BioMed Research International

BioMed Research International / 2018 / Article

Research Article | Open Access

Volume 2018 |Article ID 9531315 | 8 pages | https://doi.org/10.1155/2018/9531315

Association of Resistin Gene Polymorphisms with Oral Squamous Cell Carcinoma Progression and Development

Academic Editor: Konstantinos Michalakis
Received28 May 2018
Accepted27 Sep 2018
Published14 Oct 2018

Abstract

Oral squamous cell carcinoma (OSCC) accounts for over 90% of malignant neoplasms of the mouth. In Taiwan, OSCC is the fourth most common male cancer and the fourth leading cause of male cancer death. Resistin (RETN) is an adipokine that is associated with obesity, inflammation, and various cancers. Here, we examine the association between four single nucleotide polymorphisms (SNPs) of the RETN gene (rs3745367, rs7408174, rs1862513, and rs3219175) and OSCC susceptibility as well as clinical outcomes in 935 patients with OSCC and in 1200 cancer-free healthy controls. We found that, in 1465 smokers, RETN polymorphisms carriers with the betel-nut chewing habit had a 6.708–10.882-fold greater risk of having OSCC compared to RETN wild-type carriers without the betel-nut chewing habit. Patients with OSCC who had A/A homozygous of RETN rs3219175 polymorphism showed a high risk for an advanced tumor size (> T2), compared to those patients with G/G homozygotes. In addition, A/T/G/G haplotype significantly increased the risks for OSCC by 1.376-fold. This study is the first to examine the risk factors associated with RETN SNPs in OSCC progression and development in Taiwan.

1. Introduction

Oral squamous cell carcinoma (OSCC) accounts for over 90% of malignant neoplasms of the mouth [1]. In Taiwan, OSCC is the fourth most common male cancer and the fourth leading cause of male cancer death [2]. Despite combination treatment with radiation, surgery, and chemotherapy, the prognosis of OSCC remains poor [3, 4]. OSCC occurs through multiple genetic alterations due to chronic exposure to environmental carcinogens. Chronic inflammation, alcohol and tobacco consumption, betel quid chewing, and viral infection are all implicated as risk factors for OSCC [57]. Single nucleotide polymorphisms (SNPs) constitute the most common type of DNA sequence variation influenced gene expression and protein production and function as well as disease susceptibility in particular individuals [8, 9]. Previous research has suggested that gene polymorphisms may increase the risk of developing oral cancer. For instance, individuals carrying specific C-C chemokine ligand 4 (CCL4), interleukin-18 (IL-18), or intercellular adhesion molecule-1 (ICAM-1) SNPs have a higher susceptibility to OSCC compared with wild-type controls [2, 10, 11]. Thus, identifying genes that impact upon OSCC susceptibility is important for early detection of disease.

Resistin is a 12.5-kDa cysteine-rich adipokine that is constitutively secreted by adipose tissue [12]; resistin levels in plasma correlate with inflammatory markers and coronary artery calcification, a measure of coronary atherosclerosis [13]. Several SNPs have been discovered in the RETN promoter and 3′-untranslated regions [14]. Genetic variation in RETN is associated with a greater risk of various diseases, including metabolic syndrome and colon cancer [15, 16], while a functional RETN gene polymorphism at -420 (rs186513) appears to promote susceptibility to type 2 diabetes [17] and RETN SNPs have been found to correlate with lung cancer progression in a Chinese Han population [18]. Moreover, upregulation of resistin gene expression in human breast cancer tissues has been reported [19]. Up until now, no correlation has been established between RETN gene polymorphisms and OSCC prognosis. This case-control study sought to determine the role of four RETN SNPs and clinicopathological features in OSCC susceptibility in a cohort of Taiwan individuals.

2. Materials and Methods

2.1. Participants

We enrolled 935 patients (cases) presenting with OSCC to Chung Shan Medical University Hospital in Taichung or Changhua Christian Hospital in Changhua, Taiwan, between 2007 and 2015. A total of 1,200 anonymized healthy controls were randomly selected from the Taiwan Biobank Project; none had a previous history of cancer at any sites. The study exclusion criteria specified that subjects with oral precancerous disease, such as oral submucous fibrosis, leukoplakia, erythroplakia, or verrucous hyperplasia, were ineligible for enrollment. Data pertaining to primary tumor size, lymph node involvement, and histologic grade were extracted from medical records. Tumors were staged according to the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging criteria [20]. Prior to enrollment, all participants provided informed written consent and completed a structured questionnaire surveying sociodemographic data and cigarette and alcohol use.

