Epidemiological study and cervical cancer screening by pap smear in Delhi

To study the epidemiological characteristics of cervical cancer in Delhi. With this background we intended to find out the epidemiological characteristics associated with cervical cancer and screening of participants by pap smear. Pap smear were conducted and detail socio demographic records were obtained and details of demographic characteristic and other risk factors were noted. A total of 98 participants were evaluated of which 76.5% of women were in the age group of 30-40 years, By educational status about 46.94% were illiterate. Forty seven percent of the study subjects had a history of abortion. More than half of the study subjects (60.5%) had history of induced abortion in non-licensed clinics (70%). More than half of the study subjects (62%) were sexually active before 15 years of age and almost all the study subjects were sexually active by 18 years of age. Almost one third of the subjects did not Two third of the subjects (72%) among those using contraceptives used IUD and Tubal ligation use any contraceptive method. Thirty eight percent of the study subjects had normal cervix on per speculum examination and 40 % had cervical erosion.8.2% participants tested positive to pap smear.

Genome-Wide Analysis of DNA Methylation Dynamics During Cervical Carcinogenesis

Background Cervical cancer is the second most common gynaecological tumor of women worldwide, however, the molecular mechanism for the cervical carcinogenesis remains elusive. Current study provides a series of genome-wide DNA methylation blueprints of normal cervix and cervical cancers using Whole Genome Bisulfite Sequencing. Results DNA methylation dynamic alternations during cervical carcinogenesis were focused on the signal pathway of TGF-beta and epidermal growth factor, which could be used to monitor the treatment response and Tumorigenesis. Transcription factor of E2F6, MBD2 and STAT3 were interfered by aberrant methylation in cancer development. Furthermore, those identified novel methylation markers for the risk of progression along the spectrum of lesion grades could provide new insights into the prevention and treatment. Conclusion DNA methylation signature in cervical cancers can serve as valuable epigenetic markers to guide the clinical treatment. The epigenetic features detected in this study can be exploited for previously unidentified biomarker and prognostic marker development.

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

Background: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. Methods: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme’s relationship to several clinicopathological features and survival was explored. Results: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p < 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p < 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p < 0.05). Conclusions: CYP4Z1 expression is associated with cervical cancer patients’ survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.

TPP1 Regulates hTERT Expression and Predicts Early Malignant Event and Prognosis of Cervical Cancer

Background: Cervical cancer is one of the most common deadly cancer in women worldwide. However, identifying specific biomarkers is still needed. Telomere-binding protein 1 (TPP1) is vital to telomerase activity. However, the role of TPP1 in cervical cancer and its association with human telomerase reverse transcriptase (hTERT) is unclear.This study aimed at exploring the role of telomere-binding protein 1 (TPP1) in cervical cancer development and progression, and potential mechanisms.Methods: Tissue samples from a total of 274 participants were enrolled for the evaluation of protein expression,156 of whom diagnosed withcervical cancers, 102 with cervical intraepithelial neoplasia (CIN) and 16 with normal cervix. In addition, in vitro cellular models with cervical cancer cell lines Hela, Siha, and C33a were transfected by TPP1-siRNAand protein expression of TPP1 and hTERT were assessed. Results: Compared with normal cervix, TPP1 expression was significantly higher in CIN-III and cervical cancers (P<0.001 for both). High expression of TPP1alone (Plog-rank=0.047)andhigh co-expression of TPP1/hTERT (Plog-rank=0.005)weresignificantly associated with worse survival of cervical cancer patients.After adjusting for well-known prognosis factors, hazard ratio was 2.03(95% confidence interval [CI] 0.99-4.16)for high expression of TPP1 and 2.01(95% CI 1.10-3.67) for high co-expression of TPP1/hTERT. TPP1 and hTERT expressions were positively correlated atall levels of cervical lesions (r=0.524, P<0.001). Knockdown of TPP1 decreased hTERT mRNA and protein expression.Conclusions: High expression of TPP1 might be an early event during cervical cancer development and could be served as apotential prognosis biomarker, especially when used together with hTERT. TPP1 might regulate hTERT expression with detailed underlying mechanisms warrant further investigation.

Wnt3a/β-Catenin/CBP Activation in the Progression of Cervical Intraepithelial Neoplasia

Piwil2 reprograms HPV-infected reserve cells in the cervix into tumor-initiated cells (TICs) and upregulates Wnt3a expression sequentially, which leads to cervical intraepithelial neoplasia (CIN) and ultimately squamous cell carcinoma (SCC). However, little is known regarding Wnt signaling in the maintenance of TIC stemness during the progression of cervical lesions. We herein investigated the expression of canonical Wnt3a signaling and related genes by microarray data set analysis and immunohistochemical (IHC) staining of samples obtained by biopsy of normal cervix, low- and high-grade CIN, and invasive SCC tissue. Array data analyzed by GEO2R showed higher expression levels of Wnt signaling and their target genes, significant upregulation of stemness-associated markers, and notably downregulated cell differentiation markers in CIN and SCC tissues compared with those in the normal cervix tissue. Further, Gene Set Enrichment Analysis (GSEA) revealed that Wnt pathway-related genes significantly enriched in SCC. IHC staining showed gradually increased immunoreactivity score of Wnt3a and CBP and notable translocation of β-catenin from the membrane to the cytoplasm and nucleus during the lesion progression. The intensity and proportion of P16, Ki67 and CK17 staining also increased with the progression of cervical lesions, whereas minimal to negative Involucrin expression was observed in CIN2/3 and SCC. Therefore, canonical Wnt signaling may contribute to the progression of CIN to SCC and may be a potential therapeutic target.

