Aberrant β-Catenin Expression and Its Association With Epithelial-Mesenchymal Transition and Clinical Outcomes of Colorectal Cancer

Abstract

Background Colorectal cancer (CRC) is a significant global health challenge with high mortality rates. Dysregulation of β-catenin, epithelial-mesenchymal transition (EMT), and adenomatous polyposis coli (APC) are crucial in CRC development. Mutations in the APC gene lead to aberrant β-catenin expression, a key player in CRC pathogenesis. β-catenin not only influences canonical Wnt signaling but also regulates EMT. This study investigated the correlation between APC mutations, β-catenin dysregulation, and EMT induction in CRC. Methodology Tissue samples from 96 CRC patients and 40 para-cancerous normal tissues were collected and subjected to immunohistochemistry to assess β-catenin, E-cadherin, ZEB1, Snail, and vimentin expression. Genomic DNA was extracted and analyzed for APC mutations. Next-generation sequencing was employed for data analysis. Results Aberrant β-catenin expression was found in 82.3% of CRC cases and correlated with advanced clinicopathological factors. Aberrant β-catenin expression was associated with age (p=0.01), tumor invasion depth (p=0.03), nodal/distant metastasis (p=0.001 and 0.004), and vascular invasion (p=0.001). Aberrant β-catenin was correlated with EMT status. A positive correlation was observed between aberrant β-catenin expression and ZEB1 (p=0.001), Snail (p=0.001), vimentin (p=0.001), and loss of membranous E-cadherin (p=0001). Coexistence of aberrant β-catenin and EMT markers was associated with advanced CRC progression. Cancerous tissues displayed higher aberrant β-catenin and EMT markers expression than para-cancerous tissues. APC mutations were present in 59.3% of cases, with 91.2% of mutated APC cases showing aberrant β-catenin expression. The coexistence of APC mutation and aberrant β-catenin expression was correlated with the clinical outcomes of CRC patients. Mutated APC cases exhibited significantly increased EMT marker expression. Conclusion This study underscores the importance of aberrant β-catenin expression in CRC progression, linked to APC mutations and EMT induction. Understanding these relationships could aid in developing targeted therapies for CRC.

Keywords: apc; colorectal cancer; epithelial mesenchymal transition; mutation; β-catenin.

Figure 1. Expression and localization of β-catenin in CRC tissue specimens

(A) Representative image showed intense nuclear β-catenin expression, (B) β-catenin predominantly found in the cytoplasm C. β-catenin is predominantly expressed in the cell membrane (x100). CRC: Colorectal cancer

Figure 2. Co-expression of aberrant β-catenin and EMT-related proteins in CRC tissues

Representative images from the same tumor specimens illustrate a correlation between (A) aberrant β-catenin expression and EMT markers including (B) ZEB1, (C) Snail, (D) Vimentin, and (E) Aberrant E-cadherin (x100). EMT: Epithelial-mesenchymal transition; CRC: Colorectal cancer