2.2. Determination of Genotypes

Total genomic DNA was isolated from whole blood specimens using QIAamp DNA Blood Mini Kits (Qiagen, Valencia, CA), as per the manufacturer’s instructions. DNA was dissolved in TE buffer (10 mM Tris pH 7.8, 1 mM EDTA) and stored at −20°C until quantitative polymerase chain reaction (PCR) analysis. Four RETN SNPs were selected (rs3745367, rs7408174, rs1862513, and rs3219175) with minor allele frequencies >5% in the HapMap population. Primers and probes consisted of rs3745367 “CTCCGACTGTCCCCACCTTATCCAC[A/G]GCTCCA­AACCCAA”, rs7408174 “TTTTACCACAAAAAGGCC­CGTTGTA[C/T]TGGAAACAAAGAA”, rs1862513 “CCT­GACCAGTCTCTGGACATGAAGA[C/G]GGAGGCCCT­GTTG”, rs3219175 “CTCCAGCCCTTACTGTCTGCTCAG­G[A/G]GCTTCCTCTTGGC”. These SNPs have previously been found to correlate with progression of lung and breast cancer as well as development of rheumatoid arthritis [18, 19, 21]. We genotyped the SNPs with the commercially available TaqMan SNP genotyping assay (Applied Biosystems, Warrington, UK), according to the manufacturer’s protocols [22, 23].

2.3. Statistical Analysis

The genotype distribution of each SNP was analyzed for Hardy-Weinberg equilibrium and confirmed by Chi-square analysis. Demographic characteristics were compared between patients and controls using the Mann–Whitney U-test and Fisher’s exact test. Associations between genotypes, OSCC risk, and clinicopathological characteristics were estimated using adjusted odds ratios (AORs) and 95% confidence intervals (CIs) obtained from age- and gender-adjusted multiple logistic regression models. The statistical analysis about haplotype was according to previous studies [24, 25]. A value of <0.05 was considered statistically significant. Data were analyzed using SAS statistical software (Version 9.1, 2005; SAS Institute Inc., Cary, NC).

3. Results

Mean age did not differ significantly between men with (n=935) and without OSCC (n=1,200) (Table 1). Significant between-group differences were found for betel quid chewing (p<0.001), cigarette smoking (p<0.001), and alcohol drinking (p<0.001); all behaviors were significantly more prevalent among the OSCC cohort compared with controls (Table 1). Around half of the patients (49.8%) had stage I/II disease and half (50.2%) had stage III/IV disease (Table 1). One-third (32.8%) had N1–N3 lymph node metastasis. Nearly all tumors (99.0%) were classified as M0 status; the majority of tumors (85.1%) were moderately and poorly differentiated (Table 1).


VariableControls (N=1,200)Patients (N=935)p-value

Age (years)
 ≤54 566 (47.2%)453 (48.5%)p=0.556
 >54634 (52.8%)482 (51.5%)
Betel quid chewing
 No1,001 (83.4%)190 (20.3%)
 Yes199 (16.6%)745 (79.7%)p <0.001
Cigarette smoking
 No564 (47.0%)106 (11.3%)
 Yes636 (53.0%)829 (88.7%)p <0.001
Alcohol drinking
 No963 (80.3%)440 (47.1%)
 Yes237 (19.7%)495 (52.9%)p <0.001
Histological grade
 I+II466 (49.8%)
 III+IV469 (50.2%)
Tumor status (T)
 T1+T2540 (57.8%)
 T3+T4395 (42.2%)
Lymph node metastasis (N)
 N0628 (67.2%)
 N1+N2+N3307 (32.8%)
Distal metastasis (M)
 M0926 (99.0%)
 M1 9 (1.0%)
Cell differentiation
 Well differentiated139 (14.9%)
 Moderately or poorly differentiated796 (85.1%)

The Mann-Whitney U test or Fisher’s exact test was used to compare values between healthy controls and patients with OSCC.   p value < 0.05 was considered statistically significant.

Table 2 shows the RETN genotypes in OSCC patients and controls. In the controls, all genotypic frequencies were in Hardy-Weinberg equilibrium (p>0.05). In both patients and controls, most of those with the rs3745367 SNP were homozygous for the G/G genotype, most of those with the rs7408174 SNP were homozygous for the T/T genotype, most of those with the rs1862513 SNP were homozygous for G/G, and most of those with the rs3219175 SNP were homozygous for G/G (Table 2). After adjusting for potential confounders, we found no significant differences in the incidences of OSCC patients with the rs3745367, rs7408174, rs1862513, and rs3219175 polymorphisms compared to controls.


VariableControls (N=1,200) Patients (N=935) OR (95% CI) AOR (95% CI)

rs3745367
GG461 (38.4%)349 (37.3%)1.000 (reference)1.000 (reference)
GA561 (46.8%)449 (48.0%)1.057 (0.877-1.274)1.132 (0.888-1.444)
AA178 (14.8%)137 (14.7%)1.017 (0.782-1.322)1.066 (0.755-1.506)
GA+AA739 (61.6%)586 (62.7%)1.047 (0.878-1.249)1.116 (0.887-1.406)
rs7408174
TT603 (50.3%)499 (53.4%)1.000 (reference)1.000 (reference)
TC497 (41.4%)369 (39.5%)0.897 (0.750-1.074)0.891 (0.705-1.126)
CC100 (8.3%)67 (7.1%)0.810 (0.581-1.128)0.901 (0.588-1.380)
TC+CC597 (49.7%)436 (46.6%)0.883 (0.744-1.047)0.893 (0.714-1.116)
rs1862513
GG443 (36.9%)352 (37.7%)1.000 (reference)1.000 (reference)
GC575 (47.9%)452 (48.3%)0.989 (0.821-1.192)0.991 (0.777-1.265)
CC182 (15.2%)131 (14.0%)0.906 (0.696-1.181)0.908 (0.644-1.280)
GC+CC757 (63.1%)583 (62.3%)0.969 (0.812-1.157)0.971 (0.771-1.223)
rs3219175
GG761 (63.4%)590 (63.1%)1.000 (reference)1.000 (reference)
GA397 (33.1%)304 (32.5%)0.988 (0.822-1.187)0.918 (0.722-1.168)
AA42 (3.5%)41 (4.4%)1.259 (0.808-1.962)0.994 (0.559-1.767)
GA+AA439 (36.6%)345 (36.9%)1.014 (0.849-1.210)0.926 (0.735-1.168)

The adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) were estimated by multiple logistic regression models that controlled for betel quid chewing, tobacco smoking, and alcohol consumption.

Tobacco consumption and betel quid chewing are important risk factors for the development of OSCC [57]. The effect of the interaction between tobacco consumption and betel quid chewing with RETN genotypes on OSCC progression is shown in Table 3. Among all 1,465 smokers (healthy controls and patients combined), those who either had at least one A allele of rs3745367, one C allele of rs74081741, one C allele of rs1862513, one A allele of rs3219175 or chewed betel nuts were 5.838-fold (95% CI: 3.985-8.552), 4.105-fold (95% CI: 2.960-5.692), 5.090-fold (95% CI: 3.493-7.418), and 4.134-fold (95% CI: 3.028-5.644) more likely, respectively, to develop OSCC compared to smokers with wide-type homozygotes who did not chew betel nuts. Moreover, smokers with at least one A allele of rs3745367, one C allele of rs74081741, one C allele of rs1862513, or one A allele of rs3219175 and who chewed betel nuts had respective risks that were 8.544-fold (95% CI: 5.668-12.880), 8.583-fold (95% CI: 6.026-12.225), 6.708-fold (95% CI: 4.467-10.074), and 10.882-fold (95% CI: 7.861-15.064) higher, respectively, for developing OSCC compared with the wild-type homozygous smokers. These results suggest that RETN gene polymorphisms have a strong impact upon oral cancer susceptibility in men who smoke tobacco and/or chew betel nuts.


VariableControls (n=636) ()Patients (n=829) ()OR (95 CI)AOR (95 CI)

rs3745367
GG genotype & non-betel nut chewing178 (28.0%)39 (4.7%)1.00
(reference)
1.000
(reference)
GA or AA genotype or betel nut chewing135 (21.2%)291 (35.1%)9.838 (6.580-14.708)8.544 (5.668-12.880)
GA or AA genotype with betel nut chewing323 (50.8%)499 (60.2%)7.051 (4.852-10.246)5.838 (3.985-8.552)

rs7408174
TT genotype & non-betel nut chewing218 (34.3%)62 (7.5%)1.00
(reference)
1.000
(reference)
TC or CC genotype or betel nut chewing127 (20.0%)385 (46.4%)10.659 (7.540-15.068)8.583 (6.026-12.225)
TC or CC genotype with betel nut chewing291 (45.7%)382 (46.1%)4.616 (3.349-6.361)4.105 (2.960-5.692)

