FormalPara Key Points

The expression level of interferon-induced transmembrane protein 1 (IFITM1) is upregulated in a variety of tumor tissues and cancer cell lines.

IFITM1 stimulates cancer progression and is an independent prognostic factor for cancer patients.

IFITM1 may be a promising target for cancer treatment.

1 Introduction

The interferon-induced transmembrane (IFITM) gene family was first discovered in neuroblastoma cells treated with interferon (IFN) in 1984 [1]. The human IFN-induced transmembrane protein 1 (IFITM1), also named 9–27 or Leu13, is a member of the IFITM protein family, which is comprised of three proteins, IFITM-1, IFITM-2, and IFITM-3. IFITM1 is a 17-kDa membrane protein with a conserved CD225 domain and two transmembrane domains [2, 3]. A schematic of the IFITM1 structure and location is depicted in detail in Fig. 1. It has been more than 20 years since IFITM1 was identified as a Leu-13 leukocyte membrane surface antigen responsible for signal transduction in lymphocytes, such as antiproliferative and homotypic adhesion signaling [4,5,6]. It is also important to note that IFITM1 is known as a modulator of immunity and antiviral activity [3]. Interestingly, during the last decade, increasing evidence has shown that IFITM1 is overexpressed in a large number of solid human tumors (Table 1). Using EnVision immunohistochemistry for 69 squamous cell/adenosquamous carcinomas (SC/ASC) and 146 ordinary adenocarcinomas (ACs) of gallbladder cancer tissues, Li et al. found that IFITM1 expression was significantly higher in SC/ASC patients with high Tumor Node Metastasis (TNM) stage, lymph node metastasis, and invasion compared to patients with low TNM stage, no lymph node metastasis, and no invasion. Positive IFITM1 expression was closely related to a decreased overall survival in SC/ASC and AC patients [7]. In addition, IFITM1 messenger RNA (mRNA) levels were elevated in colorectal and stomach carcinoma samples, as detected by cancer array profiling [8]. Likewise, a recent study indicated that IFITM1 expression is positive in 93% (87/94) estrogen receptor positive (ER+) breast cancer samples and negative in all six normal breast tissues, as determined with immunohistochemistry; and it was also overexpressed in aromatase inhibitor (AI)-resistant MCF-7:5C cells assayed by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting [9]. A high IFITM1 intensity score (an indicator of immunohistochemical score) was associated with increased clinical stage and increased risk of recurrence, suggesting that high IFITM1 expression in ER+ breast cancer significantly correlates with poor clinical outcome and poor response to endocrine therapy [9]. Aberrant expression of IFITM1 plays a vital role in cancer development. It promotes tumor cell proliferation, inhibits cell death, stimulates invasion and metastasis, and also results in the induction of resistance to endocrine therapy, chemotherapy, and radiotherapy, and has prognostic value for patient clinical outcomes [7,8,9,10,11,12,13,14] (Fig. 2). As a result, it is important to gain full insights into the functions of IFITM1 in cancer biology in order to design new, targeted approaches to treat solid tumors. This review concentrates on the roles of IFITM1 in cancer cells.

Fig. 1
figure 1

Structure and topology of IFITM1. a IFITM1 contains a conserved CD225 domain and two transmembrane domains. IFITM1 is made up of 125 AAs. The two transmembrane domains consist of AA residues 37–57 and residues 87–107, respectively. The number and sequence of AAs that make up the CD225 domain are unclear. The positions of AAs are described above the scheme. b Localization of IFITM1 in the plasma membrane. AA amino acid, IFITM1 interferon-induced transmembrane protein 1

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Table 1 The high expression level of IFITM1 in different tumors
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Fig. 2
figure 2

