Human Endometrial Carcinogenesis Is Associated with Significant Reduction in Long Non-Coding RNA, TERRA.

Meera Adishesh,Josephine Drury,Lucy Button,Areege M Kamal,Dharani K Hapangama,Rafah Alnafakh,S Bridget Decruze,Rhiannon E Jones,John Kirwan,Shannon Simon,Gabriele Saretzki,Duncan M Baird

doi:10.3390/ijms21228686

Abstract

Telomeres are transcribed as long non-coding RNAs called TERRAs (Telomeric repeat containing RNA) that participate in a variety of cellular regulatory functions. High telomerase activity (TA) is associated with endometrial cancer (EC). This study aimed to examine the levels of three TERRAs, transcribed at chromosomes 1q-2q-4q-10q-13q-22q, 16p and 20q in healthy (n = 23) and pathological (n = 24) human endometrium and to examine their association with cellular proliferation, TA and telomere lengths. EC samples demonstrated significantly reduced levels of TERRAs for Chromosome 16p (Ch-16p) (p < 0.002) and Chromosome 20q (Ch-20q) (p = 0.0006), when compared with the postmenopausal samples. No significant correlation was found between TERRA levels and TA but both Ch-16p and Ch-20q TERRA levels negatively correlated with the proliferative marker Ki67 (r = −0.35, p = 0.03 and r = −0.42, p = 0.01 respectively). Evaluation of single telomere length analysis (STELA) at XpYp telomeres demonstrated a significant shortening in EC samples when compared with healthy tissues (p = 0.002). We detected TERRAs in healthy human endometrium and observed altered individual TERRA-specific levels in malignant endometrium. The negative correlation of TERRAs with cellular proliferation along with their significant reduction in EC may suggest a role for TERRAs in carcinogenesis and thus future research should explore TERRAs as potential therapeutic targets in EC.

Highlights

Endometrial cancer (EC) is the most common gynecological malignancy in the western world with an increasing incidence due to the rise in obesity and longevity [1]
We examined the immunoreactivity of two shelterin proteins known to regulate telomeric repeat-containing RNA (TERRA), TRF1 and TRF2, in the same EC samples to examine their possible correlation with the corresponding TERRA levels
Chromosome 16p (Ch-16p) (p = 0.002) and Chromosome 20q (Ch-20q) (p = 0.0006) TERRAs were significantly reduced in EC samples when compared with the healthy postmenopausal endometrium (Figure 1B,C)

Summary

Introduction

Endometrial cancer (EC) is the most common gynecological malignancy in the western world with an increasing incidence due to the rise in obesity and longevity [1]. This increase in frequency of EC is accompanied by a concomitant rise in cancer-associated mortality, a trend that is expected to continue for the few decades [2]. This is a contrasting and concerning statistic, compared with many other cancers, where the incidence of new cancers remains stable and cancer-associated mortality is decreasing.

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Results