rs1862513
GG genotype & non-betel nut chewing166 (26.1%)41 (5.0%)1.00
(reference)
1.000
(reference)
GC or CC genotype or betel nut chewing138 (21.7%)289 (34.9%)8.479 (5.698-12.617)6.708 (4.467-10.074)
GC or CC genotype with betel nut chewing332 (52.2%)499 (60.1%)6.085 (4.208-8.800)5.090 (3.493-7.418)

rs3219175
GG genotype & non-betel nut chewing287 (45.1%)78 (9.4%)1.00
(reference)
1.000
(reference)
GA or AA genotype or betel nut chewing125 (19.7%)448 (54.0%)13.187 (9.583-18.147)10.882 (7.861-15.064)
GA or AA genotype with betel nut chewing224 (35.2%)303 (36.6%)4.977 (3.672-6.746)4.134 (3.028-5.644)

The adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) were estimated by multiple logistic regression models that controlled for alcohol consumption.

Next, we compared associations between the RETN rs3219175 polymorphism and clinical status in OSCC patients aged >54 years. Compared with patients with the G/G genotype, those with the A/A genotype at the rs3219175 SNP were 2.480-fold (95% CI: 1.058-5.814) more likely to develop large tumors (>T2) (Table 4). No significant between-group differences were observed for clinical stage, lymph node metastasis, distant metastasis, or cell differentiation at the rs3219175 SNP (Table 4).


Clinical StageOR (95% CI)AOR (95% CI)
RETN rs3219175Stage I/II (n=243)Stage III/IV (n=239)
GG160 (65.8%)150 (62.8%)1.000 (reference)1.000 (reference)
GA74 (30.5%)73 (30.5%)1.052 (0.711-1.558)1.030 (0.693-1.529)
AA9 (3.7%)16 (6.7%)1.896 (0.813-4.421)1.896 (0.808-4.452)
Tumor size
RETN rs3219175T2 (n=272)> T2 (n=210)
GG181 (66.5%)129 (61.4%)1.000 (reference)1.000 (reference)
GA82 (30.2%)65 (31.0%)1.112 (0.748-1.653)1.113 (0.747-1.658)
AA9 (3.3%)16 (7.6%)2.494 (1.069-5.820)2.480 (1.058-5.814)
Lymph node metastasis
RETN rs3219175No (n=333)Yes (n=149)
GG215 (22.8%)95 (63.8%)1.000 (reference)1.000 (reference)
GA102 (54.5%)45 (30.2%)0.998 (0.652-1.528)0.969 (0.631-1.488)
AA16 (22.7%)9 (6.0%)1.273 (0.543-2.983)1.240 (0.525-2.930)
Metastasis
RETN rs3219175M0 (n=477)M1 (n=5)
GG308 (64.6%)2 (40.0%)1.000 (reference)1.000 (reference)
GA144 (30.2%)3 (60.0%)3.208 (0.530-19.411)3.009 (0.491-18.451)
AA25 (5.2%)0 (27.2%)-0.783 (0.172-3.559)
Cell differentiation
RETN rs3219175Well (n=76)Moderate/poor (n=406)
GG51 (67.1%)259 (63.8%)1.000 (reference)1.000 (reference)
GA21 (27.6%)126 (31.0%)1.181 (0.681-2.050)1.176 (0.675-2.047)
AA4 (5.3%)21 (5.2%)1.034 (0.340-3.139)0.963 (0.315-2.945)

Multivariate analysis adjusted for the effects of betel quid chewing, tobacco smoking, and alcohol consumption.
p = 0.0345; p = 0.0367.

An evaluation of the haplotypes sought to determine the combined effect of the four polymorphisms on OSCC susceptibility. In an analysis of distribution frequencies of RETN rs3745367, rs7408174, rs1862513, and rs3219175 haplotypes, the most common haplotype in healthy controls was G/T/G/G, which was therefore selected as the reference. The A/T/G/G RETN haplotype significantly increased the risk for developing OSCC by 1.376-fold (95% CI: 1.039-1.823, p<0.05) (Table 5). Furthermore, A/T/G/G RETN haplotype also enhanced the risk for developing OSCC in those who chewed betel nuts by 18.39-fold (95% CI: 12.333-27.421, p<0.05) (Table 6).


