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

Abstract

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.

Identification of IFITM1 with prognostic value in pancreatic cancer using network module-based analysis

“…Through the human cancer pro ling array containing 10 lung carcinoma as well as the corresponding normal samples, IFITM1 was detected increasing signi cantly in lung carcinoma [39]. The difference was also observed in two other studies demonstrated IFITM1 overexpression through patients' tissues and lung cancer cell lines [6,40]. Immunohistochemistry on TMA of a consecutive cohort including 174 gastroesophageal adenocarcinoma patients also detected a signi cant elevation of IFITM1 in primary tumors along with lymph node metastases, compared to the adjacent normal epithelium and intestinal metaplasia [41].…”

“…Recently, Y.G. Yang et al demonstrated IFITM1 was essentially required for the progression of non-small cell lung cancer (NSCLC) both in vitro and in vivo, and silenced expression of IFITM1 signi cantly reduced the capacity of sphere-formation, invasion, and migration of NSCLC [6].…”

“…Since it was rst discovered in neuroblastoma cells in 1984, it has been identi ed participating in various biological processes including cell proliferation and adhesion, and being important in immunity and antiviral activities [4,5]. Particularly, increasing studies have con rmed that IFITM1 is overexpressed in numerous human cancers during the last decade, such as lung, gastric, colorectal and ovarian cancers [6][7][8][9]. Furthermore, positive IFITM1 expression was illustrated in correlations with poorer prognosis in diverse tumors [10,11].…”

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

“…Among these genes, 19 genes were upregulated by >4-fold in metastatic sites compared with their levels in orthotopic sites, and the most strongly overexpressed gene in the metastatic tumors was oncogenic long non-coding RNA H19, which was reported to promote cancer progression and metastasis in many cancers, including SCLC [ 27 , 28 , 29 , 30 ] ( Table 1 ). Among the other overexpressed genes in the metastatic tumors, we focused on the IFITM1 gene, which encodes a small protein localized in the plasma membrane, because it was reported that this gene is involved in cancer progression and metastasis in several cancers; however, its roles in SCLC are unclear [ 22 , 23 , 24 , 25 ].…”

“…IFITM1 is also expressed in primordial germ cells and is required for their transition from the mesoderm into the endoderm through embryonic development in mice [ 21 ]. It was also demonstrated that IFITM1 was associated with cancer progression and metastasis in many cancers including glioma, colorectal cancer, head and neck cancer, and NSCLC [ 22 , 23 , 24 , 25 , 26 ]. However, its role in SCLC is unexplored.…”