NOTCH1 activates the Wnt/β-catenin signaling pathway in colon cancer

被引：33

作者：

Ishiguro, Hideyuki ^{[1
]}

Okubo, Tomotaka ^{[1
]}

Kuwabara, Yoshiyuki ^{[1
]}

Kimura, Masahiro ^{[1
]}

Mitsui, Akira ^{[1
]}

Sugito, Nobuyoshi ^{[1
]}

Ogawa, Ryo ^{[1
]}

Katada, Takeyasu ^{[1
]}

Tanaka, Tatsuya ^{[1
]}

Shiozaki, Midori ^{[1
]}

Mizoguchi, Koji ^{[1
]}

Samoto, Yosuke ^{[1
]}

Matsuo, Yoichi ^{[1
]}

Takahashi, Hiroki ^{[1
]}

Takiguchi, Shuji ^{[1
]}

机构：

[1] Nagoya City Univ, Grad Sch Med, Dept Surg Gastroenterol, Mizuho Ku, Nagoya, Aichi 4678601, Japan

来源：

ONCOTARGET | 2017年 / 8卷 / 36期

基金：

日本学术振兴会;

关键词：

colon cancer; beta-catenin; NOTCH1; NICD1; prognosis; SQUAMOUS-CELL CARCINOMA; HUMAN BREAST-CANCER; BETA-CATENIN; CYCLIN D1; C-MYC; INTRACELLULAR DOMAIN; TUMOR-SUPPRESSOR; PROGENITOR CELLS; DOWN-REGULATION; WNT;

D O I：

10.18632/oncotarget.19534

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose and Methods: The translocation of beta-catenin/CTNNB1 to the nucleus activates Wnt signaling and cell proliferation; however, the precise mechanism underlying this phenomenon remains unknown. Previous reports have provided evidence that NOTCH1 is involved in the Wnt signaling pathway. Therefore, we sought to determine the mechanism by which NOTCH1 influences the Wnt/beta-catenin pathway. We constructed a vector expressing the NOTCH1 intracellular domain (NICD1) and transfected the vector into HCT116 which has low expression of NICD1. Furthermore, inhibition of NOTCH signal pathway in SW480 which has abundant NICD1 expression, was performed by transfection of siNICD1 or DAPT, gamma secretase inhibitor, treatment. In addition, we evaluated NICD1 and beta-catenin localization in colon cancer cell lines and in 189 colon cancer tissue samples and analyzed the correlation between the nuclear localization of NICD1 and the clinicopathological features of colon cancer patients. Results: Immunohistochemical assays demonstrated that NICD1 and beta-catenin exhibited a similar localization pattern in colon cancer tissues. In addition, we found that NICD1 induced the translocation of beta-catenin to the nucleus and that NICD1 and beta-catenin co-localized in the nucleus. Overexpression of NICD1 increased luciferase activity of Wnt signal pathway. On the other hand, reduction of NICD1 reduced luciferase activity of Wnt signaling pathway. In the 189 analyzed colon cancer cases, multivariate COX regression analysis demonstrated the independent prognostic impact of nuclear localization of NICD1(p=0.0376). Conclusion: NOTCH1 plays a key role in the Wnt pathway and activation of NOTCH1 is associated with the translocation of beta-catenin to the nucleus.

引用

页码：60378 / 60389

页数：12

共 56 条

[1] Activation of Notch1 signaling is required for β-catenin-mediated human primary melanoma progression [J].