Dataset Information

?Np63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

ABSTRACT: p63 is a transcription factor p53 family. Two major isoforms of p63, TAp63 with transactivation (TA) domain and ?Np63 with truncated TA domain, have been reported to play opposing roles either in tumor suppression or oncogenic function. Little is known about the association of these two isoforms of p63 in the carcinogenesis of cervical cancer. In this study, the mRNA expression levels of TAp63 and ?Np63 in 40 normal, 30 low-grade squamous intraepithelial lesions (LSIL), 38 high-grade squamous intraepithelial lesions (HSIL), and 52 cervical cancer formalin-fixed paraffin-embedded tissues were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). We analyzed the association between the ?Np63 and ?N/TAp63 mRNA expression ratio and clinicopathological parameters and compared disease-specific survival of each ?Np63 mRNA expression and ?N/TAp63 mRNA expression ratio. The ?N/TAp63 mRNA expression ratio in cervical cancer showed higher sensitivity than the mRNA expression levels of ?Np63 (52.0% vs 44.2%). The level of ?N/TAp63 mRNA expression ratio in precancerous LSIL and HSIL was higher than in normal tissues (P = 0.01 and P = 0.003) and lower than in cervical cancer tissues (P = 0.03 and P = 0.02). Besides, the positive ?N/TAp63 mRNA expression ratio was associated with bulky tumor size and high expression of Ki-67, the proliferation marker, in cervical cancer (P = 0.04 and P = 0.02). The cervical cancer patients with the positive ?N/TAp63 mRNA expression ratio showed worse survival compared to those who with the negative expression ratio of ?N/TAp63 (HR = 5.7, 95% CI: 1.6-19.9). In conclusion, the balance of TAp63 and ?Np63 is closely related to the carcinogenesis of cervical cancer. The ?N/TAp63 mRNA expression ratio could be useful as a diagnostic and prognostic marker of cervical cancer.

SUBMITTER: Park S

PROVIDER: S-EPMC6459502 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ΔNp63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

Park Sunyoung S Lee Suji S Kim Jungho J Kim Geehyuk G Park Kwang Hwa KH Kim Tae Ue TU Chung Dawn D Lee Hyeyoung H

PloS one 20190411 4

p63 is a transcription factor p53 family. Two major isoforms of p63, TAp63 with transactivation (TA) domain and ΔNp63 with truncated TA domain, have been reported to play opposing roles either in tumor suppression or oncogenic function. Little is known about the association of these two isoforms of p63 in the carcinogenesis of cervical cancer. In this study, the mRNA expression levels of TAp63 and ΔNp63 in 40 normal, 30 low-grade squamous intraepithelial lesions (LSIL), 38 high-grade squamous in ...[more]

PMID: 30973901

Similar Datasets

Project description:The TP63 gene encodes two major protein variants; TAp63 contains a p53-like transcription domain and consequently has tumor suppressor activities whereas ΔNp63 lacks this domain and acts as an oncogene. The two variants show distinct expression patterns in normal tissues and tumors, with lymphocytes and lymphomas/leukemias expressing TAp63, and basal epithelial cells and some carcinomas expressing high levels of ΔNp63, most notably squamous cell carcinomas (SCC). Whilst the transcriptional functions of TAp63 and ΔNp63 isoforms are known, the mechanisms involved in their regulation are poorly understood. Using squamous epithelial cells that contain high levels of ΔNp63 and low/undetectable TAp63, the DNA demethylating agent decitabine (5-aza-2'-deoxycytidine, 5-dAza) caused a dose-dependent increase in TAp63, with a simultaneous reduction in ΔNp63, indicating DNA methylation-dependent regulation at the isoform-specific promoters. The basal cytokeratin KRT5, a direct ΔNp63 transcriptional target, was also reduced, confirming functional alteration of p63 activity after DNA demethylation. We also showed high level methylation of three CpG sites in the TAP63 promoter in these cells, which was reduced by decitabine. DNMT1 depletion using inducible shRNAs partially replicated these effects, including an increase in the ratio of TAP63:ΔNP63 mRNAs, a reduction in ΔNp63 protein and reduced KRT5 mRNA levels. Finally, high DNA methylation levels were found at the TAP63 promoter in clinical SCC samples and matched normal tissues. We conclude that DNA methylation at the TAP63 promoter normally silences transcription in squamous epithelial cells, indicating DNA methylation as a therapeutic approach to induce this tumor suppressor in cancer. That decitabine simultaneously reduced the oncogenic activity of ΔNp63 provides a "double whammy" for SCC and other p63-positive carcinomas. Whilst a variety of mechanisms may be involved in producing the opposite effects of DNA demethylation on TAp63 and ΔNp63, we propose an "either or" mechanism in which TAP63 transcription physically interferes with the ability to initiate transcription from the downstream ΔNP63 promoter on the same DNA strand. This mechanism can explain the observed inverse expression of p63 isoforms in normal cells and cancer.

Project description:BackgroundGlobally, the incidence of cervical cancer (CC) is highest among all tumors of the female reproductive system. Numerous studies have shown that the expression level of microRNA (miRNA) is highly correlated with cancer. This study aimed to establish a molecular prognostic model of CC based on miRNAs in order to provide more individualized treatment to CC patients.MethodsHuman tissues were selected from the Cancer Hospital (Chinese Academy of Medical Sciences and Peking Union Medical College) for miRNA gene sequencing. CC transcriptome expression and clinical data were downloaded from The Cancer Genome Atlas (TCGA). We distinguished between common differentially expressed miRNAs of CC miRNA-seq and TCGA-CC. To obtain a molecular prognostic model, R package was used to perform univariate Cox proportional hazard regression and least absolute shrinkage and selection operator (LASSO) Cox regression for common differentially-expressed miRNAs. Next, the model performance was evaluated by survival analysis, receiver operating characteristic (ROC) curve analysis, as well as univariate and multivariate analyses in the TCGA-CC dataset. Quantitative Real-time polymerase chain reaction (qPCR) detection was to verify the expression changes of miRNA. Transwell was used to verify the role of molecules in CC cell migration and invasion.ResultsThirty-nine miRNAs were distinguished in TCGA-CC and CC miRNA-seq, LASSO regression analysis to obtain the risk model (risk score =-0.310× expression of hsa-miR-142-3p +0.439× expression of hsa-miR-100-3p). The survival analysis, ROC curve analysis, patient risk assessment, and univariate and multivariate analyses showed that the risk score model had good predictive ability in assessing patient survival (P<0.01), risk of death, and independent prognosis (P<0.01). qPCR detection of clinical samples and cells showed that the expression of hsa-miR-142-3p and hsa-miR-100-3p was consistent with the results of the database analysis. The Transwell results indicated that miR-142-3p is an inhibiting factor and miR-100-3p serves as a promoting factor in CC cell migration and invasion.ConclusionsTwelve miRNA-seq and TCGA-CC tissues were used to build a prognostic model for CC. We have obtained a two-miRNA risk score model. Our results provide a new strategy for the individualized diagnosis and treatment of CC.

Dataset Information

?Np63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

Publications

ΔNp63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets