May 1, 2020

Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma

BioRxiv : the Preprint Server for Biology
P. GroverPinku Mukherjee

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-{beta}) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-{beta} functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-{beta}RII and negatively to TGF-{beta}RI receptors. In response to TGF-{beta}1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-{beta}1 neutralizing antibody in vivo showing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-{beta} pathway in tMUC1 high versus tMUC1 low samples. This...Continue Reading

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Mentioned in this Paper

Size
Ligand Binding
Regulation of Biological Process
Evaluation
Protein Oligomerization
Site
Binding (Molecular Function)
Genus Homo
Analysis
Ligands Activity

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