(Pro)renin receptor promotes colorectal cancer progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota

Abstract

Background We previously found that (pro)renin receptor ((P)RR) augments Wnt3 protein without affecting Wnt3 gene transcription in colorectal cancer (CRC) cells, thus contributes to CRC initiation. The present study aims to investigate whether (P)RR further promotes CRC progression following oncogenesis and the related mechanisms. Notably, we deeply elaborate how (P)RR affects Wnt3 protein level and the key enzyme that mediates this process. Methods Immunohistochemistry, western blotting and immunofluorescence were performed to detect protein expression status. A kind of gastrointestinal epithelium-specific ATP6AP2 ((P)RR encoding gene) knock-in mice were generated using Crispr/Cas9 system. Results We found that increased (P)RR expression in primary CRC lesions is positively associated with higher Wnt3 protein level and disease progression. Progressive CRC presents less colocalization of Wnt3 and an E3 ubiquitin ligase NEDD4L in primary lesions than non-progressive CRC. In colon cancer cells, (P)RR dramatically inhibits the NEDD4L-mediated Wnt3 protein ubiquitination. ATP6AP2 knock-in mice show more diminished Wnt3-NEDD4L colocalization in their gut epithelium in comparison to wildtype mice. They also have abnormal gut bacterial flora distribution. Especially, Lachnospiraceae_NK4A136 and Bacteroides genus, which are generally protective against CRC, are suppressed in guts of ATP6AP2 knock-in mice. Conclusions Collectively, (P)RR promotes CRC progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota.

Construction of a new prognostic model for colorectal cancer based on bulk RNA-seq combined with The Cancer Genome Atlas data

“…Inhibition of the renin-angiotensin system pathway has shown efficacy in reducing tumor growth and metastasis, and inhibitors targeting this pathway have demonstrated promising results in in clinical practice ( 25 ). Moreover, the (pro) renin receptor has been reported in promoting CRC progression by inhibiting NEDD4L-mediated Wnt3 ubiquitination and regulating intestinal microbiota ( 26 ). It is also considered as a potential therapeutic target for pancreatic cancer, CRC, brain cancer and other cancers ( 27 ).…”

NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor

“…Subsequently, it was reported that both Wnt and β-catenin could be downregulated by NEDD4L via ubiquitination. Downregulation of Wnt3 negatively regulated the progression of colorectal cancer, but this effect was diminished by the (pro)renin receptor, and downregulation of β-catenin inhibited the transcription of Wnt-triggered genes, such as the survival hormones cyclin D1 and MMP9 (Tanksley et al, 2013;Wang et al, 2023). NEDD4L also enhanced the sensitivity of glioma cells to temozolomide by inhibiting Wnt/β-catenin signaling (Chen et al, 2019).…”