The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

Tornesello, Maria Lina; Cerasuolo, Andrea; Starita, Noemy; Tornesello, Anna Lucia; Bonelli, Patrizia; Tuccillo, Franca Maria; Buonaguro, Luigi; Isaguliants, Maria; Buonaguro, Franco M.

doi:10.3390/cancers14215257

Cited by 9 publications

(5 citation statements)

References 169 publications

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“…Finally, telomere dysfunction-driven polyploidization is a universal source of tumor evolution that occurs continuously during neoplastic cell growth [ 94 ]. Oncoviruses deregulate telomerase activity and telomere length and promote cancer development [ 95 ]. Interestingly, HCMV activates telomerase [ 96 ], and favors the appearance of PGCCs which are considered as hallmarks of oncoviruses [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Polyploid giant cancer cells, cytokines and cytomegalovirus in breast cancer progression

2023

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Background Breast cancer is the most common cancer among women. Accumulated evidence over the past decades indicates a very high prevalence of human cytomegalovirus (HCMV) in breast cancer. High-risk HCMV strains possess a direct oncogenic effect displayed by cellular stress, polyploid giant cancer cells (PGCCs) generation, stemness, and epithelial-to-mesenchymal transition (EMT) leading to cancer of aggressive phenotype. Breast cancer development and progression have been regulated by several cytokines where the latter can promote cancer cell survival, help in tumor immune evasion, and initiate the EMT process, thereby resulting in invasion, angiogenesis, and breast cancer metastasis. In the present study, we screened cytokines expression in cytomegalovirus-transformed HMECs (CTH cells) cultures infected with HCMV high-risk strains namely, HCMV-DB and BL, as well as breast cancer biopsies, and analyzed the association between cytokines production, PGCCs count, and HCMV presence in vitro and in vivo. Methods In CTH cultures and breast cancer biopsies, HCMV load was quantified by real-time qPCR. PGCCs count in CTH cultures and breast cancer biopsies was identified based on cell morphology and hematoxylin and eosin staining, respectively. CTH supernatants were evaluated for the production of TGF-β, IL-6, IL1-β, and IL-10 by ELISA assays. The above-mentioned cytokines expression was assessed in breast cancer biopsies using reverse transcription-qPCR. The correlation analyses were performed using Pearson correlation test. Results The revealed PGCCs/cytokine profile in our in vitro CTH model matched that of the breast cancer biopsies, in vivo. Pronounced cytokine expression and PGCCs count were detected in particularly CTH-DB cultures and basal-like breast cancer biopsies. Conclusions The analysis of cytokine profiles in PGCCs present mostly in basal-like breast cancer biopsies and derived from CTH cells chronically infected with the high-risk HCMV strains might have the potential to provide novel therapies such as cytokine-based immunotherapy which is a promising field in cancer treatments.

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Section: Discussionmentioning

confidence: 99%

Polyploid giant cancer cells, cytokines and cytomegalovirus in breast cancer progression

2023

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“…This suggests potential for new therapeutic approaches, such as using TERT inhibitors, in the treatment of EBV-related cancers. 6,114 Given the important role of TERT in the pathogenesis and progression of viralassociated cancers, targeting TERT has been proposed as a potential therapeutic strategy for these cancers. 115 Several studies have shown that inhibition of TERT expression or activity can reduce cell proliferation and induce apoptosis in HPVassociated cervical cancer cells 116 and EBV-associated nasopharyngeal carcinoma cells.…”

Section: Tert and Terc In Cervical Cancermentioning

confidence: 99%

“…Notably, the inhibition of TERT in Burkitt's lymphomas and LCLs that are EBV‐positive increased the effectiveness of antiviral therapy in inducing apoptosis. This suggests potential for new therapeutic approaches, such as using TERT inhibitors, in the treatment of EBV‐related cancers 6,114 . Given the important role of TERT in the pathogenesis and progression of viral‐associated cancers, targeting TERT has been proposed as a potential therapeutic strategy for these cancers 115 .…”

Section: Introductionmentioning

confidence: 99%

Noncanonical functions of telomerase and telomeres in viruses‐associated cancer

Rasouli,

Dakic,

Wang

et al. 2024

Journal of Medical Virology

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The cause of cancer is attributed to the uncontrolled growth and proliferation of cells resulting from genetic changes and alterations in cell behavior, a phenomenon known as epigenetics. Telomeres, protective caps on the ends of chromosomes, regulate both cellular aging and cancer formation. In most cancers, telomerase is upregulated, with the telomerase reverse transcriptase (TERT) enzyme and telomerase RNA component (TERC) RNA element contributing to the maintenance of telomere length. Additionally, it is noteworthy that two viruses, human papillomavirus (HPV) and Epstein–Barr virus (EBV), utilize telomerase for their replication or persistence in infected cells. Also, TERT and TERC may play major roles in cancer not related to telomere biology. They are involved in the regulation of gene expression, signal transduction pathways, cellular metabolism, or even immune response modulation. Furthermore, the crosstalk between TERT, TERC, RNA‐binding proteins, and microRNAs contributes to a greater extent to cancer biology. To understand the multifaceted roles played by TERT and TERC in cancer and viral life cycles, and then to develop effective therapeutic strategies against these diseases, are fundamental for this goal. By investigating deeply, the complicated mechanisms and relationships between TERT and TERC, scientists will open the doors to new therapies. In its analysis, the review emphasizes the significance of gaining insight into the multifaceted roles that TERT and TERC play in cancer pathogenesis, as well as their involvement in the viral life cycle for designing effective anticancer therapy approaches.

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“…In addition, virus-related cancers, which commonly require constitutive expression of viral oncoproteins to sustain cell transformation, are characterized by high levels of telomerase activity. In particular, oncoviral proteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi’s sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, have been demonstrated to contribute to the transcriptional activation of the TERT gene by interacting with negative regulators of TERT transcription ( Tornesello et al, 2022a ).…”

Section: Introductionmentioning

confidence: 99%

Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations

Tornesello,

Cerasuolo,

Starita

et al. 2023

Front. Cell Dev. Biol.

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Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.

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The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

Cited by 9 publications

References 169 publications

Polyploid giant cancer cells, cytokines and cytomegalovirus in breast cancer progression

Polyploid giant cancer cells, cytokines and cytomegalovirus in breast cancer progression

Noncanonical functions of telomerase and telomeres in viruses‐associated cancer

Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations

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