β-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC

Abstract

Background The wnt/APC/β-catenin pathway is a critical initiator in colorectal carcinogenesis in both hereditary and sporadic colorectal cancer (CRC). The progression of this process remains incompletely understood, although inflammation is pivotal. Drivers of inflammation are elevated in malignant tissue and have been shown to regulate β-catenin expression. Interleukin-17A (IL-17A) is protumorigenic at elevated levels via COX-2 stimulation. Elevated peroxisome proliferator-activated receptor γ (PPARγ) expression has reduced risk of carcinogenesis and good overall prognosis in established CRC. Activation of PPARγ has inhibitory effect on β-catenin. Methods Using qPCR and IHC, we compared β-catenin, PPARγ, COX-2, and IL-17A in the colonic mucosa of patients with sporadic CRC, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS), against a normal control population. Results β-catenin mRNA and protein expression progressively increased from the Normal group, through IBS and IBD reaching statistical significance in CRC. COX-2 mRNA levels increased similarly with statistical significance in IBD and CRC. However, COX-2 protein expression was inverted with significant expression in the Normal and IBS groups and reduced levels in IBD and CRC. PPARγ mRNA expression was unchanged in IBD and CRC but was significantly elevated in the IBS. IL-17A mRNA was significantly reduced in IBS and CRC but unchanged in IBD. There were no differences in all parameters tested in the Normal and IBS groups. Conclusion β-catenin is confirmed as a major driver of colorectal carcinogenesis but is controlled by many more players other than APC. Elevated levels of PPARγ may have an anticarcinogenic effect. The role of COX-2 expression, especially its posttranscriptional regulation in colorectal cancer, needs further elucidation.

Prognosis in colorectal cancer beyond TNM

“…APC is a tumor suppressor gene of which main function is the regulation of the Wnt / ␤-catenin signaling pathway, which interferes with processes such as DNA repair, cell cycle, chromosomal instability, cell adhesion and apoptosis. 1,11,21 The APC mutation can be found in approximately 70% of sporadic CRCs and is responsible for the constitutive activation of the Wnt/␤-catenin pathway, resulting in adenomas. 1,21,22 The steps of this process are not yet fully known, but inflammation is thought to play a major role.…”

“…1,11,21 The APC mutation can be found in approximately 70% of sporadic CRCs and is responsible for the constitutive activation of the Wnt/␤-catenin pathway, resulting in adenomas. 1,21,22 The steps of this process are not yet fully known, but inflammation is thought to play a major role. 21 Some inflammation inducers are increased in malignant tissue and their relationship with the regulation of ␤-catenin expression, which is increased in proliferating cells, has been demonstrated.…”

“…1,21,22 The steps of this process are not yet fully known, but inflammation is thought to play a major role. 21 Some inflammation inducers are increased in malignant tissue and their relationship with the regulation of ␤-catenin expression, which is increased in proliferating cells, has been demonstrated. 21 Interleukin-17A (IL-17A) has a pro-tumorigenic role when it is expressed at high concentrations through stimulation of the Cyclooxygenase-2 (COX-2) / Prostaglandin E 2 (PGE 2 ) pathway.…”

“…21 Some inflammation inducers are increased in malignant tissue and their relationship with the regulation of ␤-catenin expression, which is increased in proliferating cells, has been demonstrated. 21 Interleukin-17A (IL-17A) has a pro-tumorigenic role when it is expressed at high concentrations through stimulation of the Cyclooxygenase-2 (COX-2) / Prostaglandin E 2 (PGE 2 ) pathway. 21 A recent study demonstrated that increased expression of IL-17A in tumor tissue is associated with increased recurrence and decreased survival, resulting in a worse prognosis.…”

“…21 Interleukin-17A (IL-17A) has a pro-tumorigenic role when it is expressed at high concentrations through stimulation of the Cyclooxygenase-2 (COX-2) / Prostaglandin E 2 (PGE 2 ) pathway. 21 A recent study demonstrated that increased expression of IL-17A in tumor tissue is associated with increased recurrence and decreased survival, resulting in a worse prognosis. 21 The increase in the expression of Peroxisome Proliferator-Activated Receptor gamma (PPAR␥) has a beneficial impact on CRC, as it provides a good prognosis by inhibiting the production of IL-17A, the effects of ␤-catenin and cell growth.…”