Radon and its progeny are confirmed to be type I carcinogenic agents accounting for increased risks in 10% of observed lung cancers globally. However, the underlying carcinogenic mechanisms are largely unknown. In the present study, BEAS2B cells were directly exposed twice to 20,000 Bq/m(3) radon gas for 20 min once (first passage) and subsequently 10 times (fifth passage). The fifth-passage cells were then subcultured for 1 and 20 generations (named Rn5-1 and Rn5-20, respectively). Molecular mechanisms indicative of malignant transformation were assessed by determination of apoptosis, seroresistance, and microRNA (miRNA) expression profiles. The microRNA profiles were used to assess the functional annotations of the target genes. Data indicated an increased seroresistance and colony efficiency on soft agar, and enhanced apoptosis resistance in the Rn5-20 cells with significant differential expressions in some miRNA, including hsa-miR-483-3p, hsa-miR-494, hsa-miR-2115*, hsa-miR-33b, hsa-miR-1246, hsa-miR-3202, hsa-miR-18a, hsa-miR-125b, hsa-miR-17*, and hsa-miR-886-3p. Functional annotation demonstrated that these miRNA target genes were predominantly involved in the regulation of cell proliferation, differentiation, and adhesion during the process of malignant transformation, which is associated with signal pathways such as mitogen-activated protein kinase (MAPK), Int and Wg (Wnt), reactive oxygen species (ROS), nuclear factor κB (NF-κB), and other genes regulating cell cycles.