Abstract
The Xuanwei area of Yunnan Province, China, is one of the regions suffering from the highest occurrence and mortality rate of lung cancer in the world. Local residents tend to use bituminous coal as domestic fuel, which causes serious indoor air pollution and is established as the main carcinogen. After the local government carried out furnace and stove reform work, lung cancer rate including incidence and mortality among residents remains high. We herein wonder if there are specific mechanisms at protein level for the development of non‐small‐cell lung cancer (NSCLC) in this area. We investigated the changes of protein profiling in tumour of the patients from Xuanwei area. Tandem mass tag (TMT) was employed to screen the differential proteins between carcinoma and para‐carcinoma tissues. We identified a total of 422 differentially expressed proteins, among which 162 proteins were significantly up‐regulated and 260 were downregulated compared to para‐carcinoma tissues. Many of the differentially expressed proteins were related to extracellular matrix (ECM)‐receptor interaction, focal adhesion, PI3K/AKT pathway and ferroptosis. Further experiments on the two differential proteins, thioredoxin 2 (TXN2) and haptoglobin (HP), showed that the change of their expressions could make the lung cancer cell lines more resistant to erastin or RSL‐induced ferroptosis in vitro, and promote the growth of tumour in nude mice. In conclusion, this study revealed that aberrant regulation of ferroptosis may involve in the development of lung cancer in Xuanwei area.
Highlights
The number of deaths due to cancer accounts for about 12% of the total deaths each year worldwide, and there are over 1 000 000 new cases of cancer per year.[1]
Several researches have proposed that the smoky coal combustion products like polycyclic aromatic hydrocarbons (PAHs) and air pollution fine-grained matter such as crystalline quartz particulate are classified as mutagens to human cancer.[7,8]
We found that the levels of Fe2+ (Figure 7D), MDA (Figure 7E), intracellular lipid Reactive oxygen species (ROS) (Figure 7F) and lipid peroxidation (Figure 7H) in A549 and NCI-H11299 were remarkably increased and GSH was decreased (Figure 7G). The effect of both erastin and RSL along with HP overexpression or thioredoxin 2 (TXN2) depletion on cell survival levels of Fe2+, MDA, intracellular lipid ROS, lipid peroxidation and GSH could be reversed by ferrostatin (Figure 7C-G).Observation by Transmission electron microscopy (TEM) revealed that the lung cancer cells with interference of TXN2 or overexpression of HP had smaller mitochondria and a decreased number of mitochondrial cristae under the treatment of erastin or RSL, and the proportion of mitochondria with ruptured outer membrane increased in these cells (Figure 7I)
Summary
The number of deaths due to cancer accounts for about 12% of the total deaths each year worldwide, and there are over 1 000 000 new cases of cancer per year.[1]. The incidence of lung cancer among non-smokers is 400/100 000, which is 20 times higher than the national average.[2,3] Previous studies have associated this excessive incidence of lung cancer with the domestic combustion of ‘smoky coal’, especially burning the coals in unvented households.[4,5] The smoky coal typically means the locally obtainable Late Permian bituminous coal,[6] which releases high level of visible smoke upon combustion. This kind of coal is available from many local coal mines within Xuanwei region and constitutes the primary fuel source for native residents. We would analyse the protein profiling changes of the lung cancer tissues form the patients of Xuanwei area, providing more insights to the large excess incidence of lung cancer in this area and finding specific bio-molecular mechanisms involving the regional lung cancer
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