MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling

Background: Cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcomes. In this study, we established two highly invasive lung cancer cell models (A549-i8 and H1299-i8) and identified mesoderm-specific transcript (MEST) as a novel invasive regulator of lung cancer. We aim to characterize its biological function and clinical significance in lung cancer metastasis. Methods: Transwell invasion assay was performed to establish high-invasive lung cancer cell model. Immunohistochemistry (IHC) was used to detect MEST expression in tumor tissues. Mass spectrometry and bioinformatic analyses were used to identify MEST-regulated proteins and binding partners. Co-immunoprecipitation assay was performed to detect the interaction of MEST and VCP. The biological functions of MEST were investigated in vitro and in vivo. Immunofluorescence staining was conducted to explore the colocalization of MEST and VCP. Results: MEST overexpression promoted metastasis of lung cancer cells in vivo and in vitro by activating NF-kappa B signaling. MEST increased the interaction between VCP and I kappa B alpha, which accelerated I kappa B alpha degradation and NF-kappa B activation. Such acceleration was abrogated by VCP silencing, indicating that MEST is an upstream activator of the VCP/I kappa B alpha/NF-kappa B signaling pathway. Furthermore, high expressions of MEST and VCP were associated with poor survival of lung cancer patients. Conclusion: Collectively, these results demonstrate that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP to coordinate the I kappa B alpha/NF-kappa B pathway. Targeting the MEST/VCP/I kappa B alpha/NF-kappa B signaling pathway may be a promising strategy to treat lung cancer.

Automated summary

The study identified MEST as a key regulator of invasion and metastasis in lung cancer, promoting cellular metastasis by activating the NF-kappa B signaling pathway. MEST interacts with VCP to coordinate the pathway, and high expressions of MEST and VCP are associated with poor survival in lung cancer patients. Targeting the MEST/VCP/I kappa B alpha/NF-kappa B signaling pathway may be a promising strategy for treating lung cancer.