Multifunctional Role of Bcl-2 in Malignant Transformation and Tumorigenesis of Cr(VI)-Transformed Lung Cells

B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI)

Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers

Objectives: To investigate the association between exposures to polycyclic aromatic hydrocarbons (PAH) that arises during asphalt paving, and risk of bladder cancer. Methods: 7298 men included in the historical cohort were first employed between 1913 and 1999 in companies applying asphalt in Denmark, Norway, Finland and Israel. The minimal duration of employment for inclusion in the cohort was two seasons of work. Occupational histories were extracted from personnel files. A follow-up for cancer incidence was conducted through national cancer registries. The authors estimated exposures to benzo(a)pyrene as a marker for 4-6 ring PAH. Exposures were reconstructed by using information about changes in asphalt paving technology in each company over time, the modelled relation between production characteristics and exposure levels, and job histories. Relative risks and associated 95% confidence intervals were estimated using Poisson regression. Results: 48 bladder cancers among asphalt paving workers were detected; of these, 39 cases were exposed at least 15 years before the diagnosis. Cumulative exposure to PAH was not associated with the incidence of bladder cancer. The association with average exposure became stronger when 15-year lag was considered, revealing a twofold increase in relative bladder cancer risk in the two higher exposure categories. There was an indication of exposure-response association with lagged averaged exposure. Risk estimates were adjusted for age, country, duration of employment and calendar period, did not show heterogeneity among countries and did not materially change when re-estimated after excluding non-primary cancers from follow-up. Previously conducted sensitivity analysis indicates that confounding by cigarette smoking is an unlikely explanation for the observed exposure-response trends. Conclusions: The authors were unable to control for all possible sources of confounding and bias. The results do not allow conclusion on the presence or absence of a causal link between exposures to PAH and risk of bladder cancer among asphalt workers