Autophagy is essential for cellular metabolism and plays pivotal roles in carcinogenesis, while excessive autophagy induces toxicity and cell death. Our previous studies have suggested that let-7a-5p/BCL-xL might regulate autophagy in lung cancer, but the regulatory mechanism is unclear. The central goal of the study was to figure out the role of let-7a-5p/BCL-xL in the initiation of autophagy and its effect on the migration, invasion, and proliferation of A549 cells as well as its therapeutic potential in lung cancer. Based on the genome-wide expression profiles of lung cancer, BCL-xL and let-7a-5p were found to be dysregulated and negatively correlated in lung adenocarcinoma, which was associated with the survival of lung cancer. The crosstalk between BCL-xL and let-7a-5p was then investigated using dual-luciferase reporter assay, and it was found to suppress the migration and invasion of A549 cells. Further, we found that the crosstalk between BCL-xL and let-7a-5p could lead to toxic autophagy and cell death through activating the PI3K-signaling pathway, which was independent of apoptosis or pyroptosis. These findings indicate that let-7a-5p is a sensitive initiator for toxic autophagy in A549 lung cancer cells and is an appealing target for lung cancer therapy.

自噬是细胞代谢必不可少的，并且在致癌作用中起着关键作用，而过度自噬则引起毒性和细胞死亡。我们以前的研究表明let-7a-5p / BCL-xL可能调节肺癌的自噬，但调节机制尚不清楚。该研究的主要目的是弄清let-7a-5p / BCL-xL在自噬启动中的作用及其对A549细胞迁移，侵袭和增殖的影响及其在肺癌中的治疗潜力。根据肺癌的全基因组表达谱，发现BCL-xL和let-7a-5p在肺腺癌中表达失调且呈负相关，这与肺癌的生存有关。然后使用双萤光素酶报告基因检测法研究BCL-xL与let-7a-5p之间的串扰，并且发现其抑制了A549细胞的迁移和侵袭。此外，我们发现BCL-xL与let-7a-5p之间的串扰可能通过激活PI3K信号通路而导致毒性自噬和细胞死亡，而PI3K信号通路与细胞凋亡或凋亡无关。这些发现表明，let-7a-5p是A549肺癌细胞中毒性自噬的敏感引发剂，并且是肺癌治疗的诱人靶标。