Figures
Abstract
Background
Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1) plays an important role in cancer development. The relationship between PIN1 −842G/C (rs2233678) polymorphism and cancer risk was inconclusive according to published literature.
Methodology/Principal Findings
A literature search, up to February 2013, was carried out using PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database. A total of 10 case-control studies including 4619 cases and 4661 controls contributed to the quantitative analysis. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant CG (OR = 0.728, 95% CI: 0.585,0.906; Pheterogeneity<0.01) and CG/CC (OR = 0.731, 95% CI: 0.602,0.888; Pheterogeneity<0.01) genotypes were associated with a significantly reduced cancer risk compared with those with wild GG genotype. Sub-group analysis revealed that the variant CG (OR = 0.635, 95% CI: 0.548,0.735; Pheterogeneity = 0.240) and CG/CC (OR = 0.645, 95% CI: 0.559,0.744, Pheterogeneity = 0.258) genotypes still showed an reduced risk of cancer in Asians; while no significant association was observed in Caucasians (CG vs.GG: OR = 0.926, 95% CI: 0.572,1.499, Pheterogeneity<0.01; CG/CC vs. GG: OR = 0.892, 95% CI: 0.589,1.353; Pheterogeneity<0.01). Furthermore, sensitivity analysis confirmed the stability of results. Begg's funnel plot and Egger's test did not reveal any publication bias.
Citation: Xu H-R, Xu Z-F, Sun Y-L, Han J-J, Li Z-J (2013) The −842G/C Polymorphisms of PIN1 Contributes to Cancer Risk: A Meta-Analysis of 10 Case-Control Studies. PLoS ONE 8(8): e71516. https://doi.org/10.1371/journal.pone.0071516
Editor: Qing-Yi Wei, The University of Texas MD Anderson Cancer Center, United States of America
Received: April 9, 2013; Accepted: June 30, 2013; Published: August 27, 2013
Copyright: © 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work is supported by Natural Science Foundation of Shandong Province, China (2011HW069). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Pro-directed phosphorylation is a critical signaling mechanism in various cellular processes, including transcription, RNA processing, cell cycle progression, cell proliferation and differentiation [1]–[3]. It has been demonstrated that the deregulation of this mechanism can lead to cell transformation and tumorigenesis [3], [4]. Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1(PIN1), which belongs to the evolutionarily conserved peptidyl-prolyl isomerase (PPIase) family, is a 18 kDa protein containing a carboxy-terminal catalytic domain and a WW amino-terminal protein–protein interaction domain which can change conformation of phosphoproteins by recognizing and binding to specific phospho-Ser/Thr-Pro motifs [4], [5]. It has been demonstrated that PIN1 is associated with different signaling pathways such as cell-cycle progression, cellular proliferation, as well as neoplastic transformation [6], [7]. Previous studies have shown that PIN1 was overexpressed in a variety of human cancers [8], [9]. Further, its expression levels parallel the malignant properties in several types of cancer, such as lung cancer, colon cancer, breast cancer, prostate cancer, and oral squamous cell carcinoma [10]–[13]. These findings suggest that PIN1 may play an important role in cancer development.
The gene that encodes PIN1 protein is mapped to chromosome 19p13.2. Several studies have investigated the relationship between the single nucleotide polymorphisms (SNP, −842G/C, rs2233678) in the PIN1 promoter region and risk of cancers, such as breast cancer [14], [15], lung cancer [16], esophageal carcinoma [17], hepatocellular carcinoma [18], nasopharyngeal carcinoma [19], laryngeal squamous cell carcinoma [20], and squamous cell carcinoma of the head and neck [21]. However, these studies yielded different or even controversial results.
To confirm the association between −842(G>C) polymorphisms of PIN1 gene and cancer risk, we performed this meta-analysis by pooling all eligible studies to calculate the estimate of overall cancer risk and evaluate influence of cancer types and ethnicity.
