Functional Characterization of TNFAIP2 Using Comprehensive Proteomic Approaches---Implication in Nasopharyngeal Carcinoma Metastasis

TNFAIP2 (TNF-α-inducible protein 2; also known as B94 and M-Sec) has been proposed to be involved in angiogenesis and inflammation as it appears to be involved in endothelial capillary tube formation in vitro and its expression can be induced by proinflammatory factors, such as TNFα. The function of TNFAIP2, however, has long been unknown. Recently, TNFAIP2 has been identified as a key molecule in formation of tunneling nanotube (TNT), which is a newly defined cell device for cell-cell communication. Morphologically TNTs are long, thin, non-adherent F-actin-based protrusions of the plasma membrane which allow direct physical connections between remote cells. The proposed functions for TNTs include the cell-to-cell transfer of cellular components and signal transduction molecules in a wide variety of cell types. Moreover, several pathogens have been shown to exploit TNTs and TNT-related structures to spread among cells. Notably, TNT-related structures are recently scrutinized as a unique and previously unrecognized form of direct cell-to-cell transmission of cellular cargo in the context of human cancer, supplying an in vivo relevance of TNTs and their potential importance in cancer pathogenesis. Nevertheless, the expressional profiling and the functional characterization of TNFAIP2 in human cancer remain limited to date. A recent study by our colleagues first demonstrates that TNFAIP2 is highly expressed in nasopharyngeal carcinoma (NPC), and is significantly correlated with high-level intratumoral microvessel density and low distant metastasis-free survival, suggesting that its expression predicts distant metastasis. Our preliminary data further revealed that TNFAIP2, as a cell migration-promoting protein, is a central factor to induce formation of TNT-like structures in NPC cells. Given that NPC is a highly metastatic head and neck cancer that is common in Taiwan, discovery of the role of TNFAIP2 in NPC cells will accelerate the understanding of TNTs regarding the physiological processes in which TNFAIP2-mediated TNTs participate and their relevance to cancer progression. In the present proposal, we attempt to conduct a comprehensive, proteome-wide analysis of TNFAIP2 function in NPC cells. We aim to (1) systemically identify the components of TNFAIP2-associated protein complexes, (2) comparatively analyze the membrane proteome isolated respectively from TNFAIP2-depleted and control cells to discover the components which are potentially regulated by TNFAIP2, and (3) focus on validation of candidates which appear to be involved in TNFAIP2-mediated TNT formation via the protein-protein interaction. This study could then lead to therapeutic targets and the development of drugs to limit or eradicate the spreading of diseases in the body.

Project ID:PC10401-0206
External Project ID:NSC102-2320-B182-029-MY3