The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells

Abstract

JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.

The oncogenic roles of JC polyomavirus in cancer

“…T antigen knockdown could suppress glycolysis, mitochondrial respiration, proliferation, migration, and invasion in lens tumor cells; however, it promoted apoptosis. T antigen can also activate the Akt/NF-kB/survivin pathway, producing an anti-apoptosis effect and causing Rb hyperexpression and p21 hypoexpression to mediate cell cycle progression (88). These findings suggest that the T antigen can aggravate the cellular phenotype, possibly by inactivating tumor suppressors, activating oncogenes, or disrupting metabolism and cell adhesion.…”

“…The upregulated proteins are involved in signaling through Cyclin-CDK, TGF-b receptor 1, fibroblast growth factor family receptor and platelet-derived growth factor receptor and the inflammatory responses mediated by Cox-2 (89). T antigen might interact with ribosomal proteins, various keratins, G proteins, apolipoproteins, ubiquitin-related proteins, CCAAT enhancer-binding proteins, b-catenin, RPL19, b-TRCP, and p53 in lens tumor cells (88). T antigen knockdown could suppress glycolysis, mitochondrial respiration, proliferation, migration, and invasion in lens tumor cells; however, it promoted apoptosis.…”

“…Multi-omics analysis has demonstrated that JCPyV-related carcinogenesis involves aberrant Forkhead box O, AMPK, p53, and PI3K/Akt signaling pathways. Moreover, T antigen can upregulate the expression of Akt, Rb, and survivin and downregulate p21 expression, indicating that it might activate the Akt/NF-kB/survivin pathway to block apoptosis and cause Rb hyper-expression and p21 hypo-expression for cell cycle progression (88). The upregulated proteins are involved in signaling through Cyclin-CDK, TGF-b receptor 1, fibroblast growth factor family receptor and platelet-derived growth factor receptor and the inflammatory responses mediated by Cox-2 (89).…”

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches

“…Computational methods to find the repurposable drugs targeting the viral cancers use supervised ML and DL methods and make use of the publicly accessible databases 28,44–47 and in‐house information resources. Most studies and methods use the target activity profiles of compounds for informed drug repurposing process 48–50 …”

“…Most studies and methods use the target activity profiles of compounds for informed drug repurposing process. [48][49][50] Moreover, a lot of drug repurposing studies using modeling, ML, and DL approaches (Figure 1) have been reported which are focusing on the viral cancers with references to the viruses that cause or increase the risk of cancer. These viruses are infectious microbes which are host dependent parasites and proliferate using host cells.…”