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Cancer Biomarkers 14 (2014) 441–447 DOI 10.3233/CBM-140421 IOS Press
The Pin1 gene polymorphism and the susceptibility of oral squamous cell carcinoma in East China Jie Yaoa,b , Jian-Ming Wangc , Zi-Lu Wangb,∗ and Yu-Nong Wua,∗ a
Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China b Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China c Department of Epidemiology and Biostatistics, Faculty of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
Abstract. Pin1 is a peptidylprolyl isomerase that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences. Genetic variants in the Pin1 gene may alter protein function and cancer risk. In this study, we genotyped the two common promoter polymorphisms -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospital-based casecontrol studies conducted in Eastern Chinese populations, including 209 patients with oral squamous cell carcinoma and 444 cancer-free controls. We found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P = 0.028, OR = 1.66, 95%CI = 1.02–2.69). However, there was no risk significant associated with the -842G/C polymorphism. Further large population-based studies are needed to confirm these results. Keywords: Polymorphism, single nucleotide (SNP), peptidylprolyl isomerase pin1, oral squamous cell carcinoma (OSCC)
1. Introduction Pin1 is a peptidylprolyl isomerase (PPIase) that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences [1]. Structure-function analyses of Pin1 revealed a two-domain structure consisting of an N-terminal WW (Trp–Trp) domain and a C-terminal PPIase domain, with unique substrate specificity [2]. The early studies reported that Pin1 paly an essential role in mitotic for eukaryotic cell cycle [1–3]. It binds to target construct of protein and alters the conformation of phosphoproteins by catalyzing the rapid cis to trans isomerization of proline amide bonds which results in final protein stabilization change [4]. ∗ Corresponding authors: Yu-Nong Wu and Zi-Lu Wang, No. 136 Hanzhong Avenue, Nanjing, Jiangsu 210029, China. Tel.: +86 25 8503 1871; Fax: +86 25 8651 6414; E-mail: [email protected].
Recent studies have shown that Pin1-catalysed conformational regulation can play a key role in multiple oncogenic signaling pathways during cancer development [4,5]. However, the contradictory conclusions exist among studies. Both facilitory and inhibitory functions for Pin1 in cancer are found [4]. The conserved WW domain specific to pSer/Thr-Pro-motifs [6] allows Pin1-induced conformational changes in proteins such as Cdc25 [7], cyclin D1 [8,9], p53 [9,10] etc., which may be involved in the occurrence and metastasis of cancer [11]. Subsequent studies have shown that Pin1 overexpression has an oncogenic role in some common cancers, such as lung [12], liver [13], prostate [14], breast cancers [15], squamous cell carcinoma of the head and neck (SCCHN) [16] etc. On the other hand, there is also research finding that Pin1 act as suppressor in tumor formation. The decreases of Pin1 negatively regulate MYC and cyclin E levels, leading to the timely degradation of these proteins [4,17,18].
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Genetic variation in the Pin1 gene may alter protein function and cancer risk. Two putative promoter single nucleotide polymorphisms (SNPs) (-842G/C, rs2233678 and -667T/C, rs2233679) have reportedly been associated with protein diseases such as Alzheimer’s disease and carcinomas [12,13,15,19–31]. An increased risk of hepatocellular carcinoma was associated with the -667 T allele expressed in hepatitis B- and C-coinfected patients in an Italian study [13]. Some studies found that -842 C variant genotypes in the Pin1 promoter were associated with a reduced risk of SCCHN and breast cancer in a non-Hispanic white population in the United States [29,30]. A Chinese report suggested that functional -842 C variants and haplotype C-C in the Pin1 promoter contributed to a reduced risk of lung cancer in Southern and Eastern Chinese populations [12]. Leung et al stated Pin1 was overexpressed in oral squamous cell cancer (OSCC) which was associated with poor differentiation and survival in OSCC [32]. However, little is known the mechanism of these phenomena. Considering the environmental exposures may play a contribution of specific risk factors in cancer formation [33]. We hypothesized that interactions between environmental and genetic factors may contribute to the etiology of oral squamous cell carcinoma (OSCC). In light of previous studies, we genotyped the two common promoter SNPs -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospitalbased case-control studies conducted in Eastern Chinese populations between January 2009 and December 2011 to identify any associations between these polymorphisms and risk of OSCC.