Haplotype blockControlsPatients
rs3745367 G/Ars7408174 T/Crs1862513 G/Crs3219175 G/An = 2400n = 1870OR (95% CI)AOR (95% CI)

GTGG679 (28.3%)492 (26.3%)1.000 (reference)1.000 (reference)
GCGG475 (19.8%)422 (22.6%)1.226 (1.029-1.461)1.212 (0.965-1.522)
ATCA318 (13.2%)291 (15.6%)1.263 (1.037-1.538)1.150 (0.890-1.486)
ATGG257 (10.7%)226 (12.1%)1.214 (0.981-1.502)1.376 (1.039-1.823)
ATCG189 (7.9%)153 (8.2%)1.117 (0.876-1.424)1.219 (0.890-1.672)
GTCG191 (8.0%)146 (7.8%)1.055 (0.826-1.347)1.062 (0.773-1.460)
GTCA67 (2.8%)57 (3.0%)1.174 (0.810-1.703)1.051 (0.644-1.716)
ACCA86 (3.6%)36 (1.9%)0.578 (0.385-0.867)0.712 (0.427-1.188)
GCCG63 (2.6%)30 (1.6%)0.657 (0.419-1.031)0.889 (0.509-1.552)
ACGG46 (1.9%)14 (0.7%)0.420 (0.228-0.773)0.343 (0.161-0.728)
ACCG19 (0.8%)1 (0.1%)0.073 (0.010-0.544)0.176 (0.019-1.643)
GCCA6 (0.2%)0 (0.0%)--
ATGA2 (0.1%)2 (0.1%)1.380 (0.194-9.831)1.620 (0.105-24.958)
GCGA2 (0.1%)0 (0.0%)--

Multivariate analysis adjusted for the effects of betel quid chewing, tobacco smoking, and alcohol consumption.
p=0.0225; p=0.0201; p=0.0081; p=0.0053; p=0.0107; p=0.0258; p=0.0054.
OSCC: oral squamous cell carcinoma; OR: odds ratio; AOR: adjusted odds ratio.

Betel quid chewingRETN haplotypeControlsPatientsAOR (95% CI)
n = 2400n = 1870

YesA-T-G-G33 (1.4%)179 (9.6%)18.390 (12.333-27.421)
YesOthers365 (15.2%)1311 (70.1%)12.774 (10.666-15.300)
NoA-T-G-G224 (9.3%)47 (2.5%)1.203 (0.856-1.690)
NoOthers1778 (74.1%)333 (17.8%)1.000 (reference)

Other haplotypes included G-T-G-G, G-C-G-G, A-T-C-A, A-T-C-G, G-T-C-G, G-T-C-A, A-C-C-A, G-C-C-G, A-C-G-G, A-C-C-G, G-C-C-A, A-T-G-A, and G-C-G-A.
Multivariate analysis adjusted for the effects of tobacco smoking and alcohol consumption.
p<0.001.
OSCC: oral squamous cell carcinoma.

4. Discussion

Resistin is an adipokine that is associated with obesity, inflammation, and various cancers [2629]. Furthermore, evidence suggests that in patients with lung cancer, high serum resistin levels may play a role in the pathogenesis of cancer cachexia [30]. Upregulation of resistin in serum has been detected in OSCC patients [31]. RETN polymorphisms have been identified in various cancers, including colon, breast, and lung [16, 18, 19], although scant data exist on the involvement of RETN polymorphisms in OSCC. To the best of our knowledge, this current study is the first to examine the distribution of the rs3745367, rs7408174, rs1862513, and rs3219175 SNPs and their possible association with susceptibility to the development of OSCC. We also investigated susceptibility to OSCC when these RETN SNPs were combined with environmental carcinogens. Interestingly, we did not find any significant differences between the frequencies of OSCC patients and controls with the rs3745367, rs7408174, rs1862513, and rs3219175 polymorphisms. We did discover that OSCC patients aged >54 years carrying the rs3219175 G/G homozygous polymorphism had a significantly high risk of developing large-size tumors compared to those carrying the rs3219175 A/A homozygous polymorphism. However, we did not recruit the survival results of OSCC patients. Future research could evaluate the association of RETN polymorphisms with survival of OSCC patients. In addition, it would be advisable to collect data on a larger number of patients for analysis of the functions of RETN polymorphisms in OSCC.

