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Collagen regulation of let-7 in pancreatic cancer involves TGF-β1-mediated membrane type 1-matrix metalloproteinase expression

Oncogene volume 30, pages 1002–1008 (2011)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich fibrosis known as desmoplastic reaction; however, the role of fibrosis in PDAC is poorly understood. In this report we show that collagen can regulate the tumor suppressive let-7 family of microRNAs in pancreatic cancer cells. PDAC cells growing in 3D collagen gels repress mature let-7 without affecting the precursor form of let-7 in part through increased expression of membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) and ERK1/2 activation. PDAC cells in collagen also demonstrate increased TGF-β1 signaling, and blocking TGF-β1 signaling attenuated collagen-induced MT1-MMP expression, ERK1/2 activation and repression of let-7 levels. Although MT1-MMP overexpression was not sufficient to inhibit let-7 on 2D tissue culture plastic, overexpression of MT1-MMP in PDAC cells embedded in 3D collagen gels or grown in vivo repressed let-7 levels. Importantly, MT1-MMP expression significantly correlated with decreased levels of let-7 in human PDAC tumor specimens. Overall, our study emphasizes the interplay between the key proteinase MT1-MMP and its substrate type I collagen in modulating microRNA expression, and identifies an additional mechanism by which fibrosis may contribute to PDAC progression.

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Acknowledgements

This research was supported by Grant R01CA126888 (HGM) from the NCI, and funding from the Elsa U Pardee Foundation (HGM) and the National Pancreas Foundation (HGM).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Chicago, IL, USA

    S Dangi-Garimella & H G Munshi

  2. Division of Surgical Oncology, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    M J Strouch, P J Grippo & D J Bentrem

  3. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA

    P J Grippo, D J Bentrem & H G Munshi

  4. The Jesse Brown VA Medical Center, Chicago, IL, USA

    D J Bentrem & H G Munshi

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  1. S Dangi-Garimella
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Correspondence to S Dangi-Garimella.

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Dangi-Garimella, S., Strouch, M., Grippo, P. et al. Collagen regulation of let-7 in pancreatic cancer involves TGF-β1-mediated membrane type 1-matrix metalloproteinase expression. Oncogene 30, 1002–1008 (2011). https://doi.org/10.1038/onc.2010.485

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