TIPE3 differentially modulates proliferation and migration of human non-small-cell lung cancer cells via distinct subcellular location.

BACKGROUND:TIPE3 (TNFAIP8L3), a transfer protein for lipid second messengers, is upregulated in human lung cancer tissues. The most popular lung cancer is non-small cell lung cancer (NSCLC) with high incidences and low survival rates, while the roles of TIPE3 in NSCLC remain largely unknown. METHODS:TIPE3 expression was examined in tissue chips from patients with NSCLC using immunohistochemistry; the correlation of plasma membrane expression of TIPE3 with T stage of NSCLC was analyzed. After endogenous TIPE3 was silenced via siRNA, or TIPE3 with N or C-terminal flag was overexpressed via transient or stable transfection, human NSCLC cells were assayed for the proliferation and migration, respectively. NSCLC cells, in which TIPE3 with C-terminal flag was stably transfected, were inoculated into mice to establish xenograft tumors, the tumor growth and the expression of TIPE3 in tumor tissues were examined. RESULTS:TIPE3 was broadly expressed in lung tissues of patients with NSCLC. The plasma membrane expression of TIPE3 was positively correlated with the T stage of NSCLC. Knockdown of endogenous TIPE3, which was predominantly expressed in the plasma membrane, inhibited the proliferation and migration of NSCLC cells. While transient overexpression of TIPE3 with N-terminal flag, which was mostly trapped in the cytoplasm, inhibited the growth and migration of NSCLC cells accompanied by inactivation of AKT and ERK. In contrast, stable overexpression of TIPE3 with C-terminal flag, which could be localized in the plasma membrane, markedly promoted the growth and migration of NSCLC cells through activation of AKT and ERK. Notably, in xenograft tumor models established with NSCLC cells, stable overexpression of TIPE3 with C-terminal flag in NSCLC cells significantly promoted the tumor growth and enhanced the expression and plasma membrane localization of TIPE3 in tumor tissues. CONCLUSION:This study demonstrates that human TIPE3 promotes the proliferation and migration of NSCLC cells depending on its localization on plasma membrane, whereas cytoplasmic TIPE3 may exert a negative function. Thus, manipulating the subcellular location of TIPE3 can be a promising strategy for NSCLC therapy.

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