Short CommunicationFoxP3 genetic variants and risk of non-small cell lung cancer in the Chinese Han population
Introduction
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases, and includes two predominant subtypes, adenocarcinoma and squamous cell carcinoma (SCC) (Dutt et al., 2011, Minna et al., 2002, Wistuba, 2007). The prognosis of NSCLC remains poor, with a five-year overall survival rate of about 15% (Ferlay et al., 2010). However, there are significant prognostic differences between early and late stages of NSCLC (Naruke et al., 2001), indicating that early detection of NSCLC is key survival of NSCLC patients. A major risk factor associated with NSCLC is tobacco smoking, followed by asbestos and other mineral exposures, air pollution, and personal and family histories of lung cancer. Nevertheless, it is critical to understand the contribution of genetic and environmental interactions in the development of NSCLC (Kriek et al., 1993, Li et al., 2004, Spitz et al., 2007, Vineis and Husgafvel-Pursiainen, 2005). For example, it has been shown that when exposed to similar environmental and occupational elements, only some individuals develop NSCLC, whereas other NSCLC patients have not been exposed to any risk factors. This discrepancy suggests that there is individual variation in cancer susceptibility in the general population and there are other unknown factors (such as genetics or host predisposition or immune defense system) that contribute to NSCLC pathogenesis (Amos et al., 1992). A previous meta-analysis using 41 published studies showed that the lung cancer family history was a risk factor of lung cancer (Lissowska et al., 2010).
The host immune defense has been shown to play a role in modulating human carcinogenesis. In the host immune defense system, regulatory T cells (Tregs) play a key role in sustaining self-tolerance and immune homeostasis via suppressing a wide variety of physiological and pathological immune responses against self and nonself (Nishikawa and Sakaguchi, 2010, Sakaguchi, 2004, Shevach, 2002, Takahashi and Sakaguchi, 2003). For example, the deficiency or dysfunction of CD4+CD25+ Treg cells, which are the most physiologically relevant Treg population, causes a breach in self-tolerance and produces autoimmune diseases in normal animals and in humans (such as severe allergy and inflammatory bowel disease) (Fontenot et al., 2003, Hori et al., 2003). Recently published data demonstrated that CD4+CD25+ Tregs dominantly infiltrate into tumors and hinder immune response against tumor cells (Nishikawa and Sakaguchi, 2010). This data suggests that Treg cell-mediated immunosuppression is one of the crucial tumor immune evasion mechanisms, and may contribute to the failure of tumor immunotherapy (Khattri et al., 2003, Nishikawa and Sakaguchi, 2010).
The forkhead box P3 (FoxP3) gene is primarily expressed in regulatory T cells under normal physiological conditions. The FoxP3 gene is located on the X chromosome at Xp11.23 (Bennett et al., 2001, Wang et al., 2009) to encode FoxP3 protein, which regulates T cell activation and functions as a transcriptional repressor to downregulate cytokine production in T cells (Gao et al., 2010, Hori et al., 2003, McHugh et al., 2002, Schubert et al., 2001, Takahashi et al., 2000). Normally, FoxP3 is expressed in epithelial cells from various organs (e.g., thymus and lung) (Gupta et al., 2007, Karanikas et al., 2008, Katoh et al., 2010). However, during tumorigenesis, FoxP3 is also expressed in a variety of cancers, such as lymphoma, lung, ovary, and prostate cancers (Kono et al., 2006, Wei et al., 2004). Mutations of FoxP3 cause immune dysregulation, polyendocrinopathy, and X-linked syndrome (IPEX) in human body or breast and prostate cancers (Spatz et al., 2004). In addition, FoxP3 gene polymorphisms result in the lack of functional CD4+CD25+ Tregs, and therefore induce some autoimmune diseases, including type I diabetes and inflammatory primary biliary cirrhosis (Bassuny et al., 2003, Park et al., 2005, Wildin et al., 2002). A single nucleotide polymorphism (SNP) of the FoxP3 gene (rs3761548) is associated with susceptibility of development and intractability of Graves' disease (Owen et al., 2006).
Thus, in this study, we analyzed FoxP3 gene SNP (rs3761548) for association with the risk of NSCLC in the Chinese Han population using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique.
