LEF/TCF full length expression and their isoforms vary between normal cells and colon cancer cells. In the normal colon, TCF-1 and TCF-4 are expressed and LEF-1 and TCF-3 are silenced., ,[ Moreover they also have different biological roles. In general LEF-1 is viewed as an activator and TCF-3 as mostly a repressor but can be a activator (; ). Both TCF-1 and TCF-4 act as both inhibitors and activators, but TCF-4 is the dominant interactor of β -catenin in the colon. TCF4 mediates the transformative process of colon epithelial cells when tumor-suppressor protein adenomatous polyposis coli (APC) is loss. The family of proteins has also been found to regulate one another. For example, transcription of LEF-1 can be directly…show more content… It also has been shown that cyclin D1 is a downstream target of the β-catenin–TCF complex and therefore when continually activated allows cells to proceed through cell cycle and continue tumor growth. In support of this, expression of the dominant-negative form of TCF, lacking the β-catenin binding domain, in colon-cancer cells strongly inhibits expression of cyclin D1 causing cells to arrest in the G1 phase of the cell cycle due to the lack of activation of cyclin D1 ).
The β-catenin/LEF-1 pathway also shows cyclin D1 as a direct target; LEF-1 binds directly in the cyclin D1 promoter . In addition, anti-sense cyclin D1 cDNA inhibits growth of SW480 colon cancer cells in nude mice; this suggests a critical role for cyclin D1 in tumorigenesis and that targeting the TCF/LEF family can downregulate its specific activity .
The end point of the cell cycle is mitosis; this is when one cell becomes two. Several studies have shown that TCF-4 maintains the crypt stem cells of the gut and its continuous activation causes uncontrolled cell proliferation). In support of this finding, another lab determined the disruption of β-catenin/TCF-4 complex resulted in decreasing the expression of c-MYC and downstream targets causing G1 arrest (). TCF-4 may be an important switch in cell cycle regulation and proliferation and when constitutively activated a monumental event in colon cancer tumorigenesis. Figure 3.
Role of TCF/LEF in metastasis: