KPNA2 drives cancer stemness, which enhances drug resistance and facilitates cancer progression in lung adenocarcinoma

KPNA2 (Importin alpha1) is a nuclear transport protein that shuttles nuclear proteins into the nucleus. While its role in cancer-associated fibroblasts and the tumor microenvironment is known, its direct function in lung cancer cells remains to be fully elucidated. In this study, we found that high KPNA2 expression is associated with poor prognosis in patients with lung adenocarcinoma. KPNA2 knockdown significantly impaired cell migration and invasion and sensitized cells to anticancer drugs in vitro. In vivo, KPNA2 depletion decreased primary tumor growth and metastasis in an orthotopic model. Mechanistically, RNA sequencing revealed that KPNA2 regulates the epithelial-mesenchymal transition (EMT) pathway. Functional studies demonstrated that KPNA2 specifically increases the responsiveness of lung cancer cells to EMT-inducing factors like TGFbeta, evidenced by enhanced plasticity in 3D Matrigel cultures. These findings establish KPNA2 as a critical regulator of lung cancer stemness and chemoresistance, representing a potential therapeutic target to suppress metastasis.