Methods
Identification of Studies
A literature search was carried out using PubMed, EMBASE and China National Knowledge Infrastructure (CNKI) database up to February 2013. There was no restriction of origin or languages. Search terms included: “PIN1” or “rs2233678” in combination with “polymorphism” or “variant” and “cancer” or “neoplasm” or “malignancy”. The reference lists of each comparative study and previous reviews were manually examined to identify additional relevant studies.
Inclusion and exclusion criteria
Studies were selected according to the following inclusion criteria: (1) case-control studies; (2) investigating the association between PIN1 rs2233678 (G>C) polymorphism and cancer risks; (3)cancers diagnosed by histopathology; (4) providing detail genotype frequencies. Studies without detail genotype frequencies were excluded. Titles and abstracts of searching results were screened and full text papers were further evaluated to confirm eligibility. Two reviewers(XH and XZ) independently selected eligible studies. Disagreement between the two reviewers was settled by discussing with the third reviewer (LZ).
Data extraction
The following data was collected by two reviewers(XH and XZ) independently using a purpose-designed form: name of first author, publishing time, country where the study was conducted, genotyping methods, ethnicity, cancer types, source of control, number of cases and controls, genotype frequency in cases and controls. Different ethnicity descents were categorized as Asian and Caucasian. Cancer types were classified as breast cancer, squamous cancer (squamous cell carcinoma of head and neck, and laryngeal squamous cell carcinoma), and other cancers (nasopharyngeal carcinoma, esophageal carcinoma, lung cancer, and hepatocellular carcinoma). Eligible studies were defined as hospital-based (HB) and population-based (PB) according to the control source.
Methodological quality assessment
The quality of eligible studies was evaluated by three reviewers (XH, XZ and LZ) independently by scoring according to a “methodological quality assessment scale” (see Table S2: Scale for methodological quality assessment), which was modified form a previous meta-analysis [22]. In the scale, 6 items were assessed, namely the representativeness of cases, the source of controls, ascertainment of relevant cancer, sample size, quality control of genotyping methods, and Hardy-Weinberg equilibrium (HWE). Quality scores ranged from 0 to 10 and a high score indicated good quality of the study. Three reviewers solved disagreement by discussion.
Statistical analysis
The association strength between −842G>C (rs2233678) polymorphism and cancer risks was measured by odds ratio (OR) with 95% confidence intervals (95% CI). The estimates of pooled ORs were achieved by calculating a weighted average of OR from each study. A 95% CI was used for statistical significance test and a 95% CI without 1 for OR indicating a significantly increased or reduced cancer risk. The pooled ORs were calculated for homozygote comparison (CC versus GG), heterozygote comparison (GC versus GG), dominant (GC/CC versus GG) and recessive (CC versus GC/GG) models, assuming dominant and recessive effects of the variant G allele, respectively. Subgroup analyses were performed according to (i) cancer types, (ii) ethnicities, and (iii) source of control, to examine the impact of these factors on the association. To test the robustness of the association and characterize possible sources of statistical heterogeneity, sensitivity analysis was carried out by excluding studies one-by-one and analyzing the homogeneity and effect size for all of rest studies.
Chi-square based Q test was used to check the statistical heterogeneity between studies, and the heterogeneity was considered significant when p<0.10 [23]. The fixed-effects model (based on Mantel-Haenszel method) and random-effects model (based on DerSimonian-Laird method) were used to pool the data from different studies. The fixed-effects model was used when there was no significant heterogeneity; otherwise, the random-effects model was applied [24]. The between studies variance (τ2) was used to quantify the degree of heterogeneity between studies and the percentage of τ2 was used to describe the extent of heterogeneity explained [25]. Publication bias was assessed using Begg and Mazumdar adjusted rank correlation test and the Egger regression asymmetry test [26], [27].
HWE (Hardy-Weinberg equilibrium) was tested by Pearson's X2 test (P<0.05 means deviated from HWE). All analyses were performed using Stata version 11.0 (StataCorp, College Station, TX).
