Deregulation of the Notch pathway as a common road in viral carcinogenesis

Vázquez-Ulloa, Elenaé; Lizano, Marcela; Sjöqvist, Marika; Olmedo-Nieva, Leslie; Contreras‐Paredes, Adriana

doi:10.1002/rmv.1988

Cited by 14 publications

(10 citation statements)

References 147 publications

(269 reference statements)

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“…Besides implication in several developmental defects in humans, this pathway has been implicated in the pathogenesis of leukemia and several other cancers including colorectal cancers [8][9][10]. Aberrantly activated Notch signaling plays a crucial role in carcinogenesis and progression of various human malignancies including the breast [11] and colorectal cancer [12]. e overexpressions of Notch signaling components are correlated with CRC progression and metastasis [13].…”

Section: Introductionmentioning

confidence: 99%

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Shaik

Alanazi

Pathan

et al. 2020

Journal of Oncology

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Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1–4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.

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Section: Introductionmentioning

confidence: 99%

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Shaik

Alanazi

Pathan

et al. 2020

Journal of Oncology

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“…According to KEGG pathway analysis, the Notch1 signaling pathway was activated in SK-RG cells and associated with KSHV infection. The Notch signaling pathway is composed of specific receptors (Notch1-4) and ligands (Delta-like 1, 3, 4, Jagged1 and Jagged2) in mammals [ 29 ]. The ligand-receptor interaction releasing the Notch intracellular domain (NICD) is carried out by the γ‐secretase complex.…”

Section: Discussionmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus infection promotes proliferation of SH-SY5Y cells by the Notch signaling pathway

Cao

Wang

et al. 2021

Cancer Cell Int

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Background The cancer caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is one of the major causes of death in AIDS patients. Some patients have neurological symptoms, which appear to be associated with KSHV infection, based on the neurotropic tendency of this virus in recent years. The objectives of this study were to investigate the effects of KSHV infection on neuronal SH-SY5Y cells and to identify differentially expressed genes. Methods KSHV was collected from islk.219 cells. Real-time PCR was used to quantify KSHV copy numbers. KSHV was used to infect SH-SY5Y cells. The KSHV copy number in the supernatants and mRNA levels of latency-associated nuclear antigen (LANA), ORF26, K8.1 A, and replication and transcriptional activator (RTA) were detected by real-time PCR. Proteins were detected by immunohistochemistry. The effect of KSHV infection on cell proliferation was detected by MTT and Ki-67 staining. Cell migration was evaluated by Transwell and wound healing assays. The cell cycle was analyzed by flow cytometry. The expression of CDK4, CDK5, CDK6, cyclin D1, and p27 were measured by western blotting. The levels of cell cycle proteins were re-examined in LANA-overexpressing SH-SY5Y cells. Transcriptome sequencing was used to identify differentially expressed genes in KSHV-infected cells. The levels of Notch signaling pathway proteins were measured by western blotting. RNA interference was used to silence Notch1 and proliferation were analyzed again. Results SH-SY5Y cells were successfully infected with KSHV, and they maintained the ability to produce virions. KSHV-infected SH-SY5Y expressed LANA, ORF26, K8.1 A, and RTA. After KSHV infection, cell proliferation was enhanced, but cell migration was suppressed. KSHV infection accelerated the G0/G1 phase. CDK4, CDK5, CDK6, and cyclin D1 expression was increased, whereas p27 expression was decreased. After LANA overexpression, CDK4, CDK6 and cyclin D1 expression was increased. Transcriptome sequencing showed that 11,258 genes were upregulated and 1,967 genes were downregulated in KSHV-infected SH-SY5Y. The Notch signaling pathway played a role in KSHV infection in SH-SY5Y, and western blots confirmed that Notch1, NICD, RBP-Jĸ and Hes1 expression was increased. After silencing of Notch1, the related proteins and cell proliferation ability were decreased. Conclusions KSHV infected SH-SY5Y cells and promoted the cell proliferation. KSHV infection increased the expression of Notch signaling pathway proteins, which may have been associated with the enhanced cell proliferation.

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“…The activation of NOTCH in cancer stem cells has been reported to promote tumor growth, invasion, angiogenesis, and therapy resistance [38], [10,39], and its blockade reduces tumor growth and augments therapy [40,41]. NOTCH activation is also known to be induced by several viruses [42]. For example, KSHV (human herpesvirus 8) activates NOTCH signaling [43] to enhance activation of transcription of its own genome [44].…”

Section: Discussionmentioning

confidence: 99%

Oncolytic HSV–Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition

Otani

Yoo

Chao

et al. 2020

Clinical Cancer Research

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Deregulation of the Notch pathway as a common road in viral carcinogenesis

Cited by 14 publications

References 147 publications

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Kaposi’s sarcoma-associated herpesvirus infection promotes proliferation of SH-SY5Y cells by the Notch signaling pathway

Oncolytic HSV–Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition

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