2. Materials and methods 2.1. Study population This study analyzed two independent case-control groups including 209 patients with histopathologically confirmed OSCC at the Stomatological Hospital of Jiangsu Province, and 440 age (± 5 years) and sexmatched controls without individual history or a family history of any maligancy, recruited from January 2009 to December 2011. The controls were selected randomly from about 10,000 individuals participating in the health check-up programs conducted at community health stations in Nanjing city. All the participants were genetically unrelated ethnic Han Chinese and none had received blood transfusions in the preceed-
ing 6 months. After providing written informed consent, each participant was interviewed using a structured questionnaire, and information on smoking status, alcohol use, and other factors including family history of cancer was recorded. Patients with a previous cancer history or multiple primary neoplasms at the time of diagnosis were excluded from this study. The approval for this study was obtained from the Medical Ethics Committee of Stomatological Hospital of Jiangsu Province, Nan Jing Medical University. Smokers were given a questionnaire about smoking years and the number of cigarettes smoked per day. Never smokers were defined as individuals who had smoked averagely 1 cigarette/day for 1 year, and all others were described as smokers. Participants who had consumed alcoholic beverages at least once a week for 6 months previously were defined as drinkers, and all others were defined as never drinkers. All eligible subjects provided a venous blood sample of 30 ml for DNA extraction. 2.2. SNP selection and genotyping We selected the only two reported common (minor allele frequency > 0.05) SNPs -842G/C, rs2233678 and -667T/C, rs2233679, using the polymerase chain reaction-restriction fragment length polymorphism method. Because -842G/C and -667T/C are close to each other, we used same forward (5’-CGGGCTCTGC AGACTCT ATT-3’) and reverse primers (5’-AAATTT GGCTCCTCCATCCT-3’) to amplify the fragments, but two different enzymes to identify the genotypes: BanII for -842G/C and SacI (both Generay, Shang Hai, China) for -667T/C. The amplified fragments were then digested, separated in 3% MetaPhor agarose gel and confirmed by direct sequencing. The genotypes were determined as shown in Fig. 1. The genotype results were evaluated by two people who were blinded to the subject’s case or control status. A random 10% of samples were genotyped twice, and no discrepancies were observed. 2.3. Statistical analysis Hardy-Weinberg equilibrium was assessed with χ2 tests in the control groups. The distributions of Pin1 genotypes and selected risk factors between cases and controls were compared using χ2 tests. The associations between Pin1 genotypes and OSCC risk were evaluated by calculating the odds ratios (ORs) and 95% confidence intervals (CIs) from both univariate and multivariate logistic regression analyses.
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Fig. 1. -667T/C and -842G/C fragments were separated in 3% MetaPhor agarose gel and confirmed by direct sequencing. Table 1 Frequency distributions of selected variables in patients with oral cancer and controls Variable Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever Stage I–II III–IV Metastasis No Yes
Cases n = 209 (%)
Controls n = 444 (%)
P value
119 (56.94) 90 (43.06)
243 (54.73) 201 (45.27)
0.596
107 (53.08) 102 (46.92)
233 (52.48) 211 (47.52)
0.760
130 (62.20) 79 (37.80)
345 (77.70) 99 (22.30)
0.00
155 (74.16) 54 (25.84)
364 (81.98) 80 (18.02)
0.021
Table 2.1 -842G/C control group genotypes Hardy-Weinberg equilibrium test
Observe Expect
146 (69.86) 63 (30.14)
3. Results 3.1. Characteristics of the study population This study included 209 patients with OSCC and 444 cancer-free controls. There were no significant differences in sex and age distributions between the case and control groups (Table 1). The average age (± standard deviation) of the patients was 59.51 ± 11.15 years, and that of the controls was 62.47 ± 10.81 years. The frequencies of smokers in the case and control groups were 37.80% and 22.30%, respectively (P < 0.001). Significantly fewer cases than controls were never drinkers (P = 0.021). 3.2. Distributions of Pin1 genotypes and risk of head and neck cancer The observed genotype frequencies of the two polymorphisms were in agreement with the Hardy-Wein-
Allele G C 674 214
χ2
P
1.28
0.53
Table 2.2 -667T/C control group genotypes Hardy-Weinberg equilibrium test
