Abstract
Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer.Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by in vitro cellular assays and in vivo mouse models. In addition, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression.Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities in vitro FAM198B also attenuated tumor growth and metastasis in vivo We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability.Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. Clin Cancer Res; 24(4); 916-26. ©2017 AACR.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is the predominant histologic subtype of lung cancer in woman, never-smokers, and younger adults [1,2,3]
We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database
Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is the predominant histologic subtype of lung cancer in woman, never-smokers, and younger adults [1,2,3]. Proteolytic degradation of the extracellular matrix (ECM) and the basement membranes surrounding the primary tumor by the matrix metalloproteinase (MMP) is a critical step for tumor angiogenesis, invasion, and metastasis [9]. The MMPs have served as potential prognostic markers and therapeutic targets in cancer [10]. We established an isogenic lung cancer metastasis cell model and discovered several metastasis-related gene [11,12,13,14,15,16,17,18]. The comprehensive understanding of mechanisms involved in the tumor metastasis remains to be explored further
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