Cancer News

Inhibition of Key Cytokine Tgf-beta in Colorectal Tumors

Colorectal cancer, as the fourth most common cancer in the world, reducing its incidence remains a major challenge. In many cancers, including colorectal cancer, the factor that normally disrupts key signaling pathways is transforming growth factor β (TGF-β). According to existing research, TGF-β protein is highly conservative in evolution. However, only TGF-β 1-3 is expressed in mammals and exhibits tissue and cell type specificity in both individual development and adult individuals. The study found that TGF-β1 has different functions in different types of cells, but in the normal epithelial system, TGF-β1 exhibits the role of tumor suppressor protein and participates in cell differentiation, apoptosis and cell cycle control. Among them, TGF-β1 can bind to type II receptors, thereby inducing heterogeneous oligomerization of type I receptors. The receptor complex can then delivery signal through Ras and Raf proteins, and finally the signal is transmitted to the intracellular signal transduction molecule SMAD. The receptor SMAD2/3 is activated by phosphorylation of the active receptor complex, and then binds to the common partner SMAD4, then transfers to the nucleus where it binds to the SMAD binding element in the regulatory region of the target gene. Then transcribe the protein related to its function.

TGF-β1 Physiological Function

Clinical studies have found that in normal colon, TGF-β1 is usually expressed in the upper region of the crypt. This suggests that TGF-β1 may be involved in maintaining the homeostasis of colorectal epithelium. In normal epithelial cells, TGF-β1 signaling triggers G1 cell cycle arrest in epithelial cells. The direct transcription reaction of TGF-β1 signaling includes the induction of cyclin-dependent kinase inhibitors and the inhibition of the proto-oncogene c-MYC. As a secreted protein, TGF-β1 can exert autocrine, paracrine or endocrine responses. Therefore, strict regulation of its level and biological activity is very important for the homeostasis of the colon.

In addition, due to the special function of TGF-β1, it also plays an important role in the development of colorectal cancer. The study found that dysregulated expression of TGF-β1 in colorectal cancer cells will have a significant effect on colorectal cancer. For example, in the early stages of tumorigenesis, colorectal adenoma remains sensitive to TGF-β1 signaling, and the tumor suppressor function of TGF-β1 constitutes an important obstacle to transformed cells; at the later stage of tumor progression, cells develop resistance to TGF-β1 inhibition (for example, through SMAD4 deletion or TGBR2 receptor mutation. This indicates that changes in TGF-β1 levels are closely related to the development of colorectal cancer. Therefore, understanding the regulation of TGF-β1 expression has a clinical role in the treatment of colorectal cancer.

Regulation of TGF-β1
In order to explore the regulation of TGF-β1, the researchers identified the research object-BAG-1 through the existing research clues. BAG-1 is a multifunctional protein, which is related to heat shock response, cell signaling, cell survival and apoptosis. Three major BAG-1 isomers of human BAG-1 can be transcribed from the BAG1 gene. Among them, the longest isomers contain domains that are partially or completely absent in the shorter isomers, for example, partial nuclear localization signals and putative DNA binding domains. It has been clinically found that BAG-1 protein is upregulated in a variety of human cancers, and this may be a relatively early event. Elevated BAG-1 levels have also been detected in colorectal adenoma. Combined with previous in vitro studies, and the relationship between high levels of BAG-1 and tumor cell metastasis, poor prognosis and low patient survival, it was found that BAG-1 plays an important role in the survival of colorectal tumor cells. In addition, the reduction of BAG-1 in colorectal cancer cells has been shown sensibility for tumor necrosis factor α and TRAIL induced apoptosis, and reduce NF-κB transcriptional activity.

Figure 1. Dual role for increased BAG-1 expression in promoting progression of colorectal tumorigenesis.

Given the importance of TGF-β1 in the homeostasis of normal colon tissues and the fact that BAG-1 levels in colorectal adenoma tissues increase significantly, the researchers speculate that the expression of BAG-1 in developing adenomas may allow cells to overcome tumors Inhibition of TGF-β1, and promotes the development of adenoma. Through experimental data, it was found that BAG-1 can directly inhibit the expression of TGFB1 in colorectal tumor cells. This study established BAG-1 as a negative regulator of TGF-β1 signaling, and the potential importance in the early stages of colorectal tumorigenesis, and emphasized the new role of BAG-1 in colorectal tumorigenesis.