The PTENP1 Pseudogene, Unlike the PTEN Gene, Is Methylated in Normal Endometrium, As Well As in Endometrial Hyperplasias and Carcinomas in Middle-Aged and Elderly Females

Abstract

The tumor suppressor PTEN controls multiple cellular functions, including cell cycle, apoptosis, senescence, transcription, and mRNA translation of numerous genes. In tumor cells, PTEN is frequently inactivated by genetic mutations and epimutations. The aim of this study was to investigate the methylation patterns of the PTEN gene and its pseudogene PTENP1 as potential genetic markers of endometrial hyperplasia (EH) and endometrial carcinoma (EC). Methylation of the 5-terminal regions of the PTEN and PTENP1 sequences was studied using methyl-sensitive PCR of genomic DNA isolated from 57 cancer, 43 endometrial hyperplasia, and normal tissue samples of 24 females aged 17-34 years and 19 females aged 45-65 years, as well as 20 peripheral venous blood samples of EC patients. None of the analyzed DNA samples carried a methylated PTEN gene. On the contrary, the PTENP1 pseudogene was methylated in all analyzed tissues, except for the peripheral blood. Comparison of PTENP1 methylation rates revealed no differences between the EC and EH groups (0.80 p 0.50). In all these groups, the methylation level was high (71-77% in patients vs. 58% in controls). Differences in PTENP1 methylation rates between normal endometrium in young (4%) and middle-aged and elderly (58%) females were significant (p 0.001). These findings suggest that PTENP1 pseudogene methylation may reflect age-related changes in the body and is not directly related to the endometrium pathology under study. It is assumed that, depending on the influence of a methylated PTENP1 pseudogene on PTEN gene expression, the pseudogene methylation may protect against the development of EC and/or serve as a marker of a precancerous condition of endometrial cells.

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

“…For instance, Du et al (2019) revealed that DUXAP8 upregulation in colorectal cancer was induced by STAT3; SIX2 played a positive role in CYP4Z2P expression in breast cancer . Some studies demonstrated that the methylation level of pseudogenes linked to the alteration of pseudogene-derived lncRNAs' expression (Kovalenko et al, 2013(Kovalenko et al, , 2018. Hormone and hormone receptor correlated with mis-regulation of pseudogene-derived lncRNAs.…”

Methylation of the PTENP1 pseudogene as potential epigenetic marker of age-related changes in human endometrium

“…In our previous study we demonstrated the absence of a correlation of PTENP1 methylation with the clinical characteristics of endometrial cancer (disease stage, FIGO grade, myometrium invasion) [ 23 ]. Here, we found higher frequency of PTENP1 methylation in patients over 45 years with EH and EC, which did not differ from methylation of NE in women of matched age groups.…”

“…The antisense transcript of PTENP1 pseudogene interacts with the promoter region of PTEN gene and inhibits its expression [ 22 ]. In our previous study we have not detected methylation of the PTEN minimal promoter region in endometrial cancer [ 23 ]. However, methylation of the 5'-terminal region of PTENP1 was observed.…”

Prognostic Analysis of PTEN Mutation in Endometrial Carcinoma

“…DNA sequencing and mutation analysis of TCGA EC data identi ed some prominently mutated genes: p53 10 , PTEN 11 and PIK3CA 12 . Among them, PTEN was signi cantly associated with the prognosis of EC 13 . However, these analyses did not provide an in-depth analysis of the prognosis of PTEN mutation-related characteristic genes on EC.…”