Observe Expect
145 (69.38) 64 (30.62)
Genotype GG GC CC 250 174 20 256 162 26
Genotype TT TC CC 58 215 171 65 214 175
Allele T C 331 557
χ2
P
0.34
0.85
berg equilibrium in the control subjects (P > 0.05 for all) (Table 2). The genotype and allele frequencies of Pin1 -667T/C differed significantly between cases and controls (P = 0.028 and 0.095, respectively). Compared with -667CC homozygotes, -667TT homozygotes had a 1.66-fold increased risk of OSCC (95% CI = 1.02–2.69). However, there was no association between Pin1 -842T/C genotype and risk of OSCC (Table 3). 3.3. Distributions of -667T/C and clinicopathological characteristics We calculated the relationship between -667T/C and clinicopathological parameters and no significant associations were found in age, gender, smoking status, drinking status, clinical staging and metastasis distributions (Table 4). 3.4. Stratification analysis of Pin1 genotypes and risk of oral squamous carcinoma The associations between risk of OSCC and Pin1667T/C (rs2233679) variant genotypes were examined by subgroup analyses according to age, sex, smoking
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J. Yao et al. / The Pin1 gene polymorphism and the susceptibility of oral squamous cell carcinoma in East China Table 3 Distribution of Pin1 polymorphisms and logistic regression analysis of association with risk of oral squamous cell carcinoma
Genotype PIN1-842G /C GG GC CC GC + CC C allele PIN1 -667T/ C CC TC TT TC + TT C allele a adjusted
Cases n = 209 (%)
Controls n = 444 (%)
P value
Crude OR (95%CI)
Adjusted OR (95%CI)a
107 (51.2) 94 (45.0) 8 (3.8) 102 (48.8) 0.263
250 (56.3) 174 (39.2) 20 (9.6) 194 (92.8) 0.243
0.370
1.00 1.26 [0.90,1.77] 0.93 [0.40, 2.19] 1.23 [0.88, 1.71]
1.00 1.28[0.90,1.80] 0.93[0.39,2.22] 1.24[0.89,1.74]
77 (36.8) 88 (42.1) 44 (21.1) 132 (63.2) 0.579
171 (38.5) 215 (48.4) 58 (13.1) 273 (61.5) 0.439
0.028
1.00 0.91 [0.63, 1.31] 1.69 [1.05, 2.71] 1.07 [0.76, 1.51]
1.00 0.92 [0.63,1.31] 1.66 [1.02, 2.69] 1.09 [0.77,1.54]
0.387
0.095
for age, sex, smoking and alcohol status.
Table 4 Association between genotype frequencies of -667 T/C and clinicopathological characteristics of oral squamous cell carcinoma patients Variables Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever Stage I–II III–IV Metastasis No Yes
-667T/C CC(77)
-667T/C TT(44)
P value
45 (66.2) 32 (60.4)
23 (33.8) 21 (39.6)
0.51
38 (63.3) 39 (63.9)
22 (36.7) 22 (36.1)
0.95
48 (64.9) 29 (61.7)
26 (35.1) 18 (38.3)
0.72
55 (64.7) 22 (61.1)
30 (35.3) 14 (38.9)
0.71
51 (62.2) 26 (66.7)
31 (37.8) 13 (33.3)
0.63
48 (58.5) 29 (74.4)
34 (41.5) 10 (25.6)
0.09
status, and alcohol drinking status (Table 5). After adjusting for age and sex, there was no significant association between the four subgroups and -667T/C polymorphisms. 3.5. Pin1 haplotypes and risk of oral squamous cell carcinoma Four possible haplotypes were calculated, and there were no significant differences in the distribution of haplotypes between the cases and controls (Table 6).
4. Discussion PPIases are evolutionarily-conserved enzymes that catalyze the cis/trans isomerization of peptidyl-prolyl
peptide bonds, which deregulate the phosphorylation of pro-directed Ser/Thr motifs, resulting in transformation and oncogenesis [34]. Pin1 is a PPIase, and recent studies have demonstrated associations between Pin1 and several human diseases, including malignancies such as lung, breast, cervical, prostate, and colon cancers, as well as lymphomas and melanomas [35]. Expression of Pin1 has been shown to correlate positively with the presence of lymph node metastasis and clinical recurrence in prostate cancer. Pin1 may therefore represent a potential therapeutic target for the treatment of cancer. Pin1 is overexpressed and hypophosphorylated in squamous cell carcinoma of the head and neck (SCCHN), and inhibition of Pin1 blocks cell cycle progression and triggers tumor cell death. Pin1 may therefore be a promising new target for the development of improved SCCHN-targeting drugs [16]. Lu J found that the variant -842G>C genotype was associated with a reduced risk of SCCHN [30] in 1,010 non-Hispanic white patients with newly diagnosed SCCHN and 1,010 cancer-free frequency-matched controls. These cases included squamous carcinoma of the oral cavity. Compared with the -842GG genotype, the -842GC heterozygote genotype was associated with a significantly reduced risk of SCCHN (OR = 0.74; 95% CI = 0.59– 0.93) [19]. Lu Y reported that the -667CT, -667CC and -842GG genotypes of the Pin1 promoter (-667CT, OR = 0.639, 95% CI = 0.452–0.903, P = 0.011; -667CC, OR = 0.441, 95% CI = 0.213–0.915, P = 0.038; -842 CG, OR = 0.465, 95% CI = 0.249–0.871, P = 0.010) were associated with a reduced risk of nasopharyngeal carcinoma in a Chinese population [26]. You Y found that individuals with the -842GC genotype had a significantly lower risk of esophageal carcinoma (OR = 0.55, 95%CI = 0.40–0.75, P = 0.001). There was no association between the -667C/T poly-