Results
Search results and characteristics of studies included in the meta-analysis
The flow diagram of study identification is shown in Figure 1. A total of 90 citations were identified during the initial search. After the primary screening of titles and abstracts, we identified 10 papers. After detailed evaluation, two studies were excluded for not present the genotype frequencies. In the study reported by Naidu R and colleagues [15], participants were recruited from three different populations (Malay, Chinese, and Indian), and the genotype frequencies were presented separately, thus each of them was considered as a separate study in this meta-analysis. At last, 10 case-control studies [14], [15], [16], [17], [18], [19], [20], [21], including 4619 cancer cases and 4661 controls, assessing the association between −842(G>C) polymorphism of PIN1 and cancer risk, published between 2007 and 2013 were included in the meta-analysis (Baseline data and other details are shown in Table 1). Of them, seven studies were conducted in Asia [15], [16], [17], [19], [20], two in United States of America [14], [21], and remaining one in Europe [18]. Cancer cases were diagnosed histologically or pathologically in all studies. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used for genotyping in 9 studies [14], [15], [16], [17], [19], [20], [21]. However, the method for genotyping was not described in one study [18]. Blood sample was used for genotyping in all studies. Genotype distribution of controls in all studies was consistent with HWE, except for Segat L's study [18] on hepatocellular carcinoma (P = 0.07).
In the study reported by Naidu R [15], three different populations (Malay, Chinese, and Indian) were included , and each of them was considered as a separate study in this meta-analysis.
Meta-analysis results
We observed a significantly reduced risk of cancer susceptibility in heterozygote comparison (CG vs GG: OR = 0.728, 95% CI: 0.585,0.906; Pheterogeneity<0.01, Figure 2) and dominant model (CC/CG vs GG: OR = 0.731, 95% CI: 0.602, 0.888; Pheterogeneity<0.01, Figure 3) when all eligible studies were pooled. The association strength between −842G/C polymorphisms in the PIN1 promoter region and cancer risk was shown in Table 2. As shown in Table 2, no significant association was found in homozygote comparison (CC vs GG: OR = 0.737, 95% CI: 0.513, 1.059; Pheterogeneity = 0.193) or recessive model (CC vs GG/CG: (,)OR = 0.653, 95% CI: 0.354, 1.203; Pheterogeneity = 0.088); however, a trend of reduced risk could be drawn.
BC: breast cancer; SC: squamous cancer; OC: other cancers.
BC: breast cancer; SC: squamous cancer; OC: other cancers.
We then performed sub-group analyses to investigate the effect of cancer types, ethnicity, and source of control. As for cancer types, increased cancer risk was found in the heterozygote comparison (CG vs GG: OR = 0.720, 95% CI: 0.573, 0.905; Pheterogeneity = 0.408) and dominant model(CC/CG vs GG: OR = 0.705, 95% CI: 0.564, 0.881; Pheterogeneity = 0.493) for breast cancer. In the sub-group analyses of squamous cancer, and other cancers, we did find any significant association between −842G/C polymorphisms in the PIN1 promoter region and cancer risk. As for hospital-based studies, we observed a significantly reduced risk of cancer susceptibility in homozygote comparison (CC vs GG: OR = 0.315, 95% CI: 0.129, 0.769; Pheterogeneity = 0.925), heterozygote comparison (CG vs GG: OR = 0.711, 95% CI: 0.562, 0.900; Pheterogeneity = 0.378), dominant model (CC/CG vs GG: OR = 0.678, 95% CI: 0.538, 0.853; Pheterogeneity = 0.425) and recessive model (CC vs GG/CG: OR = 0.332, 95% CI: 0.136, 0.808; Pheterogeneity = 0.952). However, for hospital-based studies, significant association between −842G/C polymorphisms in the PIN1 promoter region and reduced risks of cancers was found only in heterozygote comparison (CG vs GG: OR = 0.651, 95% CI: 0.572, 0.742; Pheterogeneity = 0.214), dominant model (CC/CG vs GG: OR = 0.671, 95% CI: 0.592, 0.762; Pheterogeneity = 0.194). Ethnicity, also, affected cancer susceptibility. In Asians, there was a statistically reduced cancer risk in the comparison of heterozygote (CG vs GG: OR = 0.635, 95% CI: 0.548, 0.735; Pheterogeneity = 0.240) and dominant model (CC/CG vs GG: OR = 0.645, 95% CI: 0.559, 0.744; Pheterogeneity = 0.258). Results for Asians were similar to that of overall comparisons of pooled eligible studies. In Caucasians, however, no significant association was found in each comparison. Taken together, these results revealed that −842G/C polymorphisms in the PIN1 promoter region was only associated with an increased risk of cancer in Asians.