The linkage disequilibrium is expressed across the human genome and therefore could be used as a genetic marker to locate adjacent variants that participate in the detection and treatment of disease. Haplotype analyses can provide data on disease susceptibility [32]. Our evaluation of the impact of different haplotype combinations of four RETN SNPs (rs3745367, rs7408174, rs1862513, and rs3219175) upon the risk of OSCC revealed that the A/T/G/G haplotype is associated with a high risk for OSCC when compared with the reference haplotype, G/T/G/G. Furthermore, compared with other SNPs, the A/T/G/G RETN haplotype also enhanced the risk for developing OSCC in those who chewed betel nuts. We speculate that this haplotype is in linkage disequilibrium with other functional polymorphisms that are responsible for the susceptibility to OSCC.

Exposure to environmental carcinogens might lead to an earlier onset of oral cancer development. It is known that genomic changes during hepatocarcinogenesis progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into malignancy [33]. Polymorphisms of several genes are known to be associated with the risk of OSCC [34]. Thus, genetic components may play a pivotal role in carcinogenesis. Our study demonstrates a synergistic effect between betel quid chewing and tobacco smoking with four RETN SNPs (rs3745367, rs7408174, rs1862513, and rs3219175) on the risk of developing OSCC. Smokers with at least one A allele of rs3745367, one C allele of rs74081741, one C allele of rs1862513, or one A allele of rs3219175 and who chewed betel nuts were more likely to develop OSCC, with respective odds of 8.544 (95% CI: 5.668-12.880), 8.583 (95% CI: 6.026-12.225), 6.708 (95% CI: 4.467-10.074), and 10.882 (95% CI: 7.861-15.064). Long-term exposure to tobacco smoke and betel-nut chewing has been found to promote chronic inflammation reactions in oral tissue, subsequently leading to random genetic alteration and the development of oral cancer [35]. We suggest that tobacco smoking and betel-nut chewing in combination with RETN polymorphisms can increase the risk of rapid progression to oral cancer; thus, patients with a higher RETN polymorphism need to be aware of their higher risk of oral cancer.

Our results demonstrate an association between RETN gene variants and risk of OSCC. Compared with OSCC patients carrying the G/G genotype, those with the A/A genotype at the rs3219175 SNP were prone to developing large-size tumors. In an analysis of haplotype combinations of four RETN SNPs (rs3745367, rs7408174, rs1862513, and rs3219175), the A/T/G/G haplotype was found to be associated with a high risk of OSCC. Thus, RETN could serve as a genetic prognostic marker for OSCC treatment.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

All authors confirm that they have no financial or personal relationships with other people or organizations that could inappropriately influence this work.

Acknowledgments

This work was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 106-2320-B-039-005; 107-2320-B-039-019-MY3); China Medical University under the Higher Education Sprout Project, Ministry of Education, Taiwan (CMRC-CHM-3-1); and Taichung Hospital, Ministry of Health and Welfare (107023).

