Interferon‐induced transmembrane protein 1‐mediated EGFR/SOX2 signaling axis is essential for progression of non‐small cell lung cancer

• Published in: International journal of cancer Vol. 144; no. 8; pp. 2020 - 2032
• Main Authors: Yang, Ying‐Gui, Koh, Young Wha, Sari, Ita Novita, Jun, Nayoung, Lee, Sanghyun, Phi, Lan Thi Hanh, Kim, Kwang Seock, Wijaya, Yoseph Toni, Lee, Sang Hun, Baek, Moo‐Jun, Jeong, Dongjun, Kwon, Hyog Young
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.04.2019; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - mortality; Adenocarcinoma of Lung - pathology; Adult; Aged; Aged, 80 and over; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Cancer; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell lines; CSC; Depletion; Disease Progression; Ectopic expression; EGFR; EMT; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; IFITM1; Interferon; Kinases; Lung - pathology; Lung cancer; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medical research; Mice, Inbred NOD; Middle Aged; Migration; Molecular Cancer Biology; Non-small cell lung carcinoma; NSCLC; Retrospective Studies; RNA, Small Interfering - metabolism; Signal Transduction; SOX2; SOXB1 Transcription Factors - metabolism; Squamous cell carcinoma; Survival Analysis; Transmembrane proteins; Xenograft Model Antitumor Assays; SOX2; CSC; IFITM1; NSCLC; adenocarcinoma; EMT; EGFR
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31926

Emerging data indicate that interferon‐induced transmembrane protein 1 (IFITM1) plays an important role in many cancers. However, it remains unclear whether IFITM1 is functionally indispensable in nonsmall cell lung cancer (NSCLC). Here, using NSCLC cell lines and patient‐derived samples, we show that IFITM1 is essentially required for the progression of NSCLC in vitro and in vivo. Specifically, IFITM1 depletion resulted in a significant reduction in sphere formation, migration, and invasion of NSCLC cells in vitro; these events were inversely correlated with the ectopic expression of IFITM1. In addition, tumor development was significantly impaired in the absence of IFITM1 in vivo. Mechanistically, epidermal growth factor receptor/sex‐determining region Y‐box 2 (EGFR/SOX2) signaling axis was compromised in the absence of IFITM1, and the ectopic expression of SOX2 partially rescued the defects caused by IFITM1 depletion. More importantly, using 226 patient‐derived samples, we demonstrate that a high level of IFITM1 expression is associated with a poor overall survival (OS) rate in adenocarcinoma but not in squamous cell carcinoma. Collectively, these data suggest that IFITM1 is a poor prognostic marker of adenocarcinoma and an attractive target to develop novel therapeutics for NSCLC. What's new? Interferon response genes play key roles in pathogen defense but emerging evidence also link them with cancer. The authors report that interferon‐induced transmembrane protein 1 (IFITM1) critically regulates epidermal growth factor receptor‐mediated signaling in nonsmall lung cancer models and is associated with a poor prognosis of patients with adenocarcinoma. This expands the function of this innate defense factor and might lead to improved clinical management of individuals afflicted with lung cancer.