Abstract
BackgroundMetastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized.MethodsGenetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis.ResultsNck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells.ConclusionsOur insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.
Highlights
Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung
Our previous studies further demonstrated that NAP1 is required for the protein stability of WASF3 in breast cancer cells, implicating that NAP1 is a critical regulator in favor of breast cancer metastasis [5]
NAP1 expression levels are strongly associated with Non-small-cell lung cancer (NSCLC) metastasis To identify the clinical relevance of NAP1 in human cancer, we analyzed the expression levels of the NAP1 gene among many types of cancer that were available in Oncomine
Summary
Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Increasing evidence has shown that NAP1 is critical for cell motility and adhesion by driving actin assembly and polymerization and lamellipodia formation [5, 9, 10], which are associated with the development of invasion and metastasis phenotypes. In breast cancer, univariate analysis reveals that high expression of NAP1 is strongly correlated with poor metastasis-free survival of patients with breast cancer, suggesting NAP1 as an independent prognosis factor [11]. WASF3 is a tumor metastasis driver in breast cancer, and its knockdown leads to a significant reduction in metastatic breast cancer cell invasion and metastasis in mice [5]. Our previous studies further demonstrated that NAP1 is required for the protein stability of WASF3 in breast cancer cells, implicating that NAP1 is a critical regulator in favor of breast cancer metastasis [5]
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