SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line

Oncotarget
Priyanka GroverPinku Mukherjee

Abstract

Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-β functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-β1. Simultaneously, these cells resist TGF-β induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-β induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are ...Continue Reading

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Citations

Nov 7, 2019·Molecular Biology of the Cell·Mohammed Farhan LakdawalaTina L Gumienny
Nov 7, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Divya ThomasPrakash Radhakrishnan
Feb 16, 2021·Frontiers in Pharmacology·Zeeshan JavedPaweł Helon
Dec 30, 2020·Cancers·Ruben D HouvastCornelis F M Sier
Feb 28, 2020·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Zhu ZhangJoshua Ka-Shun Ko
Apr 5, 2021·Cancer Metastasis Reviews·Saravanakumar MarimuthuMoorthy P Ponnusamy
Jul 3, 2021·International Journal of Molecular Sciences·Wenqing ChenKen Kin-Lam Yung

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Methods Mentioned

BETA
ELISA
flow cytometry

Software Mentioned

Graphpad Prism
FlowJo
ImageJ

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