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

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.

Telomere and Telomerase-Associated Proteins in Endometrial Carcinogenesis and Cancer-Associated Survival

“…TERRAs have been seen to be significantly altered in EC [ 9 ] and shelterin proteins TERF1/2 are known to interact with TERRA [ 8 ]. Thus, we also selected shelterin proteins TERF1/2 for examination.…”

“…However, TERF1 is associated with the telomere complex and the protection of telomere length. Despite high telomerase activity, EC cells have been reported to possess shorter telomeres [ 9 ] and since TERF1 imposes a negative feedback on telomerase activity [ 30 , 31 ], we can speculate that the observed loss of this protein may be beneficial for maintaining high telomerase activity in EC cells. Survival analyses for TERF1 data were non-significant, and predictable positive correlations were seen with structurally related proteins TERF2 and TERF2IP.…”

“…qPCR was conducted as previously described [ 9 , 44 , 74 ]. Briefly, total RNA from tissue samples and cultured cell lines were extracted using PureLink RNA mini kit (Invitrogen by ThermoFisher Scientific, Loughborough, UK) according to the manufacturer’s instructions.…”

“…The telomere DNA sequence has a guanosine rich 3′ overhang which may also act to protect the chromosome from degradation [ 6 , 7 ] ( Figure 1 ). Telomeres are transcribed as long non-coding RNAs called TERRAs (TElomeric Repeat containing RNA), which participate in a variety of cellular regulatory functions [ 8 , 9 ]. With normal cell division, there is loss of telomeric DNA and attrition of the telomere, resulting in an end replication problem [ 10 ].…”

Telomere Targeting Approaches in Cancer: Over the Length Maintenance.

“…TRF1 and POT1 amplification and TRF2-RAP1-TPP1 co-amplification/deletion were found associated with cancer progression defining broad molecular signatures linked to several intracellular pathways involved in oncogenesis [45]. Data collected in endometrial cancer patients suggest instead an inverse correlation between TERRA expression and cancer progression [46]. generating transcription/translation conflicts.…”