Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability

Merchut-Maya, Joanna Maria; Bártek, Jiří; Bártková, Jiřina; Galanos, Panagiotis; Pantalone, Mattia Russel; Lee, Myung‐Hee; Cui, Huanhuan; Shilling, Patrick J.; Brøchner, Christian Beltoft; Broholm, Helle; Maya-Mendoza, Apolinar; Söderberg‐Nauclér, Cecilia

doi:10.1038/s41418-022-00953-w

Cited by 14 publications

(11 citation statements)

References 55 publications

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“…Viral infectivity assay showed that no infectious virions were produced in HCMV infected Caco-2 and LS-174 cells, consistent with previous literature reporting that HCMV replicates poorly or not at all in cancer cells ( 95 ). This may be dependent on the virus inability to arrest cells in G1/G2 phase, which is important for to initiate DNA replication.…”

Section: Discussionsupporting

confidence: 91%

“…This may be dependent on the virus inability to arrest cells in G1/G2 phase, which is important for to initiate DNA replication. There was no evidence of virions produced in supernatant of these colon cancer cells at 7 dpi, indicating that the effects of HCMV on colon cancer cells may be associated with virus ability to express proteins and thereby affect cell function ( 95 ).…”

Section: Discussionmentioning

confidence: 99%

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Human cytomegalovirus infection enhances 5‑lipoxygenase and cycloxygenase‑2 expression in colorectal cancer

Pantalone,

Almazan,

Lattanzio

et al. 2023

Int J Oncol

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Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro-inflammatory enzymes 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin-embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki-67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5-LO and COX-2. The CRC cell lines Caco-2 and LS-174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti-inflammatory drug celecoxib (CCX) and analyzed by reverse transcription-quantitative PCR and immunofluorescence for 5-LO, COX-2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in ~90% of the CRC cases tested; this was correlated with COX-2, 5-LO and KI-67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. In vitro , HCMV infection upregulated 5-LO and COX-2 transcript and proteins in both Caco-2 and LS-174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX-2, 5-LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus infection enhances 5‑lipoxygenase and cycloxygenase‑2 expression in colorectal cancer

Pantalone,

Almazan,

Lattanzio

et al. 2023

Int J Oncol

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“…HCMV infection interfering with cellular replication can induce replication stress (RS) with ensuing implications for genomic integrity. In addition, expression of IE1 and IE2, driven by the viral major immediate early enhancer and promoter (MIEP), has been determined to induce RS alone [ 130 ].…”

Section: Hcmv Is a Dna Damage-inducing Factormentioning

confidence: 99%

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus

Wu,

Zhou,

Wang

et al. 2023

Virol J

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The DNA damage response (DDR) is a signaling cascade that is triggered by DNA damage, involving the halting of cell cycle progression and repair. It is a key event leading to senescence, which is characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP) that includes the expression of inflammatory cytokines. Human cytomegalovirus (HCMV) is a ubiquitous pathogen that plays an important role in the senescence process. It has been established that DDR is necessary for HCMV to replicate effectively. This paper reviews the relationship between DDR, cellular senescence, and HCMV, providing new sights for virus-induced senescence (VIS).

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“…Meanwhile, viruses hijack the human stress response transcriptional factors to enhance their own expression of IE72 and IE86. In clinical testing, CMV protein markers are elevated after DNA damage by radiochemotherapy or the recurrence of GBM [ 37 ]. CMV is also capable of inducing angiogenesis and cell migration.…”

Section: Mechanisms Of Cmv-related Glioma Tumorigenesismentioning

confidence: 99%

Cytomegalovirus and Glioblastoma: A Review of the Biological Associations and Therapeutic Strategies

Yang

Liu

Fang

et al. 2022

JCM

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Glioblastoma is the most common and aggressive malignancy in the adult central nervous system. Cytomegalovirus (CMV) plays a crucial role in the pathogenesis and treatment of glioblastoma. We reviewed the epidemiology of CMV in gliomas, the mechanism of CMV-related carcinogenesis, and its therapeutic strategies, offering further clinical practice insights. To date, the CMV infection rate in glioblastoma is controversial, while mounting studies have suggested a high infection rate. The carcinogenesis mechanism of CMV has been investigated in relation to various aspects, including oncomodulation, oncogenic features, tumor microenvironment regulation, epithelial–mesenchymal transition, and overall immune system regulation. In clinical practice, the incidence of CMV-associated encephalopathy is high, and CMV-targeting treatment bears both anti-CMV and anti-tumor effects. As the major anti-CMV treatment, valganciclovir has demonstrated a promising survival benefit in both newly diagnosed and recurrent glioblastoma as an adjuvant therapy, regardless of surgery and the MGMT promoter methylation state. Immunotherapy, including DC vaccines and adoptive CMV-specific T cells, is also under investigation, and preliminary results have been promising. There are still questions regarding the significance of CMV infection and the carcinogenic mechanism of CMV. Meanwhile, studies have demonstrated the clinical benefits of anti-CMV therapy in glioblastoma. Therefore, anti-CMV therapies are worthy of further recognition and investigation.

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Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability

Cited by 14 publications

References 55 publications

Human cytomegalovirus infection enhances 5‑lipoxygenase and cycloxygenase‑2 expression in colorectal cancer

Human cytomegalovirus infection enhances 5‑lipoxygenase and cycloxygenase‑2 expression in colorectal cancer

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus

Cytomegalovirus and Glioblastoma: A Review of the Biological Associations and Therapeutic Strategies

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