Single Nucleotide Polymorphism in SMAD7 and CHI3L1 and Colorectal Cancer Risk
Table 9
The role of TGF-β in various cell processes.
Cytostasis
(i) TGF-β can activate cytostatic gene responses at any point in the cell cycle phases G1, S, or G2 [112] (ii) TGF-β induces activation of the cyclin-dependent kinase (CDK) inhibitors [113–115] and repression of the growth-promoting transcription factors c-MYC and inhibitors of differentiation (ID1, ID2, and ID3) [116].
Apoptosis
TGF-β induces apoptosis through (i) upregulation of SH2-domain-containing inositol-5-phosphatase expression, which inhibits signaling via the survival protein kinase AKT [117] (ii) induction of TGF-β-inducible early-response gene, which induces the generation of ROS and the loss of the mitochondrial membrane potential preceding the apoptotic death [118, 119] (iii) induction of death-associated protein kinase [117]
Immunity
For immune suppression, TGF-β plays a critical role through (i) blocking antigen-presenting cells such as dendritic cells, which acquire the ability to effectively stimulate T cells during an immune response [120] (ii) decreasing the activity of natural killer cells and neutrophils [121]
Angiogenesis
(i) TGF-β induces the expression of matrix metalloproteinases (MMPs) on both endothelial cells and tumor cells, allowing the release of the endothelial cells from the basement membrane [122] (ii) TGF-β can also induce the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and connective-tissue growth factor (CTGF) in epithelial cells and fibroblasts [123, 124]
Epithelial-mesenchymal transition (EMT)
The migratory ability of epithelial cells relies on loss of cell–cell contacts, a process that is commonly referred to as the EMT. It is marked by the loss of E-cadherin and the expression of mesenchymal proteins such as vimentin and N-cadherin [125]. (i) TGF-β was reported to destabilize the E-cadherin adhesion complex resulting in its loss in pancreatic cancer [126]. Alternatively, in epithelial cell lines, TGF-β can deacetylate the E-cadherin promoter, thus repressing its transcription [127] (ii) TGF-β was found to upregulate vimentin in prostate cancer [128] (iii) TGF-β upregulates MMPs to promote invasion through proteolytic degradation and remodeling of the ECM [129]