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Table 5 Stratified analysis of Pin1-667T/C genotypes by selected variables in oral squamous carcinoma patients and controls
Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever a adjusted
Crude OR(95%CI) TT versus CC
Adjusted OR(95%CI)a TT versus CC
30 (22.9) 28 (28.6)
1.72 [0.90,3.29] 1.64 [0.81,3.32]
1.62 [0.83,3.15] 1.69 [0.83,3.47]
90 (74.4) 81 (75.0)
31 (25.6) 27 (25.0)
1.68 [0.86,3.27] 1.69 [0.86,3.34]
1.76 [0.89,3.50] 1.62 [0.80,3.26]
26 (35.1) 18 (38.3)
126 (73.7) 45 (77.6)
45 (26.3) 13 (22.4)
1.52 [0.84,2.73] 2.15 [0.92.5.04]
1.52 [0.84,2.77] 2.38 [0.99,5.73]
30 (35.3) 14 (38.9)
127 (73.4) 44 (78.6)
46 (26.6) 12 (21.4)
1.51 [0.86,2.63] 2.33 [0.93,5.89]
1.53 [0.85,2.73] 2.32 [0.90,6.00]
Cases (n = 209) CC, n (%) TT, n (%)
Controls (n = 444) CC, n (%) TT, n (%)
45 (66.2) 32 (60.4)
23 (33.8) 21 (39.6)
101 (77.1) 70 (71.4)
38 (63.3) 39 (63.9)
22 (36.7) 22 (36.1)
48 (64.9) 29 (61.7) 55 (64.7) 22 (61.1)
for age, sex, smoking and alcohol status. Table 6 Pin1 -842G/C and -667C/T haplotypes and oral squamous cell carcinoma risk
Haplotype -842G-667C -842G-667T -842C-667T -842C-667C a adjusted
Cases n (%) 57 (27.3) 53 (25.4) 79 (37.8) 20 (9.6)
OR(95%CI)a 1 1.14[0.72-1.81] 1.21[0.80-1.85] 1.37[0.72-2.60]
Controls n (%) 137 (30.9) 116 (26.1) 156 (35.1) 35 (7.9)
P value Ref. 0.57 0.37 0.34
for age, sex, smoking and alcohol status.
morphism and the risk of esophageal carcinoma [23]. In terms of the haplotypes of Pin1, the results of the current study were in disagreement with those of previous studies. For example, You Y reported that the haolotype of “C-842 -C-667 ” had a protected effect (OR = 0.67, 95% CI = 0.47–0.96, P = 0.021) [23]. Lu J found in non-Hispanic white subjects, compared with the most common –G842 -T667 haplotype, only the rare -C842 -T667 haplotype was associated with a significantly decreased risk for SCCHN (OR = 0.003; 95% CI = 0.001–0.16, P = 0.005) [30]. Any discrepancies between studies may be attributed to the combined effects of differences in environment, genetics and immunological factors on cancer risk [12,30,36]. In this study, the frequency of the -667CC genotype was higher than that of the -667 TT genotype, and we therefore chose -667CC as a baseline, in accordance with You [23] and Lu research [26]. The distribution frequencies of -667T/C (rs2233679) in the current case group were also similar to these two previous studies. The frequencies in this study were CC 36.8%, CT 42.1%, and TT 21.2%, while the equivalent frequencies were CC 34.3%, CT 45.5%, and TT 20.2%, and CC 35.9%, CT 46.6%, and TT 17.5% in Lu [26] and You [23] studies, respectively. The discrepancies between these studies and the current results may be attributed to differences in study sizes, cancer types or ethnic backgrounds. The out-
comes in this study display another possibility of functions characterized by Pin1 in OSCC. Several limitations exist in this study. The study is hospital-based, and may therefore not have been representative of the general population. Moreover, this clinical study fails to investigate deeper mechanism of Pin1 and its downstream targets such as β-catenin and cyclin D1 expressions [32]. As literature reviewed before, the roles of Pin1 in tumorigenesis were complicated and should be considered in different genetic backgrounds [4]. Further studies are essential to confirm these hypotheses. In conclusion, we found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P = 0.028, OR = 1.66, 95%CI = 1.02–2.69) and the roles of Pin1 in signaling pathway of tumorigenesis shoud be investigated further. Acknowledgement This work was supported by grants from a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, 2014-37). References [1]
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Cancer Biomarkers 14 (2014) 441–447 DOI 10.3233/CBM-140421 IOS Press
The Pin1 gene polymorphism and the susceptibility of oral squamous cell carcinoma in East China Jie Yaoa,b , Jian-Ming Wangc , Zi-Lu Wangb,∗ and Yu-Nong Wua,∗ a
Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China b Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, China c Department of Epidemiology and Biostatistics, Faculty of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
Abstract. Pin1 is a peptidylprolyl isomerase that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences. Genetic variants in the Pin1 gene may alter protein function and cancer risk. In this study, we genotyped the two common promoter polymorphisms -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospital-based casecontrol studies conducted in Eastern Chinese populations, including 209 patients with oral squamous cell carcinoma and 444 cancer-free controls. We found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P = 0.028, OR = 1.66, 95%CI = 1.02–2.69). However, there was no risk significant associated with the -842G/C polymorphism. Further large population-based studies are needed to confirm these results. Keywords: Polymorphism, single nucleotide (SNP), peptidylprolyl isomerase pin1, oral squamous cell carcinoma (OSCC)
1. Introduction Pin1 is a peptidylprolyl isomerase (PPIase) that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences [1]. Structure-function analyses of Pin1 revealed a two-domain structure consisting of an N-terminal WW (Trp–Trp) domain and a C-terminal PPIase domain, with unique substrate specificity [2]. The early studies reported that Pin1 paly an essential role in mitotic for eukaryotic cell cycle [1–3]. It binds to target construct of protein and alters the conformation of phosphoproteins by catalyzing the rapid cis to trans isomerization of proline amide bonds which results in final protein stabilization change [4]. ∗ Corresponding authors: Yu-Nong Wu and Zi-Lu Wang, No. 136 Hanzhong Avenue, Nanjing, Jiangsu 210029, China. Tel.: +86 25 8503 1871; Fax: +86 25 8651 6414; E-mail: [email protected].
Recent studies have shown that Pin1-catalysed conformational regulation can play a key role in multiple oncogenic signaling pathways during cancer development [4,5]. However, the contradictory conclusions exist among studies. Both facilitory and inhibitory functions for Pin1 in cancer are found [4]. The conserved WW domain specific to pSer/Thr-Pro-motifs [6] allows Pin1-induced conformational changes in proteins such as Cdc25 [7], cyclin D1 [8,9], p53 [9,10] etc., which may be involved in the occurrence and metastasis of cancer [11]. Subsequent studies have shown that Pin1 overexpression has an oncogenic role in some common cancers, such as lung [12], liver [13], prostate [14], breast cancers [15], squamous cell carcinoma of the head and neck (SCCHN) [16] etc. On the other hand, there is also research finding that Pin1 act as suppressor in tumor formation. The decreases of Pin1 negatively regulate MYC and cyclin E levels, leading to the timely degradation of these proteins [4,17,18].
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Genetic variation in the Pin1 gene may alter protein function and cancer risk. Two putative promoter single nucleotide polymorphisms (SNPs) (-842G/C, rs2233678 and -667T/C, rs2233679) have reportedly been associated with protein diseases such as Alzheimer’s disease and carcinomas [12,13,15,19–31]. An increased risk of hepatocellular carcinoma was associated with the -667 T allele expressed in hepatitis B- and C-coinfected patients in an Italian study [13]. Some studies found that -842 C variant genotypes in the Pin1 promoter were associated with a reduced risk of SCCHN and breast cancer in a non-Hispanic white population in the United States [29,30]. A Chinese report suggested that functional -842 C variants and haplotype C-C in the Pin1 promoter contributed to a reduced risk of lung cancer in Southern and Eastern Chinese populations [12]. Leung et al stated Pin1 was overexpressed in oral squamous cell cancer (OSCC) which was associated with poor differentiation and survival in OSCC [32]. However, little is known the mechanism of these phenomena. Considering the environmental exposures may play a contribution of specific risk factors in cancer formation [33]. We hypothesized that interactions between environmental and genetic factors may contribute to the etiology of oral squamous cell carcinoma (OSCC). In light of previous studies, we genotyped the two common promoter SNPs -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospitalbased case-control studies conducted in Eastern Chinese populations between January 2009 and December 2011 to identify any associations between these polymorphisms and risk of OSCC.
