IFN-Induced Transmembrane Protein 1 Promotes Invasion at Early Stage of Head and Neck Cancer Progression

Abstract

Purpose: Head and neck squamous cell carcinoma (HNSCC) shows persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with invasion of HNSCC remain poorly understood. We identified IFNinduced transmembrane protein 1 (IFITM1) as a candidate gene for promoting the invasion of HNSCC by comparing the gene expression profiles between parent and a highly invasive clone. Therefore, we examined the role of IFITM1in the invasion of HNSCC. Experimental Design: IFITM1 expression was examined in HNSCC cell lines and cases by reverse transcription^PCR and immunohistochemistry. IFITM1 overexpressing and knockdown cells were generated, and the invasiveness of these cells was examined by in vitro invasion assay. Gene expression profiling of HNSCC cells overexpressing IFITM1versus control cells was examined by microarray. Results: HNSCC cells expressed IFITM1mRNA at higher levels, whereas normal cells did not. By immunohistochemistry, IFITM1 expression was observed in early invasive HNSCC and invasive HNSCC. Interestingly, IFITM1 was expressed at the invasive front of early invasive HNSCC, and higher expression of IFITM1 was found in invasive HNSCC. In fact, IFITM1 overexpression promoted and IFITM1knockdown suppressed the invasion of HNSCC cells in vitro. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells revealed that several genes, including matrix metalloproteinase, were up-regulated in IFITM1overexpressing cells. Conclusion: Our findings suggest that IFITM1plays an important role for the invasion at the early stage of HNSCC progression and that IFITM1can be a therapeutic target for HNSCC.Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, with an annual incidence of >500,000 cases worldwide (1). The extent of lymph node metastasis is a major determinant in the prognosis of HNSCC. Like most epithelial cancers, HNSCC develops through the accumulation of multiple genetic and epigenetic alterations in a multistep process (2). Recent molecular studies have advanced our understanding of the disease and provided a rationale to develop novel strategies for early detection, classification, prevention, and treatment. Attempts to identify the genes involved in the metastasis are pivotal for the early prediction of HNSCC behavior. The process of metastasis consists of sequential and selective steps, including proliferation, induction of angiogenesis, detachment, motility, invasion into circulation, aggregation and survival in the circulation, cell arrest in distant capillary beds, and extravasation into organ parenchyma (2). We previously established an HNSCC cell line, MSCC-1, from lymph node metastasis (3). Moreover, we isolated a highly invasive clone MSCC-Inv1 from MSCC-1 cells by using an in vitro invasion assay device (4). Then, we compared the transcriptional profile of parent cells (MSCC-1) and a highly invasive clone (MSCC-Inv1) by microarray analysis to identify g...

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“…IFITM1 was found to be the second most overexpressed gene in highly invasive clones (33), and a high level of IFITM1 expression was found in early and late intestinal neoplasm. Thus, IFITM1 has been identified as a novel candidate gene for tumor invasion (17,26). Here, data demonstrated that their immunostaining scores were associated with the severity of cytoarchitectural atypia.…”

“…Assessment of the expression of LKB1 and IFITM1 was based on the previous studies, respectively (25,26). Immunoreactivity for ß-catenin was estimated quantitatively with reference to previous repots (27), and the staining of the membrane, cytoplasm and nucleus was assessed separately.…”

The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY

“…Of the ISGs that appear to be regulated by the Akt1/EMSY/BRCA2 pathway, IFITM1 and ISG15 have already been linked to human cancer. IFITM1 is overexpressed in squamous cell carcinomas, and its overexpression has been linked to tumor cell invasiveness (30), perhaps attributable to regulation of the expression of metalloproteinases. Knockdown of IFITM1 inhibits the invasiveness of squamous cell carcinomas.…”

Using Clinical Proteomics to Discover Novel Anti-Cancer Targets for MAb Therapeutics

“…The CD19 cell surface receptor complex regulates B lymphocyte development and function and is composed of at least four proteins; CD19, CD21 (CR2, complement receptor 2), CD81 (TSPAN-28) and IFITM1 (Sato, Miller et al 1997). Aside from its physiological role it has been shown to promote cancer progression by enhancing cell migration and invasion in head and neck cancer and gastric cancer (Yang, Lee et al 2005;Hatano, Kudo et al 2008). IFITM1 knockdown has also been shown to inhibit proliferation, migration and invasion of glioma cells (Yu, Ng et al 2010).…”