Tumor-promoting functions of IFITM1. Overexpression of IFITM1 is involved in cancer development and therapy, such as promoting tumor cell proliferation, stimulating invasion and metastasis, increasing angiogenesis, and inducing resistance to endocrine therapy, chemotherapy, and radiotherapy. Smaller letters are important target genes through which IFITM1 modulates these processes. EGFR epidermal growth factor receptor, IFITM1 interferon-induced transmembrane protein 1, MMPs matrix metalloproteinases, SOX2 sex-determining region Y-box 2, STAT signal transducer and activator of transcription

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2 Role of IFITM1 in Tumorigenesis

2.1 Proliferation

Unlimited proliferation is one of the most striking characteristics of malignant tumors. Notably, IFITM1 not only plays an essential role in IFN-γ-induced inhibition of cell proliferation of B-lymphocytes [3], it has also been shown to be one of the key modulators of tumor cell proliferation [15]. Yu et al. found that blocking IFITM1 expression inhibited proliferation of glioma cells (U-87 MG and U-373 MG) and led to cell cycle arrest, accompanied by a reduction of cyclin A, cyclin B1, cyclin D1, cyclin E, CDK2, and CDK4, and upregulation of p27kip1 [16]. This finding is corroborated by the recent data in the inflammatory breast cancer SUM149 cell line [17]. Moreover, further support for this finding is provided by data suggesting that silencing IFITM1 significantly reduces tumor growth in a mouse model of breast, lung, and colorectal cancers [9, 18, 19]. For example, loss of IFITM1 markedly increases p21 transcription, expression, and nuclear localization, which was mediated by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation (Fig. 3), eventually resulting in the suppression of tumor growth of the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer [9].

Fig. 3
figure 3

The scheme of molecular signaling of IFITM1 in tumors. Knockdown of IFITM1 results in activation of the JAK/STAT pathway. After that, STAT translocates into the nucleus, in which it binds to promoter of p21, ultimately leading to p21 transcription. In addition, IFITM1 silencing inhibits the phosphorylation of p21 and increases p21 nuclear translocation. IFITM1 interferon-induced transmembrane protein 1, JAK Janus kinase, STAT signal transducer and activator of transcription

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2.2 Invasion and Metastasis

Because invasion and metastasis affect patients overall survival and represent a significant obstacle in tumor therapy [20], a series of studies has been conducted to probe the intrinsic mechanism involved in this process. Aside from its importance in tumor cell proliferation, IFITM1 also has a role contributing to invasion and metastasis of human malignancies, suggesting that it could become a promising biomarker for determining the likelihood of a malignancy having invasive properties [9, 17, 21,22,23] (Table 2). Employing a signal sequence trap, Yang et al. found that IFITM1 was overexpressed in gastric tumor tissues as well as cancer cell lines (SNU-216, SNU-620, and SNU-638) when compared with their normal counterpart. The IFITM1-overexpressed cells had a stronger capability for invasiveness [24]. This finding was supported by the work of Lee et al., who suggested that there was an upregulated level of IFITM1 in gastric cancer tissues and cancer cell lines (AGS and SNU-638), and silencing IFITM1 decreased migration and invasiveness of cancer cells [25]. Interestingly, several studies have demonstrated that IFITM1 is correlated with the expression of matrix metalloproteinases (MMPs) [11, 16, 19]. MMPs are involved in the extracellular matrix (ECM) degradation and regulation of adhesion and cytoskeletal proteins, as related to tumor invasion [26]. Overexpression of IFITM1 gives rise to the promotion of invasion of head and neck squamous cell carcinoma (HNSCC) cells; this together with upregulation of MMPs was detected by microarray [11]. Along with the modulation of MMPs, the underlying mechanism by which IFITM1 facilitates invasion is through targeting caveolin-1, as shown by the finding that knockdown of caveolin-1 abrogated small interfering IFITM1-induced decrease of invasion of colorectal cancer cells [10]. However, the mechanisms discussed above are not the only way by which IFITM1 stimulates cancer invasion. For instance, the latest findings indicate that the epidermal growth factor receptor/sex-determining region Y-box 2 (EGFR/SOX2) signaling axis plays an essential role in IFITM1-induced migration and invasion of non-small cell lung cancer cells (NSCLCs) [27]. Furthermore, IFITM1 is also essential for the maintenance of the epithelial-to-mesenchymal transition (EMT) signature of NSCLC cells, as evidenced by the fact that IFITM1 depletion gives rise to upregulation of E-cadherin expression and downregulation of N-cadherin and SNAIL expression in NSCLC cells (H1650 and A549) [27]. However, another study challenges this concept; it showed that IFITM1 expression is not significantly associated with EMT markers, E-cadherin, and vimentin expression in lung AC tissues examined by immunohistochemistry [28]. Hence, the role of IFITM1 in EMT remains elusive, and it still warrants further investigation to address this concern.

