American Association for Cancer Research
Browse
- No file added yet -

Supplementary Figure 1 from Novel Mechanistic Insights into Ectodomain Shedding of EGFR Ligands Amphiregulin and TGF-α: Impact on Gastrointestinal Cancers Driven by Secondary Bile Acids

Download (92.83 kB)
journal contribution
posted on 2023-03-30, 22:33 authored by Nagaraj S. Nagathihalli, Yugandhar Beesetty, Wooin Lee, M. Kay Washington, Xi Chen, A. Craig Lockhart, Nipun B. Merchant

PDF file - 92KB, AREG and TGF-alpha mRNA expression.

History

ARTICLE ABSTRACT

Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment. Cancer Res; 74(7); 2062–72. ©2014 AACR.

Usage metrics

    Cancer Research

    Categories

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC