R-Spondins 2 and 3 Are Overexpressed in a Subset of Human Colon and Breast Cancers

Abstract

Wnt signaling is activated in many cancer types, yet targeting the canonical Wnt pathway has been challenging for cancer therapy. The pathway might be effectively targeted at many levels depending on the mechanism by which it has become hyperactive. Recently, mouse genetic screens have found that R-spondins (RSPOs) act as oncogenes. Evidence includes recurrent genomic rearrangements that led to increased RSPO2 or RSPO3 expression in human colorectal adenocarcinomas, exclusive of APC mutations. RSPOs modulate Wnt signaling to promote epithelial cell proliferation and survival. These secreted proteins modulate Wnt signaling by binding to G-coupled receptors LGR4/5/6, ultimately inhibiting frizzled membrane clearance by RNF43 and ZNRF3. They also exert their function independent of leucine-rich repeat-containing, G protein-coupled receptors (LGRs) by binding to ZNRF3 and RNF43. This results in increased b-catenin concentration that, after translocation to the nucleus, acts as a transcriptional coactivator of genes necessary for proliferation and cell survival. In this article, we aimed to identify the role of RSPOs in colon and breast cancers by using in silico and in vitro studies. We found that expression of RSPO2 and RSPO3 at high levels characterized a subset of colorectal cancers (CRCs). RSPO2 expression was found to characterize a subset of triple-negative breast cancers. In both instances, increased expression of RSPOs was associated with an activated Wnt signaling gene expression profile. Furthermore, knockdown of RSPO2 decreased Wnt signaling and proliferation in human breast cancer cells. Our findings show and confirm that RSPO2 and RSPO3 expression is upregulated in a subset of colorectal adenocarcinomas and breast cancers and that both are attractive druggable oncoprotein targets against such cancers. We also describe novel fusion transcripts that occur in CRC.

RSPO2 as Wnt signaling enabler: Important roles in cancer development and therapeutic opportunities

“… 77 Up-regulation of RSPO2 in liver cancer cell lines was contrary to what was observed in colon and breast cancer cell lines. 75 , 76 Conceptually similar work has been carried out by Conboy et al in 2019, highlighting in the literature that hepatomegaly and liver cancer were progressively induced by the overexpression of RSPO2 and loss of the TP53 protein through activation of the Wnt signaling pathway. Additionally, it has been concluded that oncogenic activation of RSPO2 leads to the initiation and progression of hepatocellular carcinoma through the Hippo/Yap mediated pathway, suggesting that RSPO2 may be the new and potential target in liver cancer therapy.…”

“…Further, it has also been concluded that the knockdown of RSPO2 results in decreased Wnt signaling and proliferation of the human breast cancer cell BT-549. 76 …”

Plasma protein changes reflect colorectal cancer development and associated inflammation

“…SCRN1 accelerates tumor progression by the regulation of exocytosis of matrix metalloproteinase-2/9 (MMP-2/9) ( 55 ), while RSPO3 is an oncogenic driver that causes CRC and extensive crypt hyperplasia, concomitantly stimulating stem cells and supportive niche cells ( 56 ). It was found that overexpression of RSPO2 and RSPO3 was presented by 4-10% of colon subjects ( 54 ) and recurrent R-spondin fusions in colon cancer activate the Wnt signaling and increase the tumorigenesis ( 57 ). Additionally, lower plasma levels of potential tumor suppressor proteins, such as RET and ARHGEF12 were detected in CRC patients.…”

Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling

“…Treatment with an RSPO3 was found to protect the epithelium from GVHD damage and radiation-induced colitis by accelerating ISC proliferation ( Bhanja et al, 2009 ; Takashima et al, 2011 ). Conversely, mutations that induce Rspo3 genetic fusion are owed for the magnification of Wnt signaling causal of human colorectal tumorigenesis ( Seshagiri et al, 2012 ; Conboy et al, 2021 ).…”