terms of lung cancer–specific survival (LCSS) and overall survival (OS) rates. Propensity score–matched comparative analysis and a Cox regression model were used. Results A total of 3269 patients met our criteria, including 1459 (44.6%) who underwent no LN dissection, 891 (27.3%) who underwent dissection of 1 to 3 regional LNs, 919 (28.1%) who underwent dissection of ≥4 regional LNs. Compared with no LN dissection, LN dissection was associated with more favorable LCSS and OS rates in patients who underwent sublobar resection for stage IA tumors ≤2 cm. More extensive regional LN dissection (≥4 regional LNs) was associated with better LCSS and OS rates compared with less extensive regional LN dissection (1 to 3 regional LNs). A multivariable analysis of our patient population revealed independent associations of no LN dissection and less extensive regional LN dissection with poorer LCSS and OS rates compared with overall LN dissection and more extensive regional LN dissection, respectively. Conclusions This propensity score–matched analysis reveals an association of LN dissection, particularly more extensive regional LN dissection (≥4 regional LNs), with better survival rates in patients who undergo sublobar resection for stage IA NSCLC tumors ≤2 cm.

Survival Rates After Lobectomy, Segmentectomy, and Wedge Resection for Non-Small Cell Lung Cancer

BACKGROUND This study aimed to compare the survival rates after lobectomy, segmentectomy, and wedge resection for the eighth edition of the tumor, node, metastasis classification for stage IA non-small cell lung cancer (NSCLC). METHODS Patients who underwent lobectomy, segmentectomy, or wedge resection for stage IA NSCLC were identified from the Surveillance, Epidemiology, and End Results database. A Cox regression model and propensity-matched analysis were used. The overall survival (OS) rates and lung cancer-specific survival (LCSS) rates among the three groups were compared by tumor size. RESULTS A total of 16,819 patients met our criteria. Although the OS rate was better for lobectomy than for wedge resection, no statistical differences in the LCSS rate were identified among the three treatment groups of patients with tumors that were 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy showed no statistical differences in the LCSS rate, but both conferred better OS and LCSS rates than wedge resection. For tumors from 2.1 to 3.0 cm, the OS and LCSS rates were better for lobectomy than for segmentectomy or wedge resection, but similar for segmentectomy and wedge resection. CONCLUSIONS Lobectomy, segmentectomy, and wedge resection are comparable oncologic procedures for patients with stage IA NSCLC that is 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy could lead to equivalent survival rates but showed better survival rates than that observed with wedge resection. For tumors from 2.1 to 3.0 cm, lobectomy is still the standard surgical procedure; for patients who are unsuitable candidates for lobectomy, segmentectomy and wedge resection show similar survival rates.