Research Papers:

Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer

Jared A. Sninsky, Kumar S. Bishnupuri, Iván González, Nikolaos A. Trikalinos, Ling Chen and Brian K. Dieckgraefe _

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Oncotarget. 2021; 12:278-291. https://doi.org/10.18632/oncotarget.27896

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Jared A. Sninsky5, Kumar S. Bishnupuri1, Iván González2, Nikolaos A. Trikalinos3, Ling Chen4 and Brian K. Dieckgraefe1

1 Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110, USA

2 Division of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA

3 Division of Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA

4 Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO 63110, USA

5 Division of Gastroenterology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA

Correspondence to:

Brian K. Dieckgraefe,email: [email protected]

Keywords: Reg4; CD44; CD44ICD; colorectal cancer

Received: August 06, 2020     Accepted: January 26, 2021     Published: February 16, 2021

Copyright: © 2021 Sninsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, recurrence and overall survival. The TMA data analysis showed a significant correlation between Reg4 and CD44 (r2 = 0.23, P = 0.028), CD44 and CD44ICD (r2 = 0.36, p = 0.0004), and Reg4 and CD44ICD (r2 = 0.45, p ≤ 0.0001). Reg4 expression was associated with larger tumor size (r2 = 0.23, p = 0.026). Although, no association was observed between Reg4, CD44, or CD44ICD expression and disease recurrence, Reg4-positive patients had a median survival of 4 years vs. 7 years for Reg4-negative patients (p = 0.04) in patients who recurred. Inhibition of the Reg4-CD44/CD44ICD pathway may be a future therapeutic target for colon cancer patients.

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