Table 2 The role of IFITM1 in tumor invasion and metastasis
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2.3 Angiogenesis

In order to grow without limitations and to metastasize, tumors rely on newly formed vessels, which provide the nutrition needed. It is of importance to point out that the level of IFITM1 has a positive correlation with microvessel density in lung AC specimens and orthotopic models of breast cancer [9, 28], as measured by CD31 staining (a biomarker of microvessel density). To the best of our knowledge, angiogenesis is a complex multistep process that involves several pivotal components, such as endothelial cells (ECs), pro-angiogenic [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF)] and angiostatic [thrombospondin-1 (TSP-1) and endostatin] [29,30,31] factors. A link between IFITM1 and ECs is suggested by a study that explored angiogenesis [32]. Specifically, IFITM1 expression in ECs increases when ECs sprout and form lumens. In accordance with this result, suppression of IFITM1 disorganizes lumen formation both in vitro and in vivo. The molecular study demonstrated that IFITM1 modulates tight junction assembly in ECs through binding to occludin, a tight junction protein [32]. In addition, Kim et al. found that zoledronate, which was usually used in osteoporosis treatment and prevention of bone metastases in several cancers, inhibited ECs proliferation, VEGF-induced tube formation, and IFITM1 expression in human umbilical vein ECs. Moreover, the mRNA and protein level of IFITM1 in ECs was elevated when treating ECs with VEGF [33]. This may suggest that IFITM1 has a role to play in angiogenesis).

3 Cancer Therapy Resistance

Endocrine therapy, chemotherapy, and radiotherapy are crucial and effective strategies in the treatment of many types of cancer. Unfortunately, cancer cells gradually become resistant to these approaches, resulting in disease relapse and ultimately metastasis. As a result, there is an urgent need to perform relevant studies to probe the intrinsic molecular mechanism of treatment resistance in order to exploit new therapeutic approaches. Given that IFITM1 functions in many kinds of cellular processes, it would be foolish not to question whether it might also play a significant role in treatment resistance. Intriguingly, some investigations show that IFITM1 is a potential candidate which participates in endocrine therapy, chemo- and radio-resistance (Table 3).

Table 3 The role of IFITM1 in tumor therapy resistance
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3.1 Endocrine Therapy Resistance

About 70–80% of breast cancers are ER+, and ER pathway signaling plays a key role in the progress of breast cancer [34]. Given the importance of ER signaling in breast cancer, therapies targeting this pathway, such as AIs, have been used in clinical therapy for ER+ breast cancer. However, approximately 30% of patients eventually have a poor response to AIs [35]. With regard to the underlying mechanism of poor response, researchers find that IFITM1 is overexpressed in AI-resistant breast cancer cells and tissues [9, 22, 36, 37]. As anticipated, silencing of IFITM1 expression with small interfering RNA (siRNA) in letrozole-resistant breast cancer cells results in therapy re-sensitization [37]. Moreover, reduction of IFITM1 leads to an increase in the expression of p21, Bax, and Noxa and induces cell death in resistant cells [22]. Aside from the breast cancer, there is, to date, no evidence that IFITM1 is involved in the resistance of other tumors to endocrine therapy.

3.2 Chemoresistance

IFITM1 is associated with poor clinical prognosis in some cancer patients [7, 10, 25, 38,39,40]. One of the main drivers of clinical outcomes is the development of chemoresistance, as chemotherapy is one of the standard treatments for many types of tumors. A study more than 10 years ago suggested firstly that IFITM1 was a potent marker for cisplatin sensitivity in human esophageal SC carcinoma cell lines KYSE-170 and KYSE-2270 in vitro [39]. The sensitivity to cisplatin was suppressed or enhanced by IFITM1 overexpression or knockdown, respectively [41]. Consistent with the findings in esophageal cancer cells, Lee et al. applied annealing control primer-based reverse transcriptase-polymerase chain reaction (ACP RT-PCR) technology to confirmed that IFITM1 was highly expressed in a cisplatin-resistant human gastric cancer cell line compared with the parental one [42]. However, these studies mainly explored drug sensitivity in vitro and did not take into account the host in vivo environment, which is of prime importance to clinical response. Interestingly, gene expression profiles in a human ovarian carcinoma mouse xenograft model suggested that the expression of IFITM1 decreased 24 h after administrating drug-sensitive xenografts with paclitaxel, which also hinted that IFITM1 was involved with the responsiveness to chemotherapy drugs [43].

3.3 Radioresistance

There is also evidence that IFITM1 may be involved in radioresistance [44]. In human RSa cells, interferon α induces resistance of the cells to cytotoxicity of X rays, along with the up-regulation of IFITM1 levels detected by mRNA differential display and Northern blotting analysis. High IFITM1-expressing cells show increased resistance to X-rays. In good agreement with this phenomenon, silencing of IFITM1 by antisense oligonucleotides results in the loss of IFN-α-induced resistance of RSa cells to killing by X-rays [45]. In addition, this notion is further supported by recent findings in oral cancer [12]. Herein, IFITM1 has been shown to be overexpressed in oral neoplasm tissues and cells, and the expression level elevates with the increase in the time and dose of radiation. Moreover, siRNA-mediated knockdown of IFITM1 gives rise to an increase in radiation-induced DNA damage and cell apoptosis in vitro, and it also significantly inhibits oral neoplasm tumorigenesis in a mouse xenograft model, which implies that the combination of radiotherapy with inhibition of IFITM1 maybe a promising strategy for oral cancer therapy. At the molecular level, IFITM1 silence results in an increase in pSTAT1/2/p21 as well as a decline of pSTAT3/p-p21, through which IFITM1 affects the radiation tolerance of oral cancer cells after radiotherapy [12].

4 Conclusions

Tumors are one of the major causes of death across the world [46]. Most patients are in the middle/advanced stage at the time of diagnosis. Unfortunately, some tumors undergo intrinsic molecular changes after therapy and become resistant to conventional treatments (endocrine, chemo-, and radiotherapy), eventually resulting in a poor prognosis. Consequently, it is imperative to search for new molecular targets in order to circumvent this dilemma. Accumulating evidence has indicated that IFITM1 may have great potential. As seen from this article, IFITM1 is overexpressed in a wide range of neoplasms and plays a promoting role in cell proliferation, invasion, metastasis, angiogenesis, and therapy resistance. However, it is still unclear how IFITM1 is activated by the upstream pathway. Furthermore, studies about IFITM1 in tumor therapy resistance are relatively few and the underlying molecular mechanisms by which IFITM1 is involved in angiogenesis and therapy resistance are not fully understood. Whether targeting IFITM1 may become an additional, feasible, and effective tool for personalized therapy of patients requires further research, including investigations to (1) shed light on more biochemical features of IFITM1; (2) decipher the upstream and downstream signaling pathways of the IFITM1 network; and (3) exploit inhibitors of IFITM1 and confirm their effectiveness in tumors. In all, this short review provides an overview of our current understanding of the tumor-promoting role of IFITM1 and points out the direction for future research in tumors.