Heterogeneity between studies
Heterogeneity between studies in each comparison was shown in Table 2. After stratification, the heterogeneities decreased obviously in the subgroups of breast cancer, squamous cancer, the Asian population, Caucasian population, hospital-based controls, and population-based controls(Pheterogeneity>0.1 in most genetic comparisons).
Sensitivity analysis
Sensitivity analysis was performed to explore individual study's influence on the pooled results by deleting one single study each time from pooled analysis. The results showed that no individual study affected the pooled OR significantly (data not shown), since no substantial change was found.
Publication Bias
The potential publication bias of the literatures was .evaluated by funnel plot and Egger's test. No visual publication bias was found in the funnel plot (Figure 4). And Egger's test suggested that no publication bias was detected in all the comparison models (P>0.05).
Heterozygous genetic model for overall comparison: GC vs GG. No publication bias was observed among studies using Begg's P value (P = 0.93) and Egger's (P = 0.73) test, which suggested there was no evidence of publication bias.
Discussion
In the present meta-analysis of 10 case-control studies, including 4619 cancer cases and 4661 controls, a significant association was found between PIN1 −842G/C polymorphism and reduced cancer risk under the heterozygous and dominant genetic models. Under the homozygous and recessive genetic model, there was no significant association between PIN1 −842G/C polymorphism and cancer risk. Overall, a significant association exists between −842G/C polymorphisms in the PIN1 promoter region and cancer risk. This finding indicates that the genetic variant in PIN1 promoter region may crucially modify the susceptibility of cancers.
Although PIN1 is not an oncogene itself, it is able to potentiate the function of several oncogenic pathways depending on other oncogenes [9]. Numerous targets of PIN1 were often deregulated in cancer, such as p53 [28], [29], p73 [30], beta-catenin [12], [31], cyclin D [13], [32], [33], [34], cyclin E [35], RAF1 [36], erbB2 [37] , MYC [38], and interleukin-8 [39]. Lu J et al found that the change from G to C may cause loss of the known gene-binding site that may regulate the PIN1 expression, and thereby deregulate its target protein leading to cancer development [19]. Previous studies suggested that high expression of PIN1 is correlated with tumor development and poor prognosis [40], [41].
In stratified analysis by cancer site, we found that −842G/C polymorphism in the PIN1 promoter region was statistically related with reduced breast cancer risks. However, we did not observe any significant association between the genetic variant and the susceptibility of other cancers. However,there are only two studies [20], [21] investigating the association between −842G/C polymorphism and squamous cell carcinoma risk, and only one study investigating the association between −842G/C polymorphism and risk of other cancers, including lung cancer [16], esophageal carcinoma [17],hepatocellular carcinoma [18], nasopharyngeal carcinoma [19]. So we should treat the result with caution, and more original case-control studies are needed to further evaluate the association between −842G/C polymorphism and different cancer types.
In the sub-group analysis of ethnicity, we found a significant association between −842G/C polymorphism and reduced risk of cancer in Asians but not in Caucasians. The different cancer risks in Asians and Caucasians were also reported in other meta-analyses [22], [42]. It is possible that different genetic backgrounds and the different environment they live in may account for these differences. As we know, different populations carry different genotype and/or allele frequencies of this locus polymorphism and may lead to various degrees of cancer susceptibility [43]. And different ethnic groups live with multiple life styles and environmental factors and thus yield diverse gene-environment interactions [44]. In addition, it was also likely that the relatively small sample size in Caucasians might cause the inconspicuousness.
