(Pro) renin receptor promotes colorectal cancer through the Wnt/β-catenin signaling pathway despite constitutive pathway component mutations

[Speaker] Akira Nishiyama:1
[Co-author] Yuki Shibayama:1, Zhiyu Wang:2, Juan Wang:1,2
1:Department of Pharmacology, Kagawa University Medical School, Japan, 2:Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, P. R. China

Background: Although constitutive activating mutations in the Wnt/β-catenin signaling pathway play an important role in colorectal cancer development, canonical signaling stimulation with Wnt ligands is essential for the activation of β-catenin. Here, we investigated the role of (pro)renin receptor ((P)RR), a component of the Wnt receptor complex, in the pathogenesis of colorectal cancer.
Methods: (P)RR silencing was performed in human colorectal cancer cell lines containing constitutive activating mutations in the Wnt/β-catenin signaling pathway. Induction of (P)RR overexpression was performed in a normal colon epithelial cell line. Protein levels of Wnt/β-catenin pathway components were detected by western blotting, and Wnt signaling activity was measured using a β-catenin reporter. Cell proliferation was evaluated by WST-1 assay in vitro and tumor formation was evaluated in a xenograft mouse model in vivo.
Results: (P)RR expression was significantly greater in colorectal cancer tissues and cells than in normal colorectal samples. Patients with strong (P)RR expression took more proportion in groups with poorly-differentiated, advanced and early progressed cancers. Silencing of (P)RR by siRNA significantly attenuated the Wnt/β-catenin signaling pathway in colorectal cancer cells, impaired their proliferation in vitro and inhibited tumor growth in vivo. In contrast, (P)RR overexpression activated the Wnt/β-catenin signaling pathway and proliferation of normal colon epithelial cells.
Conclusions: These data demonstrated that aberrant (P)RR expression promotes the progression of colorectal cancer through the activation of the Wnt/β-catenin signaling pathway despite the presence of constitutive pathway-activating mutations. Our results suggest that (P)RR is a potential diagnostic and therapeutic target for colorectal cancer.
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