References

  1. S. V. K. Rao, G. Mejia, K. Roberts-Thomson, and R. Logan, “Epidemiology of oral cancer in Asia in the past decade - An update (2000-2012),” Asian Pacific Journal of Cancer Prevention, vol. 14, no. 10, pp. 5567–5577, 2013. View at: Publisher Site | Google Scholar
  2. M.-Y. Lien, C.-W. Lin, H.-C. Tsai et al., “Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics,” Oncotarget , vol. 8, no. 19, pp. 31424–31434, 2017. View at: Publisher Site | Google Scholar
  3. S. Xie, H. Xu, X. Shan et al., “Clinicopathological and Prognostic Significance of Survivin Expression in Patients with Oral Squamous Cell Carcinoma: Evidence from a Meta-Analysis,” PLoS ONE, vol. 10, no. 2, p. e0116517, 2015. View at: Publisher Site | Google Scholar
  4. C. Lee, N. Chiang, Y. Lu et al., “Benzyl isothiocyanate (BITC) triggers mitochondria-mediated apoptotic machinery in human cisplatin-resistant oral cancer CAR cells,” Biomedicine, vol. 8, no. 3, p. 15, 2018. View at: Publisher Site | Google Scholar
  5. M. C. Chang, C. P. Chiang, C. L. Lin, J. J. Lee, L. J. Hahn, and J. H. Jeng, “Cell-mediated immunity and head and neck cancer: With special emphasis on betel quid chewing habit,” Oral Oncology, vol. 41, no. 8, pp. 757–775, 2005. View at: Publisher Site | Google Scholar
  6. Y.-J. Chen, J. T.-C. Chang, C.-T. Liao et al., “Head and neck cancer in the betel quid chewing area: Recent advances in molecular carcinogenesis,” Cancer Science, vol. 99, no. 8, pp. 1507–1514, 2008. View at: Publisher Site | Google Scholar
  7. V. Ajila, H. Shetty, S. Babu, V. Shetty, and S. Hegde, “Human Papilloma Virus Associated Squamous Cell Carcinoma of the Head and Neck,” Journal of Sexually Transmitted Diseases, vol. 2015, Article ID 791024, 5 pages, 2015. View at: Publisher Site | Google Scholar
  8. B. S. Shastry, “SNP alleles in human disease and evolution,” Journal of Human Genetics, vol. 47, no. 11, pp. 561–566, 2002. View at: Publisher Site | Google Scholar
  9. M. Yang, K. Lin, M. Lu et al., “Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan,” Biomedicine, vol. 7, no. 2, p. 10, 2017. View at: Publisher Site | Google Scholar
  10. H. Tsai, C. Hsin, Y. Hsieh et al., “Impact of Interleukin-18 Polymorphisms -607A/C and -137G/C on Oral Cancer Occurrence and Clinical Progression,” PLoS ONE, vol. 8, no. 12, p. e83572, 2013. View at: Publisher Site | Google Scholar
  11. C. Lin, C. Chuang, C. Tang et al., “Combined Effects of ICAM-1 Single-Nucleotide Polymorphisms and Environmental Carcinogens on Oral Cancer Susceptibility and Clinicopathologic Development,” PLoS ONE, vol. 8, no. 9, p. e72940, 2013. View at: Publisher Site | Google Scholar
  12. C. M. Steppan, S. T. Bailey, S. Bhat et al., “The hormone resistin links obesity to diabetes,” Nature, vol. 409, no. 6818, pp. 307–312, 2001. View at: Publisher Site | Google Scholar
  13. M. P. Reilly, M. Lehrke, M. L. Wolfe, A. Rohatgi, M. A. Lazar, and D. J. Rader, “Resistin is an inflammatory marker of atherosclerosis in humans,” Circulation, vol. 111, no. 7, pp. 932–939, 2005. View at: Publisher Site | Google Scholar
  14. C. M. Steppan, E. J. Brown, C. M. Wright et al., “A family of tissue-specific resistin-like molecules,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 98, no. 2, pp. 502–506, 2001. View at: Publisher Site | Google Scholar
  15. S. Kumar, V. Gupta, N. Srivastava et al., “Resistin 420C/G gene polymorphism on circulating resistin, metabolic risk factors and insulin resistance in adult women,” Immunology Letters, vol. 162, no. 2, pp. 287–291, 2014. View at: Publisher Site | Google Scholar
  16. R. N. Alharithy, “Polymorphisms in RETN gene and susceptibility to colon cancer in Saudi patients,” Annals of Saudi Medicine, vol. 34, no. 4, pp. 334–339, 2014. View at: Publisher Site | Google Scholar
  17. C.-M. Chung, T.-H. Lin, J.-W. Chen et al., “Common quantitative trait locus downstream of RETN gene identified by genome-wide association study is associated with risk of type 2 diabetes mellitus in Han Chinese: A Mendelian randomization effect,” Diabetes/Metabolism Research and Reviews, vol. 30, no. 3, pp. 232–240, 2014. View at: Publisher Site | Google Scholar
  18. W. Hu, C. Tang, Y. Sun et al., “Correlation between resistin gene polymorphism and clinical aspects of lung cancer,” Medicine, vol. 96, no. 52, p. e9485, 2017. View at: Publisher Site | Google Scholar
