Background
Lung cancer is one of the most common malignant tumors worldwide and the first leading cause of cancer-related mortality in China [
1,
2]. According to World Health Organization, lung cancer is divided into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which NSCLC accounts for almost 85% of lung cancer cases [
3]. Epidemiological studies have identified several risk factors for lung cancer, such as tobacco smoking, atmospheric pollution and occupational environment challenge [
4]. However, many individuals who have been exposed to these risk factors do not get lung cancer during lifetime, so genetic factor is likely play an important role.
The initiation and progression of cancer are closely linked to inflammation and angiogenesis [
5,
6]. As one of potent mediators of inflammation, the tumor necrosis factor (TNF) family plays an important role in the process of immunoregulation and further contributes to cancer development [
7]. Tumor necrosis factor superfamily 15 (
TNFSF15), also known as vascular endothelial growth inhibitor (
VEGI), belongs to the
TNF ligand family, which negatively regulates angiogenesis [
8]. By stimulating T cell, TNFSF15 is involved in the modulation of inflammation [
9,
10]. Studies have shown that over-expression of TNFSF15 inhibits tumor growth in various cancers whereas reduced expression of TNFSF15 is associated with poor prognosis in cancer patients [
11‐
15].
Single nucleotide polymorphisms (SNPs) in regulatory region of a gene can influence the gene expression and further contribute to the development of various cancers [
16‐
19]. In our previous study, we identified two SNPs (−638A > G and -358 T > C) in the
TNFSF15 promoter by direct sequencing, and found that -358 T > C variant changed the transcriptional activity of
TNFSF15 and was significantly associated with the susceptibility to gastric adenocarcinoma [
20]. In the present study, we tested if these two variants in the
TNFSF15 promoter region contributed to the risk of developing lung cancer by performing a case-control study in a Chinese population.
Discussion
Small-cell lung cancer (SCLC) is a deadly tumor with poor prognosis, which originates from high-grade malignant neuroendocrine cells [
22]. Although sensitive to chemotherapy and radiotherapy, SCLC typically recurs rapidly after primary treatment and the five-year survival is only 6% after diagnosis [
23]. Platinum-etoposide doublet has been officially approved for clinical use against SCLC [
23]; however, few improvement has been made in SCLC treatment in past several years. Since SCLC is known as a stubborn cancer, there is an urgent need for the identification of biomarkers that can act as a potential therapeutic target in SCLC.
TNF superfamily members play an important role in cell proliferation, differentiation and apoptosis and are used for clinical treatment, or in clinical trials [
24,
25]. TNFSF15, a member of
TNF superfamily, is likely to inhibit the growth of tumors by suppressing neovascularization. TNFSF15 inhibits the proliferation of vascular endothelial cells in the G0 and G1 phases of cell cycle, and ultimately inhibits angiogenesis.
TNFSF15 gene encodes three splice variants, namely
VEGI-174,
VEGI-251 and
VEGI-192 depending on the number of amino acids included [
26].
VEGI-251, also known as
TL1A (
TNF-like molecule 1A), is the longest one of the splice variants. The combination of
TL1A and
DR3 (Death Receptor 3) activates different signal transduction pathways by inducing
NF-kB to activate initial T cell [
10] and activating Caspases cascade to promote cell apoptosis [
27]. These processes play an important role in the occurrence and development of tumors.
Till now, a few studies have been carried out to demonstrate the association of
TNFSF15 polymorphisms with the susceptibility to cancer. In our previous study, we found that
TNFSF15–638A > G polymorphism was associated with the development of gastric adenocarcinoma [
20]. In another study, authors indicated that
TNFSF15 rs6478106 is related to the risk of breast cancer in Chinese Han population [
28]. In this study, we explored the association of
TNFSF15 variants with the susceptibility to lung cancer and found that -638A > G and -358 T > C variants elevated the risk of SCLC, but not of NSCLC. These findings suggested that the
TNFSF15 polymorphisms were involved in the development of various cancer types; however, the specific mechanism is not fully clear. We speculate that the TNFSF15 genetic variation affects the expression of TNFSF15 protein and then controls the downstream signal transduction molecules. These changes affect inflammatory and immune response, and further contribute to the development of cancers. Matijja and Clara found that an intron polymorphism of
TNFSF15 (rs6478108) affected the expression level of
TNFSF15 and increased NOD2-induced signaling and cytokines through caspase-8–induced IL-1 [
29]. In our previous study, we found that the − 358 T > C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the -358C containing haplotypes had a significantly decreased reporter gene activity in gastric cells [
20].
Tobacco smoking is recognized as one of the most important risk factors contributing to lung cancer [
30]. Thus, we analyzed the effects of
TNFSF15 variants on SCLC by smoking status. Studies have shown a strong association between tobacco exposure and the development of SCLC [
31,
32]. Cigarette smoke contains many carcinogenic chemicals such as nicotine and carbon monoxide tar. The complexity of cigarette smoke makes the mechanisms of developing lung cancer even more complicated. At least, tobacco smoking potentially alters the tumor immune microenvironment by creating DNA damage and causing inflammatory response [
33,
34]. TNFSF15 is closely related to the inflammatory response. It has been reported that TNFSF15 can directly induce proinflammatory cytokines [
35]. Long-term exposure of DNA to the carcinogens in tobacco smoke will lead to a higher mutation load in SCLC [
36]. Our present data showed that
TNFSF15 -358 T > C polymorphism was related to SCLC among non-smokers instead of smokers, which needs more studies to explain. After stratified by smoking status, the sample size is not enough to evaluate the risk of this genetic variant with the risk of SCLC.
Age and gender are considered to be risk factors for tumor development and progression [
37]. Our study showed the
TNFSF15–638GG genotype elevated the risk of SCLC among males and individuals aged 60 years and older. Whether gender is related to the risk of lung cancer is controversial after taking into account smoking [
38‐
40]. Due to the small size of several subgroups, a further larger-scale study needs to be conducted in order to carefully evaluate these findings.
In the future, it is necessary to evaluate the usability of these polymorphisms as a low-cost NSCLC screening tool for predicting individual lung cancer risk.