Expression of Cellular and Extracellular TERRA, TERC and TERT in Hepatocellular Carcinoma

Manganelli, Michele; Grossi, Ilaria; Corsi, Jessica; D’Agostino, Vito; Juríková, Katarína; Cusanelli, Emilio; Molfino, Sarah; Portolani, Nazario; Salvi, Alessandro; Petro, Giuseppina De

doi:10.3390/ijms23116183

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…We also found an inverse correlation between TERT and TERRA expression levels after hit 17 treatments, being TERRA up-regulated and TERT down-regulated, and in addition, by mass spectroscopy, we excluded direct binding to the TERT promoter by hit 17. This trend is in accordance with results from previous published studies [ 45 , 46 ]. In in vivo experiments, we found that systemically administered hit 17 exerted a significant anti-MM activity as demonstrated by tumor shrinkage associated with a strong reduction of proliferative Ki67 index.…”

Section: Discussionsupporting

confidence: 94%

TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma

Scionti

Juli

Rocca

et al. 2023

J Exp Clin Cancer Res

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Background Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability, and telomere dysfunction is an important cause of acquired genomic alterations. Telomeric repeat-containing RNA (TERRA) transcripts are long non-coding RNAs involved in telomere stability through the interaction with shelterin complex. Dysregulation of TERRAs has been reported across several cancer types. We recently identified a small molecule, hit 17, which stabilizes the secondary structure of TERRA. In this study, we investigated in vitro and in vivo anti-MM activities of hit 17. Methods Anti-proliferative activity of hit 17 was evaluated in different MM cell lines by cell proliferation assay, and the apoptotic process was analyzed by flow cytometry. Gene and protein expressions were detected by RT-qPCR and western blotting, respectively. Microarray analysis was used to analyze the transcriptome profile. The effect of hit 17 on telomeric structure was evaluated by chromatin immunoprecipitation. Further evaluation in vivo was proceeded upon NCI-H929 and AMO-1 xenograft models. Results TERRA G4 stabilization induced in vitro dissociation of telomeric repeat‐binding factor 2 (TRF2) from telomeres leading to the activation of ATM-dependent DNA damage response, cell cycle arrest, proliferation block, and apoptotic death in MM cell lines. In addition, up-regulation of TERRA transcription was observed upon DNA damage and TRF2 loss. Transcriptome analysis followed by gene set enrichment analysis (GSEA) confirmed the involvement of the above-mentioned processes and other pathways such as E2F, MYC, oxidative phosphorylation, and DNA repair genes as early events following hit 17-induced TERRA stabilization. Moreover, hit 17 exerted anti-tumor activity against MM xenograft models. Conclusion Our findings provide evidence that targeting TERRA by hit 17 could represent a promising strategy for a novel therapeutic approach to MM.

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Section: Discussionsupporting

confidence: 94%

TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma

Scionti

Juli

Rocca

et al. 2023

J Exp Clin Cancer Res

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“…The MS-ddPCR assays were optimized according to the principles of MS-PCR ( 34 , 35 ) to detect the methylation levels of SEPT9 and SHOX2 . MS-ddPCR experiments were performed using QX200™ ddPCR System (Bio-Rad Laboraties, Inc.) ( 36 , 37 ). The MS-ddPCR reaction mix consisted of the 2X ddPCR Supermix for Probes, and locus-specific primers and probes.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of DNA methylation levels of SEPT9 and SHOX2 in plasma of patients with head and neck squamous cell carcinoma using droplet digital PCR

Grossi,

Assoni,

Lorini

et al. 2024

Oncol Rep

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Head and neck squamous cell carcinoma (HNSCC) is the seventh most commonly diagnosed cancer globally. HNSCC develops from the mucosa of the oral cavity, pharynx and larynx. Methylation levels of septin 9 ( SEPT9 ) and short stature homeobox 2 ( SHOX2 ) genes in circulating cell-free DNA (ccfDNA) are considered epigenetic biomarkers and have shown predictive value in preliminary reports in HNSCC. Liquid biopsy is a non-invasive procedure that collects tumor-derived molecules, including ccfDNA. In the present study, a droplet digital PCR (ddPCR)-based assay was developed to detect DNA methylation levels of circulating SEPT9 and SHOX2 in the plasma of patients with HNSCC. The assay was first set up using commercial methylated and unmethylated DNA. The dynamic changes in the methylation levels of SEPT9 and SHOX2 were then quantified in 20 patients with HNSCC during follow-up. The results highlighted: i) The ability of the ddPCR-based assay to detect very low copies of methylated molecules; ii) the significant decrease in SEPT9 and SHOX2 methylation levels in the plasma of patients with HNSCC at the first time points of follow-up with respect to T 0 ; iii) a different trend of longitudinally DNA methylation variations in small groups of stratified patients. The absolute and precise quantification of SEPT9 and SHOX2 methylation levels in HNSCC may be useful for studies with translational potential.

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“…In HCC, both cellular and extracellular expression of TERRA are dysregulated. 42 This downregulation of TERRA considerably promotes HCC cell proliferation and metastasis by increasing telomerase activity and promoting telomere elongation. 43…”

Section: Telomere Biology and Hccmentioning

confidence: 99%

Telomerase, an Accomplice of RNA-induced Silencing Complex in Hepatocellular Carcinoma

Puttahanumantharayappa¹,

Shiragannavar²,

Gowda³

et al. 2023

Gene Expr

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Hepatocellular carcinoma (HCC) is one of the most lethal and widespread cancers in the human race. Despite its fatal attributes, there is only a limited understanding of the factors contributing to its pathogenesis at the cellular and molecular levels. Consequently, unraveling new facets involved in HCC progression is elemental for establishing novel targets and biomarkers for this disease. Over the last few years, emerging evidence signifies the role of RNA-induced silencing complex in mediating gene silencing and contributing to HCC. Recent studies also highlight the importance of human telomerase holoenzyme and its complex accessory proteins in the development of HCC. The current review encompasses the multifaceted roles of RNAinduced silencing complex and telomerase activity as well as their synergistic function in HCC.

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Expression of Cellular and Extracellular TERRA, TERC and TERT in Hepatocellular Carcinoma

Cited by 18 publications

References 38 publications

TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma

TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma

Evaluation of DNA methylation levels of SEPT9 and SHOX2 in plasma of patients with head and neck squamous cell carcinoma using droplet digital PCR

Telomerase, an Accomplice of RNA-induced Silencing Complex in Hepatocellular Carcinoma

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