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

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

doi:10.18632/oncotarget.27896

Jared A Sninsky, Nikolaos A Trikalinos + Show 4 more

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https://doi.org/10.18632/oncotarget.27896

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Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States
We constructed a tissue microarray (TMA) of 94 stage II and III colon cancer patients matched by patient/ tumor characteristics and disease recurrence
We found that Protein encoded by Reg4 gene (Reg4) expression is associated with larger tumors and higher mortality in metastatic disease, but not with recurrence risk per se

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates 101,420 new cases of colon cancer, 44,180 new cases of rectal cancer and about 51,020 deaths from CRC in the United States for 2019. While stage I CRC is overwhelmingly curable with resection, metastatic or stage IV disease is commonly fatal with a 5-year survival rate of 15% and requires a multidisciplinary approach with a chemotherapy backbone [1]. For locally advanced (stage II) and node positive (III) disease the approach is still curative, but 5-year survival rates range from 50–80%, with mortality ascribed to recurrent disease [2,3,4]. Chemotherapy in stage II and III disease is hypothesized to treat micrometastases that account for disease recurrence following surgery [6,7,8]

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