β-catenin interaction with NHERF1 and RASSF1A methylation in metastatic colorectal cancer patients

There is an increasing need to identify new biomarkers in colorectal cancer (CRC) to further characterize this malignancy. beta-catenin plays a central role in the Wnt signaling pathway. It also binds Na+/H+ exchanger regulating factor 1 (NHERF1) and interacts with the RAS-association domain family 1, isoform A (RASSF1A), but the mechanisms of this possible crosstalk are still not fully understood. In this study, we analyzed for the first time the different subcellular expression of beta-catenin, NHERF1, and RASSF1A and their relationships with RASSF1A methylation in the progression of CRC. We assessed immunohistochemical expression and RASSF1A methylation in 51 patients with stage IV colorectal cancer. Biomarker expression analysis was carried out considering the tumor-adjacent normal tissue, the primary tumor, and the paired liver metastases. Regarding the tumor compartment, it was found that cytoplasmic beta-catenin expression was positively correlated to membranous (r = 0.3002, p = 0.0323) and nuclear NHERF1 (r = 0.293, p = 0.0368). In the liver metastases, instead, we found a positive correlation of cytoplasmic and nuclear beta-catenin expression with RASSF1A methylation (r = 0.4019, p = 0.0068 and r = 0.3194, p = 0.0345, respectively). In conclusion, our results showed that beta-catenin was the crucial protagonist in metastatic CRC through different effector proteins involved in this developing process. In tumor tissues, beta-catenin was predominantly associated with NHERF1 in a dynamic context, while interestingly in liver metastases, we noted an increase of its oncogenic function through RASSF1A inactivation.