Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ

Molecular Cancer

Research

Xiyong Liu¹  Jia Wu²  Jingwen Liu²  Saisai Yang²  Dingting Xu²  Yongjiang Wang²  Tianhui Pan²  Yiming Zhao²  Jianshan Mao³  Yongliang Zhu³  Zhenzhen Wen⁴  Haiying Tao⁵  Wei Shao⁶ 

[1] Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, 62232, Duarte, CA, USA;Laboratory of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88#, 310009, Hangzhou, Zhejiang, China;Laboratory of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88#, 310009, Hangzhou, Zhejiang, China;Cancer Institute and Education Ministry Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China;Laboratory of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88#, 310009, Hangzhou, Zhejiang, China;Present address: Department of Gastroenterology, Sir Run Run Shaw Hospital of Zhejiang, University School of Medicine, 310016, Hangzhou, Zhejiang, China;People’s Hospital of Huangyan district, 318020, Taizhou, Zhejiang, China;People’s Hospital of Putuo district, 316100, Zhoushan, Zhejiang, China;

关键词: Colorectal cancer initiating cells;    Self-renewal;    Non-canonical Wnt pathway;    NRIP2;    RORβ;    HBP1;   

DOI  :  10.1186/s12943-017-0590-2

 received in 2016-10-06, accepted in 2017-01-17,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundColorectal cancer remains one of the most common malignant tumors worldwide. Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors of colorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However, the underlying mechanism(s) remain poorly understood.MethodsVia retroviral library screening, we identified Nuclear Receptor-Interacting Protein 2 (NRIP2) as a novel interactor of the Wnt pathway from enriched colorectal cancer colosphere cells. The expression levels of NRIP2 and retinoic acid-related orphan receptor β (RORβ) were further examined by FISH, qRT-PCR, IHC and Western blot. NRIP2 overexpressed and knockdown colorectal cancer cells were produced to study the role of NRIP2 in Wnt pathway. We also verified the binding between NRIP2 and RORβ and investigated the effect of RORβ on CCICs both in vitro and in vivo. Genechip-scanning speculated downstream target HBP1. Western blot, ChIP and luciferase reporter were carried to investigate the interaction between NRIP2, RORβ, and HBP1.ResultsNRIP2 was significantly up-regulated in CCICs from both cell lines and primary colorectal cancer tissues. Reinforced expression of NRIP2 increased Wnt activity, while silencing of NRIP2 attenuated Wnt activity. The transcription factor RORβ was a key target through which NRIP2 regulated Wnt pathway activity. RORβ was a transcriptional enhancer of inhibitor HBP1 of the Wnt pathway. NRIP2 prevented RORβ to bind with downstream HBP1 promoter regions and reduced the transcription of HBP1. This, in turn, attenuated the HBP1-dependent inhibition of TCF4-mediated transcription.ConclusionsNRIP2 is a novel interactor of the Wnt pathway in colorectal cancer initiating cells. interactions between NRIP2, RORβ, and HBP1 mediate a new mechanism for CCIC self-renewal via the Wnt activity.

【 授权许可】

CC BY   
© The Author(s). 2017