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Licensed Unlicensed Requires Authentication Published by De Gruyter January 10, 2015

Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression

  • George S. Karagiannis , Natasha Musrap , Punit Saraon , Ann Treacy , David F. Schaeffer , Richard Kirsch , Robert H. Riddell and Eleftherios P. Diamandis EMAIL logo
From the journal Biological Chemistry

Abstract

Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.


Corresponding author: Eleftherios P. Diamandis, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St., Toronto M5T 3L9, Ontario, Canada; and Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada, e-mail:

Acknowledgments

George S Karagiannis is supported by the University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada. The authors would like to thank Chris Smith, Ihor Batruch, Annie Bang, Kuruzar Gordana and Antoninus Soosapillai for technical assistance.

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Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2014-0221) offers supplementary material, available to authorized users.


Received: 2014-6-26
Accepted: 2014-8-1
Published Online: 2015-1-10
Published in Print: 2015-2-1

©2015 by De Gruyter

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