Section snippets
Study subjects
In this study, we carried out a hospital-based case–control study by recruiting 192 NSCLC patients (141 males and 51 females, mean age of 57.42 ± 10.26 years) from The West China Hospital of Sichuan University between April 2008 and December 2011. The diagnosis of NSCLC was confirmed by histopathological examination of the resected or biopsy tissue specimens in all cases. The control population consisted of 259 healthy subjects (181 males and 78 females, mean age: 58.90 ± 12.91 years) from a routine
Results
The cohort of 192 NSCLC patients with a mean age of 57.4 year old contained slightly more men (73.4%) than women (26.6%), whereas the 259 control individuals with a mean age of 58.9 year old consisted of 69.9% men and 30.1% women. Between case and control, the age and gender were well balanced and the distribution of rs3761548 A/C allele frequencies was also in Hardy–Weinberg equilibrium (P = 0.066 and P = 0.073), indicating that the frequencies fell into the expected equilibrium and were thus
Discussion
To the best of our knowledge, the current study is the first to assess the association of genetic variants of FoxP3 gene with the risk of NSCLC. In this hospital-based, case–control study, we analyzed FoxP3 gene SNP for NSCLC susceptibility in a Chinese Han population. Our data demonstrated that FoxP3 SNP/rs3761548 was significantly associated with risk of NSCLC, suggesting that FoxP3 polymorphism might be involved in pathogenesis of NSCLC in the Chinese Han population. We demonstrated that AA,
Conclusions
In conclusion, the current study showed that FoxP3 AA and AC genotypes had an effect on the risk of NSCLC in a Chinese Han population. Additionally, the combined AA + AC genotype was significantly associated with stage II patients. The precise mechanism by which FoxP3 gene polymorphism influences the pathogenesis of NSCLC remains to be determined. Future studies are warranted to investigate whether the SNP rs3761548 affects expression levels of FoxP3 protein and determine the role of FoxP3
Conflict of interest
The authors declare no conflict of interest.
References (44)
Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients
J. Dermatol. Sci.
(2010)- et al.
Signalling through FOXP3 as an X-linked tumor suppressor
Int. J. Biochem. Cell Biol.
(2010) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor
Immunity
(2002)- et al.
Focus on lung cancer
Cancer Cell
(2002) - et al.
Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience
Ann. Thorac. Surg.
(2001) - et al.
Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation
J. Biol. Chem.
(2001) - et al.
The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition
J. Thorac. Oncol.
(2008) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate
Cancer Cell
(2009)- et al.
Regulatory T cells in immune surveillance and treatment of cancer
Semin. Cancer Biol.
(2006) - et al.
Genetic association study of FOXP3 polymorphisms in allergic rhinitis in a Chinese population
Hum. Immunol.
(2009)
Host factors in lung cancer risk: a review of interdisciplinary studies
Cancer Epidemiol. Biomarkers Prev.
A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes
Immunogenetics
A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA– > AAUGAA) leads to the IPEX syndrome
Immunogenetics
Association between EGF + 61 genetic polymorphisms and non-small cell lung cancer increased risk in a Portuguese population: a case–control study
Tumour Biol.
The three Es of cancer immunoediting
Annu. Rev. Immunol.
Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer
PLoS One
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int. J. Cancer
Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells
Nat. Immunol.
Intratumoral FOXP3 expression in infiltrating breast carcinoma: its association with clinicopathologic parameters and angiogenesis
Acta Oncol.
Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer
Cancer Res.
In Crohn's disease, Anti-TNF-alpha treatment changes the balance between mucosal IL-17, FOXP3, and CD4 Cells
ISRN Gastroenterol.
Control of regulatory T cell development by the transcription factor Foxp3
Science
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2022, ClinicsCitation Excerpt :Two SNV in the promoter region of the FOXP3 gene located on chromosome X were genotyped: -924 G>A (rs2232365) at position 49259426 and -3279 C>A (rs3761548) at position 49261784 according to listed in the international database and to GenBank accession number NG_007392.1, as described in Stadlober et al.16 Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) analysis was used to detect the rs2232365 and rs3761548 SNV, as previously reported by Banin-Hirata et al.25 with some modifications described in Stadlober et al.16 For rs2232365 genotyping, the following primers were used: 5´-AGGAGAAGGAGTGGGCATTT-3´ (forward) and 5´-TGTGAGTGGAGGAGCTGAGG -3´ (reverse), according to Paradowska-Gorycka et al.26 The rs3761548 genotyping was performed with the following primers: 5′-GGCAGAGTTGAAATCCAAGC-3′ (forward) and 5’-CAACGTGTGAGAAGGCAGAA-3′ (reverse), according to He et al.27 As described in Stadlober et al.,16 all reactions were performed with negative control (without a DNA sample). The PCR products of rs2232365 [249 base pairs (bp)] were digested overnight at 37°C with Esp3I restriction endonuclease (Invitrogen™, Life Technologies, Carlsbad, CA, USA), generating two fragments of 132 bp and 117 bp corresponding to G allele, while the A allele that did not undergo enzymatic cleavage and remained with 249 bp.
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2021, CytokineCitation Excerpt :Furthermore, the A allele of rs3761548 was correlated with higher susceptibility to GA. In consistent with our data, noticeable association was also found among the presence of AA genotype or A allele at rs3761548 in the Foxp3 gene and some malignancies such as non-small cell lung cancer [30], colorectal cancer [31], thyroid cancer [32] and breast cancer [24]. It has been suggested the Foxp3 involvement in tumor suppression of breast cancer [33,34].
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2019, CytokineCitation Excerpt :There is no study on the association of the SNP rs3761548 with PC. However, in agreement with our results, a considerable relationship was also reported between the existence of AA genotype or A allele at rs3761548 in the FOXP3 gene and a number of malignancies such as breast cancer [24], colorectal cancer [38] non-small cell lung cancer [39] and thyroid cancer [15]. It has been also indicated that FOXP3 acts as an important tumor suppressor in breast cancer [40,41].
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