How SV40 Causes Cancer
The SV40 is a type of polyoma virus. The term “poly” means many and “oma” means tumor. Its very name designates its ability to cause many types of cancers. The specific biological mechanisms by which SV40 transforms (turns cancerous) cells have been well studied since its discovery in the early 1960’s. In fact, there are volumes of scientific publications on this subject. Below is a brief outline of some of the mechanisms. Supporting documentation can be found through Medline by simply entering the term SV40 with the appropriate mechanism.
1. Telomerase activity
The telomere is a repetitive stretch of DNA found at each end of a chromosome. Telomeres are shortened each time a cell divides. This is the reason that normal cells can only divide roughly 50 times. An enzyme, telomerase, extends the telomere. Tumors cells often have telomerase activity which allows the cancer cells to divide without limit. SV40 infection leads to telomerase activity.
2. Binding to and inhibition of cellular p53 and retinoblastoma (RB) proteins
The p53 gene and the retinoblastoma (Rb) gene are tumor suppressor genes. They promote cell-cycle arrest (stop cells from dividing) when the cells are injured or damaged. Their ability to function properly is critical because their respective proteins stop the formation of tumors. The major SV40 oncoprotein is the Large tumor antigen (Tag). Tag binds to and inactivates cellular p53 and Rb. Therefore, the presence of SV40 stops these tumor suppressor genes from doing their job.
3. Inhibition of protein phosphatase 2A (PP2A)
Protein Phosphatase 2A (PP2A) plays a role in the critical cellular processes of protein synthesis, DNA replication, transcription, and metabolism. Small t antigen of SV40 comprises 174 amino acids. The region between residues 97-103 interacts with the PP2A. This interaction reduces the ability of PP2A to inactivate ERK1 and MEK1 protein kinases, resulting in stimulation of proliferation of cells.
4. Inhibition of tumor suppressor gene RASSF1A
Loss or altered expression of the RASSF1A gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene. SV40 large tumor antigen (Tag) blocks RASSF1A.
5. Upregulation of Notch-1
Notch-1 is a key cell regulatory gene. Notch can either suppress or promote tumors depending on the cell type and context. Aberrant Notch signaling has been linked to a wide variety of tumors and the involvement of Notch signaling in several cancers has been well studied. SV40 infection of human mesothelial cells directly causes overexpression of Notch-1 which promotes cell cycle progression.
6. Upregulation of the MET oncogene
The activation of hepatocyte growth factor (HGF) receptor (Met) leads to cell growth and motility in cells of different origin. SV40 infection can cause Met activation.
7. Upregulation of insulin-like growth factor (IGF-1)
The insulin-like growth factor (IGF) receptor (IGF-IR) mediates the mitogenic, transforming, differentiating, and anti-apoptotic effects of the IGF ligands. SV40 upregulates IGF.