ST3Gal IV Mediates the Growth and Proliferation of Cervical Cancer Cells In Vitro and In Vivo Via the Notch/p21/CDKs Pathway

ST3Gal IV is one of the principal sialyltransferases responsible for the biosynthesis of α2, 3-sialic acid to the termini N-glycans or O-glycans of glycoproteins and glycolipids. It has been reported that ST3Gal IV expression is associated with gastric carcinoma, pancreatic adenocarcinoma and breast cancer. While the expression and functions of ST3Gal IV in cervical cancer are still poorly understood. In this study, we found that ST3Gal IV was downregulated in human cervical cancer tissues compared to normal cervix tissues, and ST3Gal IV expression was negatively associated with the pathological grade of cervical cancer. ST3Gal IV upregulation inhibited the growth and proliferation of cervical cancer HeLa and SiHa cells in vitro and in vivo. Furthermore, ST3Gal IV overexpression enhanced the expression of several Notch pathway components such as Jagged1, Notch1, Hes1 and Hey1, while cell cycle protein expression like Cyclin D1, Cyclin E1, CDK2 and CDK4 were decreased. These results indicate that expression of ST3Gal IV is reduced in cervical cancer and plays a negative role in cell proliferation via Notch/p21/CDKs signaling pathway. Thus, sialyltransferase ST3Gal IV might be a target for the diagnosis and therapy of cervical cancer.

High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC (n = 31) and normal cervix (n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (&gt;10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins.

Transcriptome analysis uncovers the diagnostic value of miR-192-5p/HNF1A-AS1/VIL1 panel in cervical adenocarcinoma

Despite the fact that the incidence of cervical squamous cell carcinoma has decreased, there is an increase in the incidence of cervical adenocarcinoma. However, our knowledge on cervical adenocarcinoma is largely unclear. Transcriptome sequencing was conducted to compare 4 cervical adenocarcinoma tissue samples with 4 normal cervical tissue samples. mRNA, lncRNA, and miRNA signatures were identified to discriminate cervical adenocarcinoma from normal cervix. The expression of VIL1, HNF1A-AS1, MIR194-2HG, SSTR5-AS1, miR-192-5p, and miR-194-5p in adenocarcinoma were statistically significantly higher than that in normal control samples. The Receiver Operating Characteristic (ROC) curve analysis indicated that combination of miR-192-5p, HNF1A-AS1, and VIL1 yielded a better performance (AUC = 0.911) than any single molecule -and could serve as potential biomarkers for cervical adenocarcinoma. Of note, the combination model also gave better performance than TCT test for cervical adenocarcinoma diagnosis. However, there was no correlation between miR-192-5p or HNF1A-AS1 and HPV16/18 E6 or E7. VIL1 was weakly correlated with HPV18 E7 expression. In summary, our study has identified miR-192-5p/HNF1A-AS1/VIL1 panel that accurately discriminates adenocarcinoma from normal cervix. Detection of this panel may provide considerable clinical value in the diagnosis of cervical adenocarcinoma.

Establishment of multifactor predictive models for the occurrence and progression of cervical intraepithelial neoplasia

Background To study the risk factors involved in the occurrence and progression of cervical intraepithelial neoplasia (CIN) and to establish predictive models. Methods Genemania was used to build a gene network. Then, the core gene-related pathways associated with the occurrence and progression of CIN were screened in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments were performed to verify the differential expression of the identified genes in different tissues. R language was used for predictive model establishment. Results A total of 10 genes were investigated in this study. A total of 30 cases of cervical squamous cell cancer (SCC), 52 cases of CIN and 38 cases of normal cervix were enrolled. Compared to CIN cases, the age of patients in the SCC group was older, the number of parities was greater, and the percentage of patients diagnosed with CINII+ by TCT was higher. The expression of TGFBR2, CSKN1A1, PRKCI and CTBP2 was significantly higher in the SCC groups. Compared to patients with normal cervix tissue, the percentage of patients who were HPV positive and were diagnosed with CINII+ by TCT was significantly higher. FOXO1 expression was significantly higher in CIN tissue, but TGFBR2 and CTBP2 expression was significantly lower in CIN tissue. The significantly different genes and clinical factors were included in the models. Conclusions Combination of clinical and significant genes to establish the random forest models can provide references to predict the occurrence and progression of CIN.