Oncotarget

Research Papers:

Role of DDX3 in the pathogenesis of inflammatory bowel disease

Saritha Tantravedi, Farhad Vesuna, Paul T. Winnard Jr, Marise R. Heerma Van Voss, Paul J. Van Diest and Venu Raman _

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Oncotarget. 2017; 8:115280-115289. https://doi.org/10.18632/oncotarget.23323

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Abstract

Saritha Tantravedi1, Farhad Vesuna1, Paul T. Winnard Jr1, Marise R. Heerma Van Voss1,2, Paul J. Van Diest2 and Venu Raman1,2,3

1Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

2Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

3Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

Correspondence to:

Venu Raman, email: [email protected]

Keywords: DDX3; inflammatory bowel disease; colorectal cancer; MMP; small molecule inhibitor

Received: September 29, 2017     Accepted: November 26, 2017     Published: December 15, 2017

ABSTRACT

When crypt stem cells of the gastrointestinal tract become injured, the result is increased synthesis of pro-inflammatory cytokines and matrix metalloproteinases by their progeny – the colonic epithelium. Chronic inflammation of the gastrointestinal tract is a characteristic of inflammatory bowel disease, which includes Crohn’s Disease and Ulcerative Colitis. In our ongoing investigation to decipher the characteristic functions of a RNA helicase gene, DDX3, we identified high DDX3 expression by immunohistochemistry of colon biopsy samples, which included chronic/mild Morbus Crohn, active Morbus Crohn, Chronic/mild Colitis Ulcerosa and active Colitis Ulcerosa in epithelium and stromal compartments. We used a small molecule inhibitor of DDX3, RK-33, on two human colonic epithelial cell lines, HCEC1CT and HCEC2CT and found that RK-33 was able to decrease expression of MMP-1, MMP-2, MMP-3, and MMP-10. Moreover, forced differentiation of a human colonic cancer cell line, HT29, resulted in decreased DDX3 levels, indicating that DDX3 contributes to the modulation of colonic epithelium differentiation. In conclusion, our results revealed novel functions of DDX3 in inflammatory bowel disease and indicate a potential for using RK-33 as a systemic therapy to promote not only differentiation of transformed colonic epithelium but also to reduce MMP expression and thus elicit a decreased inflammatory response.


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