These findings demonstrate that TTP acts as a negative regulator of VEGF gene expression in colon cancer cells, suggesting that it can be used as novel therapeutic agent to treat colon cancer.
To analyze the biological activities of these VEGF isoforms on tumor growth, we transfected human VEGF121, VEGF165 or VEGF189 cDNA into the human colon cancer cell line SW-480, and established several clones overexpressing these VEGF isoforms.
These studies demonstrate that the IGF ligand-receptor system plays an important role in multiple mechanisms that mediate human colon cancer growth including regulation of VEGF and angiogenesis.
Although the VEGF -2578C > A polymorphism had no influence on susceptibility to colon cancer, some genotypes showed a significant difference between the case and control groups when the data were stratified by gender and the original location of tumor, suggesting that the VEGF -2578C > A polymorphism, at least in Koreans, is a genetic determinant of colon cancer risk.
These factors could allow neoplastic tissues to survive and withstand the stress induced by hypoxia and/or disruption of the ECM, including vascular endothelial growth factor and matrix metalloproteinases that were found to be highly elevated in tumor tissues of colon cancer patients.
IHC studies performed on human colon adenocarcinoma specimens showed that TGF-beta signaling is inversely correlated with VEGFA expression, indicating that TGF-beta-mediated suppression of VEGFA expression exists in colon cancer patients.
After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFArs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors.
A stable VEGF gene-transfected human colon cancer cell line, LoVo, was made by genetic manipulation using eukaryotic expression constructs designed to express the complete VEGF121 cDNA in the sense orientation.
In vitro assessments were then made of the ability of anti-VEGF siRNA to knock down expression of VEGF and the subsequent effect this decreased expression had on colon cancer cell proliferation.
Hydrogen peroxide increases vascular endothelial growth factor expression in colon cancer cells, and it is likely that reactive oxygen species such as hydrogen peroxide facilitates the development of colon cancer.
Our previous studies demonstrated that mutant KRAS alleles can interact with hypoxia to induce vascular endothelial growth factor (VEGF) in colon cancer.
Insulin-like growth factors and their principal receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF).