Background The identification of novel therapeutic targets in lung cancer for the generation of targeted drugs is an urgent challenge. Lung-specific X (LunX) is a member of the palate, lung, and nasal epithelium clone (PLUNC) protein family. Some reports have suggested that the human PLUNC gene (also named LUNX) might be a potential marker for NSCLC, and PLUNC mRNA has been identified in peripheral blood and mediastinal lymph nodes from NSCLC patients.It is unclear whether LunX expression is associated with the pathological type and pathological severity in lung cancer patients. The utility of LunX as a potential therapeutic target in NSCLC is uncertain.
Methods Clinically, 80% of lung cancers are non-small-cell lung cancers (NSCLCs). Here, we analyzed 158 NSCLC samples and detected LunX expression.
Results It showed that the expression of LunX were elevated in 90% (108/150) lung cancers by IHC staining, which accompanied with significantly lower rate of postsurgery survival. Further evaluation of LunX expression in invasive tumor cells in subclavicular lymph nodes, draining lymph nodes, hydrothorax of lung cancer patients, turned out that LunX is highly expressed in invasive lung cancer cells. These data indicated that LunX overexpresses in lung cancer and associates with tumorigenesis and tumor progression.
Mechanistically, we discovered that LunX bound to 14-3-3 protein and facilitated their activation by maintaining these proteins in a dephosphorylated state, thereby contributing to the activation of pathways downstream of 14-3-3 protein, such as the Erk1/2 and JNK pathways. Thus, LunX promoted tumor growth and metastasis.
Furthermore, we generated a therapeutic antibody specific for lung cancer, which not only inhibited lung cancer growth and reduced Ki67 staining and angiogenesis in xenograft model of subcutaneously transplanted tumor, but also blocked tumor metastasis and invasion, improved the survival of these mice. We also detected that antibody treatment induces LunX antigen-antibody complex endocytosis and the degradation of LunX protein.
Conclusions Our study suggests that LunX is a novel therapeutic target in lung cancer and that the LunX-targeted therapeutic antibody may have considerable clinical benefit.
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