Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor at early stages to a tumor promoter in the late stages of tumor development, by yet unknown mechanisms. Tumor associated MUC1 is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. MUC1 expression is found in the early stages of PDA development with subsequent increase in later stages. Analysis of human PDA samples from TCGA database showed significant differences in gene expression and survival profiles between low and high MUC1 samples. Further, high MUC1 expression was found to positively correlate to TGF-βRII expression and negatively correlate to TGF-βRI expression in PDA cell lines. We hypothesized that MUC1 overexpression induces TGF-β mediated non-canonical signaling pathways which is known to be associated with poor prognosis. In this study, we report that MUC1 overexpression in PDA cells directly activates the JNK pathway in response to TGF-β, and leads to increased cell viability via up-regulation and stabilization of c-Myc. Conversely, in low MUC1 expressing PDA cells, TGF-β preserves its tumor-suppressive function and inhibits phosphorylation of JNK and stabilization of c-Myc. Knockdown of MUC1 in PDA cells also results in decreased phosphorylation of JNK and c-Myc in response to TGF-β treatment. Taken together, the results indicate that overexpression of MUC1 plays a significant role in switching the TGF-β function from a tumor-suppressor to a tumor promoter by directly activating JNK. Lastly, we report that high-MUC1 PDA tumors respond to TGF-β neutralizing antibody in vivo showing significantly reduced tumor growth while low-MUC1 tumors do not respond to TGF-β neutralizing antibody further confirming our hypothesis.
Highlights
Pancreatic Cancer is currently the third leading cause of cancerrelated deaths in the United States
Out of >4,000 genes that were differentially expressed, the top 30 genes that are involved in the TGF-β, MAPK and BMP pathways were selected to create the heatmap since these pathways are known to be regulated by TGF-β
Several known transcription factors like CREB3L3, FOXH1, PLA2G3, BMP4 as well as immune related genes such as the IL1R1 and IL1R2 were upregulated in high MUC1 samples which are all associated with increased epithelial to mesenchymal transition (EMT) and poor survival (Hamada et al, 2007; Zhang J et al, 2021; Zhang M et al, 2021)
Summary
Pancreatic Cancer is currently the third leading cause of cancerrelated deaths in the United States (http://pancreatic.org/). It has been projected to become the second leading cause of cancerrelated deaths in the US, surpassing colorectal cancer by the year 2030 (http://pancreatic.org/). The transforming growth factor beta (TGF-β) signaling pathway belongs to a large superfamily that primarily consists of TGF-β (including isoforms of TGF-β1, 2, and 3), bone morphogenetic proteins, activins, and inhibins (Namwanje and Brown, 2016) This family of growth factors activates many biological signals, such as cell growth, apoptosis, differentiation, immune response, angiogenesis, and inflammation (Cárcamo et al, 1994; Shi, 2001; Isabel et al, 2014). TGF-β induces invasion and migration and eventually leads to epithelial-to-mesenchymal transition (EMT) (Massagué, 2008) This process helps facilitate the migration and invasion of cancer cells to distant locations leading to metastasis, the major cause of cancer-related deaths (Mittal, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