2. Materials and methods 2.1. Study population This study analyzed two independent case-control groups including 209 patients with histopathologically confirmed OSCC at the Stomatological Hospital of Jiangsu Province, and 440 age (± 5 years) and sexmatched controls without individual history or a family history of any maligancy, recruited from January 2009 to December 2011. The controls were selected randomly from about 10,000 individuals participating in the health check-up programs conducted at community health stations in Nanjing city. All the participants were genetically unrelated ethnic Han Chinese and none had received blood transfusions in the preceed-
ing 6 months. After providing written informed consent, each participant was interviewed using a structured questionnaire, and information on smoking status, alcohol use, and other factors including family history of cancer was recorded. Patients with a previous cancer history or multiple primary neoplasms at the time of diagnosis were excluded from this study. The approval for this study was obtained from the Medical Ethics Committee of Stomatological Hospital of Jiangsu Province, Nan Jing Medical University. Smokers were given a questionnaire about smoking years and the number of cigarettes smoked per day. Never smokers were defined as individuals who had smoked averagely 1 cigarette/day for 1 year, and all others were described as smokers. Participants who had consumed alcoholic beverages at least once a week for 6 months previously were defined as drinkers, and all others were defined as never drinkers. All eligible subjects provided a venous blood sample of 30 ml for DNA extraction. 2.2. SNP selection and genotyping We selected the only two reported common (minor allele frequency > 0.05) SNPs -842G/C, rs2233678 and -667T/C, rs2233679, using the polymerase chain reaction-restriction fragment length polymorphism method. Because -842G/C and -667T/C are close to each other, we used same forward (5’-CGGGCTCTGC AGACTCT ATT-3’) and reverse primers (5’-AAATTT GGCTCCTCCATCCT-3’) to amplify the fragments, but two different enzymes to identify the genotypes: BanII for -842G/C and SacI (both Generay, Shang Hai, China) for -667T/C. The amplified fragments were then digested, separated in 3% MetaPhor agarose gel and confirmed by direct sequencing. The genotypes were determined as shown in Fig. 1. The genotype results were evaluated by two people who were blinded to the subject’s case or control status. A random 10% of samples were genotyped twice, and no discrepancies were observed. 2.3. Statistical analysis Hardy-Weinberg equilibrium was assessed with χ2 tests in the control groups. The distributions of Pin1 genotypes and selected risk factors between cases and controls were compared using χ2 tests. The associations between Pin1 genotypes and OSCC risk were evaluated by calculating the odds ratios (ORs) and 95% confidence intervals (CIs) from both univariate and multivariate logistic regression analyses.
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Fig. 1. -667T/C and -842G/C fragments were separated in 3% MetaPhor agarose gel and confirmed by direct sequencing. Table 1 Frequency distributions of selected variables in patients with oral cancer and controls Variable Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever Stage I–II III–IV Metastasis No Yes
Cases n = 209 (%)
Controls n = 444 (%)
P value
119 (56.94) 90 (43.06)
243 (54.73) 201 (45.27)
0.596
107 (53.08) 102 (46.92)
233 (52.48) 211 (47.52)
0.760
130 (62.20) 79 (37.80)
345 (77.70) 99 (22.30)
0.00
155 (74.16) 54 (25.84)
364 (81.98) 80 (18.02)
0.021
Table 2.1 -842G/C control group genotypes Hardy-Weinberg equilibrium test
Observe Expect
146 (69.86) 63 (30.14)
3. Results 3.1. Characteristics of the study population This study included 209 patients with OSCC and 444 cancer-free controls. There were no significant differences in sex and age distributions between the case and control groups (Table 1). The average age (± standard deviation) of the patients was 59.51 ± 11.15 years, and that of the controls was 62.47 ± 10.81 years. The frequencies of smokers in the case and control groups were 37.80% and 22.30%, respectively (P < 0.001). Significantly fewer cases than controls were never drinkers (P = 0.021). 3.2. Distributions of Pin1 genotypes and risk of head and neck cancer The observed genotype frequencies of the two polymorphisms were in agreement with the Hardy-Wein-