  19. K. A. Vallega, N. Liu, J. S. Myers, K. Yu, Q. A. Sang, and M. Tan, “Elevated Resistin Gene Expression in African American Estrogen and Progesterone Receptor Negative Breast Cancer,” PLoS ONE, vol. 11, no. 6, p. e0157741, 2016. View at: Publisher Site | Google Scholar
  20. J.-N. Vauthey, G. Y. Lauwers, N. F. Esnaola et al., “Simplified staging for hepatocellular carcinoma,” Journal of Clinical Oncology, vol. 20, no. 6, pp. 1527–1536, 2002. View at: Publisher Site | Google Scholar
  21. L. Wang, C. Tang, T. Lu et al., “Resistin polymorphisms are associated with rheumatoid arthritis susceptibility in Chinese Han subjects,” Medicine, vol. 97, no. 12, p. e0177, 2018. View at: Publisher Site | Google Scholar
  22. Y.-J. Lin, T.-J. Ho, T.-H. Lin et al., “P-coumaric acid regulates exon 12 splicing of the ATP7B gene by modulating hnRNP A1 protein expressions,” BioMedicine (Netherlands), vol. 5, no. 2, pp. 22–30, 2015. View at: Publisher Site | Google Scholar
  23. T.-C. Li, C.-I. Li, L.-N. Liao et al., “Associations of EDNRA and EDN1 polymorphisms with carotid intima media thickness through interactions with gender, regular exercise, and obesity in subjects in Taiwan: Taichung Community Health Study (TCHS),” BioMedicine (Netherlands), vol. 5, no. 2, pp. 8–14, 2015. View at: Publisher Site | Google Scholar
  24. B. Wang, Y.-E. Chou, M.-Y. Lien, C.-M. Su, S.-F. Yang, and C.-H. Tang, “Impacts of CCL4 gene polymorphisms on hepatocellular carcinoma susceptibility and development,” International Journal of Medical Sciences, vol. 14, no. 9, pp. 880–884, 2017. View at: Publisher Site | Google Scholar
  25. C.-Q. Wang, C.-H. Tang, Y. Wang et al., “FSCN1 gene polymorphisms: Biomarkers for the development and progression of breast cancer,” Scientific Reports, vol. 7, no. 1, p. 15887, 2017. View at: Publisher Site | Google Scholar
  26. C.-H. Tsai, H.-C. Tsai, H.-N. Huang et al., “Resistin promotes tumor metastasis by down-regulation of miR-519d through the AMPK/p38 signaling pathway in human chondrosarcoma cells,” Oncotarget , vol. 6, no. 1, pp. 258–270, 2015. View at: Google Scholar
  27. C.-M. Su, C.-J. Hsu, C.-H. Tsai, C.-Y. Huang, S.-W. Wang, and C.-H. Tang, “Resistin promotes angiogenesis in endothelial progenitor cells through inhibition of microRNA206: Potential implications for rheumatoid arthritis,” Stem Cells, vol. 33, no. 7, pp. 2243–2255, 2015. View at: Publisher Site | Google Scholar
  28. C. M. Su, C. Y. Huang, and C. H. Tang, “Characteristics of resistin in rheumatoid arthritis angiogenesis,” Biomarkers in Medicine, vol. 10, no. 6, pp. 651–660, 2016. View at: Publisher Site | Google Scholar
  29. C. Su, C. Tang, M. Chi et al., “Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells,” Biochemical Pharmacology, vol. 154, pp. 234–242, 2018. View at: Publisher Site | Google Scholar
  30. G. Demiray, S. Değirmencioğlu, E. Uğurlu, and A. Yaren, “Effects of Serum Leptin and Resistin Levels on Cancer Cachexia in Patients With Advanced-Stage Non–Small Cell Lung Cancer,” Clinical Medicine Insights: Oncology, vol. 11, p. 117955491769014, 2017. View at: Publisher Site | Google Scholar
  31. C.-C. Wu, H.-W. Chu, C.-W. Hsu, K.-P. Chang, and H.-P. Liu, “Saliva proteome profiling reveals potential salivary biomarkers for detection of oral cavity squamous cell carcinoma,” Proteomics, vol. 15, no. 19, pp. 3394–3404, 2015. View at: Publisher Site | Google Scholar
  32. W. Hu, P.-Y. Liu, Y.-C. Yang et al., “Association of HMGB1 gene polymorphisms with lung cancer susceptibility and clinical aspects,” International Journal of Medical Sciences, vol. 14, no. 12, pp. 1197–1202, 2017. View at: Publisher Site | Google Scholar
  33. S. S. Thorgeirsson and J. W. Grisham, “Molecular pathogenesis of human hepatocellular carcinoma,” Nature Genetics, vol. 31, no. 4, pp. 339–346, 2002. View at: Publisher Site | Google Scholar
  34. K.-W. Chang, T.-C. Lee, W.-I. Yeh et al., “Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers,” British Journal of Cancer, vol. 91, no. 8, pp. 1551–1555, 2004. View at: Publisher Site | Google Scholar
  35. C.-C. Wang, H.-L. Lin, S.-P. Wey, and T.-R. Jan, “Areca-nut extract modulates antigen-specific immunity and augments inflammation in ovalbumin-sensitized mice,” Immunopharmacology and Immunotoxicology, vol. 33, no. 2, pp. 315–322, 2011. View at: Publisher Site | Google Scholar

Copyright © 2018 Wei-Hung Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

782 Views | 306 Downloads | 3 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.