Significance of positive and inhibitory regulators in the TGF-β signaling pathway in colorectal cancers

Abstract

Inactivation of genes in the transforming growth factor (TGF)-β/SMAD signaling pathway is a well-known step for the progression of colorectal cancers (CRCs). Genetic mutations can occur in the precursors, and the combined prevalence of SMAD4, SMAD2, and SMAD3 mutations was seen in up to 50% of CRCs. High levels of serum TGF-β1 were reported in patients with CRC and were associated with poor clinical outcome. PPM1A is an important inhibitory regulator in the TGF-β signaling pathway and contributes to terminating the TGF-β/SMAD signaling activity. We recently showed that PPM1A expression was lost in approximately 45% of pancreatic ductal adenocarcinomas and loss of PPM1A was associated with worse overall survival. Genome-wide analyses from The Cancer Genome Atlas revealed that abnormal TGF-β signaling pathway is among the most common molecular changes in CRC. The complexity of the TGF-β signaling pathway is its dual function as a tumor suppressor and tumor-promoting factor, depending on the cellular and molecular context. In this study, we simultaneously investigated the protein expression pattern of 3 regulators in the TGF-β/SMAD signaling pathway, including SMAD4, PPM1A, and TGF-β1, and their clinicopathological correlations in CRCs by immunohistochemistry. We observed that loss of SMAD4 and PPM1A was seen in 37.8% and 7.3% of CRCs, respectively. Loss of SMAD4, lymphovascular invasion, and distant metastasis were independently associated with worse overall survival in multivariate analysis. However, loss of PPM1A was associated with worse overall survival with less statistical strength. Our findings would provide new insights into the pathophysiological function of different components in the TGF-β signaling pathway in CRC.