During sub-group analyses, we found that control source also affected the association between −842G/C polymorphisms in the PIN1 promoter region and cancer risk. As for hospital-based studies, we observed a significantly reduced risk of cancer susceptibility in homozygote model, and recessive model. However, for hospital-based studies, no significant association between −842G/C polymorphisms in the PIN1 promoter region and risk of cancers was found in homozygote model, and recessive model. Further, it's worth noting that the majority (66.7%) studies of Caucasians use hospital-based controls, while most (57.1%) studies of Asians use population-based controls. So the ethnic interpretations are available to the inconsistency in control source stratification.
Some limitations might be included in the meta-analysis. First, we did not search for unpublished studies, so only published studies were included in our meta-analysis. Therefore, publication bias may have occurred although no publication bias was indicated from both visualization of the funnel plot and Egger's test. Second, the sample size of the included studies was not large enough, which could decrease the statistical power to better evaluate the association between −842G/C polymorphism in the PIN1 promoter region and cancer risk. Third, most of the included studies had conducted on Asians, and a few Caucasians. Thus, more samples should be collected from Caucasians.
In conclusion, this meta-analysis suggests that the −842G/C polymorphism in PIN1 gene is associated with a significantly reduced risk of cancer, especially in Asian populations. More well-designed studies focusing on different ethnicities and cancer types are warranted in the future.
Supporting Information
Table S2.
Scale for methodological quality assessment.
https://doi.org/10.1371/journal.pone.0071516.s002
(DOC)
Author Contributions
Conceived and designed the experiments: HRX ZFX YLS JJH ZJL. Performed the experiments: HRX ZFX YLS JJH ZJL. Analyzed the data: HRX ZJL. Contributed reagents/materials/analysis tools: HRX ZJL. Wrote the paper: HRX ZJL.
References
- 1. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411: 355–365.
- 2. Lu KP (2003) Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics. Cancer Cell 4: 175–180.
- 3. Lu KP (2004) Pinning down cell signaling, cancer and Alzheimer's disease. Trends Biochem Sci 29: 200–209.
- 4. Lu KP, Zhou XZ (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8: 904–916.
- 5. Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Curr Top Med Chem 3: 1315–1347.
- 6. Lu KP, Liou YC, Zhou XZ (2002) Pinning down proline-directed phosphorylation signaling. Trends Cell Biol 12: 164–172.
- 7. Yeh ES, Means AR (2007) PIN1, the cell cycle and cancer. Nat Rev Cancer 7: 381–388.
- 8. Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, et al. (2004) Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol 164: 1727–1737.
- 9. Ryo A, Liou YC, Wulf G, Nakamura M, Lee SW, et al. (2002) PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol Cell Biol 22: 5281–5295.
- 10. Ayala G, Wang D, Wulf G, Frolov A, Li R, et al. (2003) The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer. Cancer Res 63: 6244–6251.
- 11. Miyashita H, Mori S, Motegi K, Fukumoto M, Uchida T (2003) Pin1 is overexpressed in oral squamous cell carcinoma and its levels correlate with cyclin D1 overexpression. Oncol Rep 10: 455–461.
- 12. Ryo A, Nakamura M, Wulf G, Liou YC, Lu KP (2001) Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat Cell Biol 3: 793–801.
- 13. Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, et al. (2001) Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. EMBO J 20: 3459–3472.
- 14. Han CH, Lu J, Wei Q, Bondy ML, Brewster AM, et al. (2010) The functional promoter polymorphism (−842G>C) in the PIN1 gene is associated with decreased risk of breast cancer in non-Hispanic white women 55 years and younger. Breast Cancer Res Treat 122: 243–249.
- 15. Naidu R, Har YC, Taib NA (2011) Analysis of peptidyl-propyl-cis/trans isomerase 1 (PIN1) gene −842(G>C) and −667(T>C) polymorphic variants in relation to breast cancer risk and clinico-pathological parameters. Scand J Clin Lab Invest 71: 500–506.
- 16. Lu J, Yang L, Zhao H, Liu B, Li Y, et al. (2011) The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations. Hum Mutat 32: 1299–1308.
- 17. You Y, Deng J, Zheng J, Jiang L, Li N, et al. (2013) Functional polymorphisms in PIN1 promoter and esophageal carcinoma susceptibility in Chinese population. Mol Biol Rep 40: 829–838.
