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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. 5Fh7m3ebJHKpa3LjUnmMxG Video Abstract

The significance of autophagy for signal transduction has been unclear. Autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. The von Hippel-Lindau protein ubiquitylates Dvl to faciliatate its recruitment to autophagosomes through p62. In eukaryotic cells, autophagy is a highly conserved self-digestion process to promote cell survival in response to nutrient starvation and other metabolic stresses. Autophagy is regulated by cell signalling such as the mTOR (mammalian target of rapamycin) pathway. However, the significance of autophagy in modulation of signal transduction is unclear. Here we show that autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. Von Hippel–Lindau protein-mediated ubiquitylation is critical for the binding of Dvl2 to p62, which in turn facilitates the aggregation and the LC3-mediated autophagosome recruitment of Dvl2 under starvation; the ubiquitylated Dvl2 aggregates are ultimately degraded through the autophagy–lysosome pathway. Moreover, a reverse correlation between Dvl expression and autophagy is observed in late stages of colon cancer development, indicating that autophagy may contribute to the aberrant activation of Wnt signalling in tumour formation.