Air pollution is one of the leading causes of lung cancer. Air pollution-related lungcancer is a deteriorating public health problem, particularly in developing countries.The MUC16 gene is one of the most frequently mutated genes in air pollution-relatedlung cancer. In the present study, MUC16 mRNA expression was increased in ~50%of air pollution-related lung cancer samples obtained from patients residing in air-polluted regions (Xuanwei and Fuyuan, Yunnan, China), and MUC16 mRNA levelswere correlated with the degree of air pollution. Furthermore, sequencing of thecaptured MUC16 gene identified 561 mutation sites within the MUC16 gene in theair pollution-related lung cancer tissues. Interestingly, some mutations at specificsites and one region were associated with MUC16 mRNA up-regulation. Therefore,we further investigated the impacts of gene mutation on MUC16 expressions andcell behaviors in cultured cells by inducing certain mutations within the MUC16 geneusing CRISPER/Cas9 genome editing technology. Certain mutations within the MUC16gene induced MUC16 overexpression at both the mRNA and the protein level in thecultured cells. Additionally, MUC16 overexpression induced by gene mutations hadfunctional effects on the behavior of lung cancer cells, including increasing theirresistance to cisplatin, promoting their growth, and enhancing their migration andinvasion capabilities. Based on the data, we suggest that MUC16 mutations potentiallyassociated with air pollution may participate in the development and progressionof air pollution-related lung cancer. In addition to ovarian cancer, MUC16 may be acandidate biomarker for lung cancer.