Sninsky Jared A, Bishnupuri Kumar S, González Iván, Trikalinos Nikolaos A, Chen Ling, Dieckgraefe Brian K
Division of Gastroenterology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Oncotarget. 2021 Feb 16;12(4):278-291. doi: 10.18632/oncotarget.27896.
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 (r = 0.23, = 0.028), CD44 and CD44ICD (r = 0.36, = 0.0004), and Reg4 and CD44ICD (r = 0.45, ≤ 0.0001). Reg4 expression was associated with larger tumor size (r = 0.23, = 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 ( = 0.04) in patients who recurred. Inhibition of the Reg4-CD44/CD44ICD pathway may be a future therapeutic target for colon cancer patients.
Reg4在胃肠道恶性肿瘤中高表达，并作为一种促有丝分裂和促侵袭因子发挥作用。我们最近的研究表明，Reg4与CD44结合并诱导其蛋白水解切割，以释放CD44的胞质内结构域（CD44ICD）。本研究的目的是证明Reg4-CD44/CD44ICD通路在II/III期结肠癌中的临床意义及其与侵袭性临床参数的关联。我们构建了一个包含93例II/III期配对结肠癌患者的组织微阵列（TMA），其中23例有复发疾病。对该TMA进行Reg4、CD44和CD44ICD蛋白的免疫组织化学染色，并进行分析以确定与肿瘤特征、复发和总生存期的关联。TMA数据分析显示Reg4与CD44之间存在显著相关性（r = 0.23，P = 0.028），CD44与CD44ICD之间存在显著相关性（r = 0.36，P = 0.0004），Reg4与CD44ICD之间存在显著相关性（r = 0.45，P≤0.0001）。Reg4表达与更大的肿瘤大小相关（r = 0.23，P = 0.026）。虽然未观察到Reg4、CD44或CD44ICD表达与疾病复发之间的关联，但在复发患者中，Reg4阳性患者的中位生存期为4年，而Reg4阴性患者为7年（P = 0.04）。抑制Reg4-CD44/CD44ICD通路可能是未来结肠癌患者的治疗靶点。
