Functional polymorphism of PIN1 rs2233679 is associated with the progression of CIN to early cervical cancer in Hunan Chinese.

OBJECTIVE: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) involves alteration of the structure, function, intracellular localization and/or stability of the phosphorylated protein on serine or threonine residues which relates to inflammation and tumorigenesis. Association between PIN1 promoter polymorphisms and cancer risk were reported in several cancers. We intend to study the relationship between the polymorphism of PIN1 promoter and cervical cancer initiation and development. MATERIALS AND METHODS: We genotyped two common single nucleotide polymorphisms (SNPs) (rs2233678 and rs2233679) in the promoter of the PIN1 gene in healthy controls, patients with CIN or cervical cancer. We used polymerase chain reaction and DNA sequencing methods to analyze these two SNPs in 179 patients and 223 healthy controls. Luciferase activity assay was used to detect PIN1 expression driven by the rs2233679. RESULTS: The results revealed that the carriers of rs2233679 genotypes CT/TT had a significantly increased risk of cervical cancer in patients with CIN compared with genotype CC (odds ration [OR] = 2.924, 95% confidence interval [CI] = 1.093-7.819, P = 0.033). Luciferase activity assay results revealed that PIN1 expression driven by the rs2233679 genotype TT was higher than the genotype CC (P < 0.05). On the other hand, no significant correlation between the healthy controls and patients was found for PIN1 rs2233678 which showed that rs2233678 genotypes CG/GG is 95% in healthy controls and 100% in patients. CONCLUSION: PIN1 rs2233679 genotype CT/TT may be a risk factor of early cervical cancer compared with genotype CC in Hunan populations. Our findings suggest that PIN1 rs2233679 genotype CT/TT might involve in the progression of the precancerous stage developing to early cancer by enhancing PIN1 expression.

Epigenetic silencing of Rab39a promotes epithelial to mesenchymal transition of cervical cancer through AKT signaling.

The objective of this study was to investigate the functional role of Rab39a in human cervical cancer (CC) and the underlying molecular mechanisms. We first measured Rab39a mRNA expression in CC tissues and paired non-tumor tissues by quantitative real-time PCR (QRT-PCR). Overall survival of CC patients with different mRNA levels of Rab39a in The Cancer Genome Atlas (TCGA) database was assessed by Kaplan-Meier survival curves analysis. Next methylation-specific PCR (MSP) was performed to determine the expression mechanism of Rab39a. Then cell proliferation, migration and invasion of Rab39a-transfected or mock-transfected cervical cancer cells were determined by CCK-8, flow cytometry, wound healing, transwell migration and invasion assays, respectively. Finally, the molecular mechanism by which Rab39a modulated CC cell epithelial-mesenchymal transition (EMT) was explored. It was found that Rab39a mRNA was significantly down-regulated in the high-risk patients compared to the low-risk patients (p = 0.0054). Six of seven cancer tissues with lymph node metastasis express low Rab39a mRNA compared to the surrounding non-tumor tissues. Cervical cancer patients with low level of Rab39a were showed a poorly clinical outcome (p = 0.004). Loss of Rab39a expression in cervical cancer tissues was associated with the aberrant DNA methylation in the promoter of Rab39a gene. Disrupted Rab39a expression in cervical cancer cells could be restored after treatment with the demethylated agent 5-Aza-2'-deoxycytidine. Furthermore, it was found that Rab39a hardly influenced cell growth but significantly suppressed cell migration, invasion and EMT process. Rab39a exerted its potential suppressor functions through inhibiting AKT phosphorylation. The inhibition effects of Rab39a could be blocked by AKT pathway inhibitor. Collectively, our data shows that Rab39a is a potential epigenetic silenced tumor suppressor inhibiting cancer invasion and migration through modulating the AKT signaling.

[Analysis of human papillomavirus infection in 16 320 patients from gynecologic clinic].

OBJECTIVE: To evaluate the genital human papillomavirus (HPV) infection in patients from gynecology clinic, and to investigate the association of persistent HPV infection with cervical lesions. METHODS: From January, 2009 to December, 2013, clinical data of 16 320 patients in Third Xiangya Hospital were collected. A retrospective analysis was carried out to evaluate the overall prevalence of HPV infection. The prevalence of HPV infection in different ages and subtypes were compared. The prevalence of persistent HPV infection and results of cervical cytology were analyzed. RESULTS: The overall HPV prevalence was 26.54%. The lowest overall and high-risk HPV prevalence were found in women at the age of 30-39 years old (P<0.05); the highest ones were found at the age of over 60 years old, with significant difference among the aged groups (P<0.05). There was no significant difference in low-risk HPV prevalence among the aged groups (P=0.693). The clearance rate of HPV was 87.65% one year later. There was no significant difference in high-risk and low-risk HPV infection between the non-persistent positive group and the persistent positive group (P=0.545), but the difference in single and multiple subtypes infection between these 2 groups was significant (P<0.05). In the persistent positive group, the most common genotypes were HPV 16, 52, 58, CP8304, and 33. The incidence of ASC-US, HSIL or SCC was significantly increased in the persistent positive group. CONCLUSION: Persistent HPV infection mainly consists of multiple and high-risk HPV infection. It is necessary to focus on the prevention of HPV 16, 52 and 58 persistent infection in our region.

Association Study of Single-Nucleotide Polymorphisms of STAT2/STAT3/IFN-γ Genes in Cervical Cancer in Southern Chinese Han Women.

OBJECTIVE: Interferon-γ (IFN-γ) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-γ and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-γ with cervical cancer susceptibility in Chinese Han women in Hunan province. MATERIALS AND METHODS: Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction-restriction enzyme (PCR-RE) analysis. IFN-γ genotyping was detected by PCR-amplification of specific allele (PASA). RESULTS: For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-γ +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. CONCLUSION: These results suggest that polymorphisms in STAT2, STAT3 and IFN-γ genes are not likely to be strong predictors of cervical cancer in Han women in southern China.