LACTB2 Promotes the Growth and Migration of Non‐Small Cell Lung Cancer By Regulating Mitochondrial Function

Lung cancer remains one of the most commonly diagnosed cancers and the leading cause of cancer-related mortality worldwide. As a mitochondrial matrix protein, the role of β-lactamase-like protein 2 (LACTB2) is unclear in non-small cell lung cancer (NSCLC). In this study, we show that LACTB2 expression enhances the cell viability, anchorage-independent growth, migration and epithelial-mesenchymal transition(EMT) of NSCLC cells. Mechanistically, LACTB2 binds to mitochondrial DNA (mtDNA) and activates mitochondrial RNA (mtRNA) expression. Silencing LACTB2 induces mitochondrial dysfunction, which correlates with impaired proliferation, migration, and EMT in NSCLC cells. Furthermore, depletion of LACTB2 results in an increased expression of p53 and cleaved-PARP, indicating that LACTB2-mediated mitochondrial dysfunction activates the mitochondrial retrograde signaling-p53 pathway to regulate apoptosis in A549 cells. Additionally, we found that high LACTB2 expression is statistically correlated with poor overall survival in NSCLC patients, and silencing LACTB2 inhibits tumor growth in xenograft mouse models. In summary, our findings reveal that LACTB2 plays a critical role in NSCLC progression by modulating mtRNA expression and mitochondrial function. Therefore, the LACTB2-mtDNA-mitochondrial dysfunction axis may serve as a novel target for diagnosis and treatment of NSCLC.