Interferon-Induced Transmembrane Protein 1 (IFITM1) Promotes Distant Metastasis of Small Cell Lung Cancer

• Published in: International journal of molecular sciences Vol. 21; no. 14; p. 4934
• Main Authors: Sakamoto, Shuichi, Inoue, Hiroyuki, Kohda, Yasuko, Ohba, Shun-Ichi, Mizutani, Taketoshi, Kawada, Manabu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13-07-2020; MDPI
• Subjects: Adrenal Gland Neoplasms - secondary; Adrenal glands; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; Biotechnology; Bone Neoplasms - secondary; Carcinoma, Small Cell - genetics; Carcinoma, Small Cell - metabolism; Carcinoma, Small Cell - secondary; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA chips; DNA microarrays; experimental metastasis model; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Heterografts; Humans; IFITM1; Interferon; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Malignancy; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis - genetics; Neoplasm Metastasis - physiopathology; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasm Transplantation; Organ Specificity; orthotopic transplantation model; Proteins; RNA Interference; RNA, Neoplasm - genetics; RNA, Small Interfering - genetics; Signal transduction; small cell lung cancer; Transplantation; Tumor cells; Tumors; Xenografts; Xenotransplantation; IFITM1; experimental metastasis model; small cell lung cancer; metastasis; orthotopic transplantation model
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21144934

Small cell lung cancer (SCLC) is a severe malignancy associated with early and widespread metastasis. To study SCLC metastasis, we previously developed an orthotopic transplantation model using the human SCLC cell line DMS273. In the model, metastatic foci were found in distant tissues such as bone and the adrenal gland, similarly as observed in patients with SCLC. In this study, we evaluated the differentially expressed genes between orthotopic and metastatic tumors in the model. We isolated tumor cells from orthotopic and metastatic sites, and the tumor cell RNA was analyzed using DNA microarray analysis. We found that 19 genes in metastatic tumors were upregulated by more than 4-fold compared with their expression in orthotopic tumors. One of these genes encodes a transmembrane protein, interferon (IFN)-induced transmembrane protein 1 (IFITM1), and immunohistochemical analysis confirmed the higher expression of the protein in metastatic sites than in orthotopic sites. IFITM1 was also detected in some SCLC cell lines and lung tumors from patients with SCLC. The overexpression of IFITM1 in DMS273 cells increased their metastatic formation in the orthotopic model and in an experimental metastasis model. Conversely, the silencing of IFITM1 suppressed metastatic formation by DMS273 cells. We also found that IFITM1 overexpression promoted the metastatic formation of NCI-H69 human SCLC cells. These results demonstrate that IFITM1 promotes distant metastasis in xenograft models of human SCLC.