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. 2017 Jan 3;8(11):18456–18485. doi: 10.18632/oncotarget.14472

Figure 3. Key molecular pathways potentially linking diabetes and colorectal cancer.

Figure 3

The example of β-catenin activation. A. In the absence of Wnt signaling, APC-bound glycogen synthase kinase 3-beta (GSK-3β) phosphorylates β-catenin (βCat), targeting it for ubiquitination and proteasomal degradation. In the absence of nuclear β-catenin, Groucho binds to transcription factors of the TCF family, repressing transcription. The TCF family includes TCF7L2 which has been associated to DM, DM complications and colon cancer by GWAS studies. B. Colon cancer is characterized by loss of function mutations of APC and in DM Wnt signaling is activated. Klotho and vitamin D prevent Wnt signaling and are protective against tumors and against DM complications. Wnt signaling prevents β-catenin phosphorylation and degradation allowing its nuclear migration, where it displaces Groucho and promotes transcription of genes involved in cell proliferation as well as other genes such as miR-21. miR21 contributes to tumorigenesis and to diabetes complications such as kidney injury. GWAS identified a GREM1 SNP associated with CRC susceptibility that facilitates TCF7L2 binding to DNA, leading to stronger GREM1 gene expression. A GREM1 SNP also associate with diabetic kidney disease. The gene product, Gremlin, promotes kidney injury in DM as well as colon cancer cell migration. KCNQ1 was associated with T2DM by GWAS. This locus encodes KCNQ1OT1, a β-catenin target upregulated in CRC.