Allele G C 674 214
χ2
P
1.28
0.53
Table 2.2 -667T/C control group genotypes Hardy-Weinberg equilibrium test
Observe Expect
145 (69.38) 64 (30.62)
Genotype GG GC CC 250 174 20 256 162 26
Genotype TT TC CC 58 215 171 65 214 175
Allele T C 331 557
χ2
P
0.34
0.85
berg equilibrium in the control subjects (P > 0.05 for all) (Table 2). The genotype and allele frequencies of Pin1 -667T/C differed significantly between cases and controls (P = 0.028 and 0.095, respectively). Compared with -667CC homozygotes, -667TT homozygotes had a 1.66-fold increased risk of OSCC (95% CI = 1.02–2.69). However, there was no association between Pin1 -842T/C genotype and risk of OSCC (Table 3). 3.3. Distributions of -667T/C and clinicopathological characteristics We calculated the relationship between -667T/C and clinicopathological parameters and no significant associations were found in age, gender, smoking status, drinking status, clinical staging and metastasis distributions (Table 4). 3.4. Stratification analysis of Pin1 genotypes and risk of oral squamous carcinoma The associations between risk of OSCC and Pin1667T/C (rs2233679) variant genotypes were examined by subgroup analyses according to age, sex, smoking
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J. Yao et al. / The Pin1 gene polymorphism and the susceptibility of oral squamous cell carcinoma in East China Table 3 Distribution of Pin1 polymorphisms and logistic regression analysis of association with risk of oral squamous cell carcinoma
Genotype PIN1-842G /C GG GC CC GC + CC C allele PIN1 -667T/ C CC TC TT TC + TT C allele a adjusted
Cases n = 209 (%)
Controls n = 444 (%)
P value
Crude OR (95%CI)
Adjusted OR (95%CI)a
107 (51.2) 94 (45.0) 8 (3.8) 102 (48.8) 0.263
250 (56.3) 174 (39.2) 20 (9.6) 194 (92.8) 0.243
0.370
1.00 1.26 [0.90,1.77] 0.93 [0.40, 2.19] 1.23 [0.88, 1.71]
1.00 1.28[0.90,1.80] 0.93[0.39,2.22] 1.24[0.89,1.74]
77 (36.8) 88 (42.1) 44 (21.1) 132 (63.2) 0.579
171 (38.5) 215 (48.4) 58 (13.1) 273 (61.5) 0.439
0.028
1.00 0.91 [0.63, 1.31] 1.69 [1.05, 2.71] 1.07 [0.76, 1.51]
1.00 0.92 [0.63,1.31] 1.66 [1.02, 2.69] 1.09 [0.77,1.54]
0.387
0.095
for age, sex, smoking and alcohol status.
Table 4 Association between genotype frequencies of -667 T/C and clinicopathological characteristics of oral squamous cell carcinoma patients Variables Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever Stage I–II III–IV Metastasis No Yes
-667T/C CC(77)
-667T/C TT(44)
P value
45 (66.2) 32 (60.4)
23 (33.8) 21 (39.6)
0.51
38 (63.3) 39 (63.9)
22 (36.7) 22 (36.1)
0.95
48 (64.9) 29 (61.7)
26 (35.1) 18 (38.3)
0.72
55 (64.7) 22 (61.1)
30 (35.3) 14 (38.9)
0.71
51 (62.2) 26 (66.7)
31 (37.8) 13 (33.3)
0.63
48 (58.5) 29 (74.4)
34 (41.5) 10 (25.6)
0.09
status, and alcohol drinking status (Table 5). After adjusting for age and sex, there was no significant association between the four subgroups and -667T/C polymorphisms. 3.5. Pin1 haplotypes and risk of oral squamous cell carcinoma Four possible haplotypes were calculated, and there were no significant differences in the distribution of haplotypes between the cases and controls (Table 6).
4. Discussion PPIases are evolutionarily-conserved enzymes that catalyze the cis/trans isomerization of peptidyl-prolyl
peptide bonds, which deregulate the phosphorylation of pro-directed Ser/Thr motifs, resulting in transformation and oncogenesis [34]. Pin1 is a PPIase, and recent studies have demonstrated associations between Pin1 and several human diseases, including malignancies such as lung, breast, cervical, prostate, and colon cancers, as well as lymphomas and melanomas [35]. Expression of Pin1 has been shown to correlate positively with the presence of lymph node metastasis and clinical recurrence in prostate cancer. Pin1 may therefore represent a potential therapeutic target for the treatment of cancer. Pin1 is overexpressed and hypophosphorylated in squamous cell carcinoma of the head and neck (SCCHN), and inhibition of Pin1 blocks cell cycle progression and triggers tumor cell death. Pin1 may therefore be a promising new target for the development of improved SCCHN-targeting drugs [16]. Lu J found that the variant -842G>C genotype was associated with a reduced risk of SCCHN [30] in 1,010 non-Hispanic white patients with newly diagnosed SCCHN and 1,010 cancer-free frequency-matched controls. These cases included squamous carcinoma of the oral cavity. Compared with the -842GG genotype, the -842GC heterozygote genotype was associated with a significantly reduced risk of SCCHN (OR = 0.74; 95% CI = 0.59– 0.93) [19]. Lu Y reported that the -667CT, -667CC and -842GG genotypes of the Pin1 promoter (-667CT, OR = 0.639, 95% CI = 0.452–0.903, P = 0.011; -667CC, OR = 0.441, 95% CI = 0.213–0.915, P = 0.038; -842 CG, OR = 0.465, 95% CI = 0.249–0.871, P = 0.010) were associated with a reduced risk of nasopharyngeal carcinoma in a Chinese population [26]. You Y found that individuals with the -842GC genotype had a significantly lower risk of esophageal carcinoma (OR = 0.55, 95%CI = 0.40–0.75, P = 0.001). There was no association between the -667C/T poly-