- 18. Segat L, Milanese M, Crovella S (2007) Pin1 promoter polymorphisms in hepatocellular carcinoma patients. Gastroenterology 132: 2618–2619; author reply 2619–2620.
- 19. Lu Y, Huang GL, Pu XX, He YX, Li BB, et al. (2012) Association between PIN1 promoter polymorphisms and risk of nasopharyngeal carcinoma. Mol Biol Rep
- 20. Cao WP, Ruan HY, Tang HL (2012) Association between polymophisms in prolyl isomerase Pin1 and the risk for laryngeal squamous cell carcinoma. Jiangsu Med J May 2012, Vol , No 38: 1067–1070.
- 21. Lu J, Hu Z, Wei S, Wang LE, Liu Z, et al. (2009) A novel functional variant (−842G>C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity. Carcinogenesis 30: 1717–1721.
- 22. Guo J, Jin M, Zhang M, Chen K (2012) A genetic variant in miR-196a2 increased digestive system cancer risks: a meta-analysis of 15 case-control studies. PLoS One 7: e30585.
- 23. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127: 820–826.
- 24. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188.
- 25. Whitehead A, Whitehead J (1991) A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med 10: 1665–1677.
- 26. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50: 1088–1101.
- 27. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
- 28. Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, et al. (2002) The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419: 853–857.
- 29. Zheng H, You H, Zhou XZ, Murray SA, Uchida T, et al. (2002) The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419: 849–853.
- 30. Mantovani F, Piazza S, Gostissa M, Strano S, Zacchi P, et al. (2004) Pin1 links the activities of c-Abl and p300 in regulating p73 function. Mol Cell 14: 625–636.
- 31. Chen SY, Wulf G, Zhou XZ, Rubin MA, Lu KP, et al. (2006) Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol Cell Biol 26: 929–939.
- 32. Li H, Wang S, Zhu T, Zhou J, Xu Q, et al. (2006) Pin1 contributes to cervical tumorigenesis by regulating cyclin D1 expression. Oncol Rep 16: 491–496.
- 33. Liou YC, Ryo A, Huang HK, Lu PJ, Bronson R, et al. (2002) Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc Natl Acad Sci U S A 99: 1335–1340.
- 34. Nakashima M, Meirmanov S, Naruke Y, Kondo H, Saenko V, et al. (2004) Cyclin D1 overexpression in thyroid tumours from a radio-contaminated area and its correlation with Pin1 and aberrant beta-catenin expression. J Pathol 202: 446–455.
- 35. Yeh ES, Lew BO, Means AR (2006) The loss of PIN1 deregulates cyclin E and sensitizes mouse embryo fibroblasts to genomic instability. J Biol Chem 281: 241–251.
- 36. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, et al. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17: 215–224.
- 37. Lam PB, Burga LN, Wu BP, Hofstatter EW, Lu KP, et al. (2008) Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol Cancer 7: 91.
- 38. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, et al. (2004) A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 6: 308–318.
- 39. Atkinson GP, Nozell SE, Harrison DK, Stonecypher MS, Chen D, et al. (2009) The prolyl isomerase Pin1 regulates the NF-kappaB signaling pathway and interleukin-8 expression in glioblastoma. Oncogene 28: 3735–3745.
- 40. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, et al. (2003) Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 63: 196–206.
- 41. Fukuchi M, Fukai Y, Kimura H, Sohda M, Miyazaki T, et al. (2006) Prolyl isomerase Pin1 expression predicts prognosis in patients with esophageal squamous cell carcinoma and correlates with cyclinD1 expression. Int J Oncol 29: 329–334.
- 42. Wang F, Ma YL, Zhang P, Yang JJ, Chen HQ, et al. (2012) A genetic variant in microRNA-196a2 is associated with increased cancer risk: a meta-analysis. Mol Biol Rep 39: 269–275.
- 43. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4: 45–61.
- 44. Dick DM (2011) Gene-environment interaction in psychological traits and disorders. Annu Rev Clin Psychol 7: 383–409.