Abstract
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.
Highlights
Colorectal cancer remains one of the most common malignant tumors worldwide
Colorectal cancer cells have a high level of activity of HedgeHog (HH)-GLI signaling, and the self-renewal of cancer initiating cells (CCICs) relies on the direct function of HH-GLI activity in xenograft tumors [12]; Akt can activate 14-3-3zeta in the beta-catenin complex, which contributes to the stabilization and nuclear translocation of β-catenin, facilitating CCSC self-renewal by activating Wnt [13]
Wnt activity is important for the self-renewal of CCICs To evaluate the effect of Wnt activity on CCIC selfrenewal, we first enriched colospheres in vitro from primary colorectal cancer tissues and colorectal cancer cell lines and identified their stem-like properties
Summary
Colorectal 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. CCICs are a small subpopulation of cells within colorectal tumors that can self-renew, There are several pathways participating in the regulation of the self-renewal of CCICs. Notch signaling plays an important role in promoting CCIC self-renewal. MiR-34a targeting Notch promotes the differentiation of CCICs [10]; The BMP pathway maintains a stem cell selfrenewal balance by inhibiting the Wnt pathway. Akt phosphorylates Oct to promote iPS factor transcription [14] Among these pathways, the abnormal activation of the Wnt pathway is one of the most critical events in the tumorigenesis and development of colorectal cancer and plays a key role in maintaining the self-renewal of CCICs [15,16,17,18]. Wnt activity is an important target for inhibition of the selfrenewal of CCICs
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