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445
Table 5 Stratified analysis of Pin1-667T/C genotypes by selected variables in oral squamous carcinoma patients and controls
Sex Male Female Age 60 > 60 Smoking status Never Ever Drinking status Never Ever a adjusted
Crude OR(95%CI) TT versus CC
Adjusted OR(95%CI)a TT versus CC
30 (22.9) 28 (28.6)
1.72 [0.90,3.29] 1.64 [0.81,3.32]
1.62 [0.83,3.15] 1.69 [0.83,3.47]
90 (74.4) 81 (75.0)
31 (25.6) 27 (25.0)
1.68 [0.86,3.27] 1.69 [0.86,3.34]
1.76 [0.89,3.50] 1.62 [0.80,3.26]
26 (35.1) 18 (38.3)
126 (73.7) 45 (77.6)
45 (26.3) 13 (22.4)
1.52 [0.84,2.73] 2.15 [0.92.5.04]
1.52 [0.84,2.77] 2.38 [0.99,5.73]
30 (35.3) 14 (38.9)
127 (73.4) 44 (78.6)
46 (26.6) 12 (21.4)
1.51 [0.86,2.63] 2.33 [0.93,5.89]
1.53 [0.85,2.73] 2.32 [0.90,6.00]
Cases (n = 209) CC, n (%) TT, n (%)
Controls (n = 444) CC, n (%) TT, n (%)
45 (66.2) 32 (60.4)
23 (33.8) 21 (39.6)
101 (77.1) 70 (71.4)
38 (63.3) 39 (63.9)
22 (36.7) 22 (36.1)
48 (64.9) 29 (61.7) 55 (64.7) 22 (61.1)
for age, sex, smoking and alcohol status. Table 6 Pin1 -842G/C and -667C/T haplotypes and oral squamous cell carcinoma risk
Haplotype -842G-667C -842G-667T -842C-667T -842C-667C a adjusted
Cases n (%) 57 (27.3) 53 (25.4) 79 (37.8) 20 (9.6)
OR(95%CI)a 1 1.14[0.72-1.81] 1.21[0.80-1.85] 1.37[0.72-2.60]
Controls n (%) 137 (30.9) 116 (26.1) 156 (35.1) 35 (7.9)
P value Ref. 0.57 0.37 0.34
for age, sex, smoking and alcohol status.
morphism and the risk of esophageal carcinoma [23]. In terms of the haplotypes of Pin1, the results of the current study were in disagreement with those of previous studies. For example, You Y reported that the haolotype of “C-842 -C-667 ” had a protected effect (OR = 0.67, 95% CI = 0.47–0.96, P = 0.021) [23]. Lu J found in non-Hispanic white subjects, compared with the most common –G842 -T667 haplotype, only the rare -C842 -T667 haplotype was associated with a significantly decreased risk for SCCHN (OR = 0.003; 95% CI = 0.001–0.16, P = 0.005) [30]. Any discrepancies between studies may be attributed to the combined effects of differences in environment, genetics and immunological factors on cancer risk [12,30,36]. In this study, the frequency of the -667CC genotype was higher than that of the -667 TT genotype, and we therefore chose -667CC as a baseline, in accordance with You [23] and Lu research [26]. The distribution frequencies of -667T/C (rs2233679) in the current case group were also similar to these two previous studies. The frequencies in this study were CC 36.8%, CT 42.1%, and TT 21.2%, while the equivalent frequencies were CC 34.3%, CT 45.5%, and TT 20.2%, and CC 35.9%, CT 46.6%, and TT 17.5% in Lu [26] and You [23] studies, respectively. The discrepancies between these studies and the current results may be attributed to differences in study sizes, cancer types or ethnic backgrounds. The out-
comes in this study display another possibility of functions characterized by Pin1 in OSCC. Several limitations exist in this study. The study is hospital-based, and may therefore not have been representative of the general population. Moreover, this clinical study fails to investigate deeper mechanism of Pin1 and its downstream targets such as β-catenin and cyclin D1 expressions [32]. As literature reviewed before, the roles of Pin1 in tumorigenesis were complicated and should be considered in different genetic backgrounds [4]. Further studies are essential to confirm these hypotheses. In conclusion, we found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P = 0.028, OR = 1.66, 95%CI = 1.02–2.69) and the roles of Pin1 in signaling pathway of tumorigenesis shoud be investigated further. Acknowledgement This work was supported by grants from a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, 2014-37). References [1]
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