PIN1 promoter polymorphism (−842 G>C) contributes to a decreased risk of cancer: Evidence from meta-analysis

Abstract

Peptidyl-prolylcis-trans isomerase NIMA-interacting 1 (encoded by the PIN1 gene) regulates the conformation of proline-directed phosphorylation sites and is important in the etiology of cancer. Since the identification of a functional polymorphism of PIN1, (−842 G>C; rs2233678), in the PIN1 promoter region, numerous studies have evaluated the association between the PIN1 promoter polymorphism (−842 G>C) and cancer risk. However, the available results are inconclusive. To derive a more precise estimation, a meta-analysis of seven previous case-control studies was performed, which included 4,524 cases exhibiting different tumor types and 4,561 control subjects. The published literature was retrieved from PubMed and EMBASE. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Overall, the results of the present study demonstrated that individuals carrying the variant C allele (G/C and C/C) were associated with a significantly decreased cancer risk (OR, 0.75; 95% CI, 0.62–0.90 for GC vs. GG; OR, 0.75; 95% CI, 0.64–0.88 for GC/CC vs. GG). In further stratified analyses, a decreased cancer risk was observed in the following subgroups: Breast and lung cancer patients, Asian individuals, and in studies with a sample size >500. The results indicated that the PIN1 promoter polymorphism (−842 G>C; rs2233678) contributes to a decreased risk of cancer via attenuating the transcriptional activity.

Oncogenic Hijacking of the PIN1 Signaling Network

“…Indeed, neurodegeneration is mainly associated to low levels or activity of PIN1, while on the contrary overexpression of PIN1 is prevalently found in cancers and inflammatory diseases. Of note, the rs2233678 polymorphism in the human PIN1 promoter is associated to decreased gene expression and to a lower risk of breast (50) and lung (51) cancer incidence, while the rs2287839 polymorphism hampers suppression of PIN1 transcription by the AP4 transcription factor and correlates with delayed onset of Alzheimer's disease (52).…”

“…Indeed, PIN1 is transcriptionally regulated by E2F in response to growth factors (67, 70) and by NOTCH1/4 activation in cancer (17, 58). On the contrary, the PIN1 rs2233678 (−842G>C) promoter polymorphism is associated to a reduced expression of the gene and a reduced risk of cancer (50, 51). PIN1 is also negatively controlled by tumor-suppressor microRNAs, such as miR-200b (160), a promoter of anoikis, miR-200c (140) that restrains EMT in breast cancer, and by miR-296-5p in prostate cancer (161), and some others only recently identified (20).…”

Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease

“…Inhibition of Pin1 in cancer cells leads either to apoptosis or reversal of transformation [3, 72], and Pin1-deficient mice are almost completely resistant to breast cancers induced by over-expression of the oncogene Ras or Neu [73], or by deletion of tumor suppressor p53 [74]. Moreover, a functional polymorphism in the Pin1 promoter that reduces Pin1 expression is associated with reduced risk for multiple cancers, further supporting the tumor-promoting activity of Pin1 [75]. Overexpression of Pin1 may also promote oncogenesis by increasing the levels of functional tau and APP.…”