Active cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcome. We here established high-invasive lung cancer cell models, A549-i8 and H1299-i8, and identified mesoderm-specific transcript (MEST) as a novel invasive regulator for lung cancer. MEST overexpression promoted the metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST enhanced the interaction of VCP with IκBα, which accelerated IκBα degradation and NF-κB activation. Such an acceleration could be abrogated by VCP silencing, indicating that MEST is an upstream regulator to induce the sequential VCP/IκBα/NF-κB signaling. Furthermore, high MEST and VCP expressions were associated with poor survival of lung cancer patients. Collectively, we demonstrated that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP, coordinating IκBα/NF-κB pathway. Targeting MEST/VCP/IκBα/NF-κB signaling may represent a promising therapeutic strategy for lung cancer.