Abstract
The WNT/β-catenin signaling pathway controls stem and progenitor cell proliferation, survival and differentiation in epithelial tissues. Aberrant stimulation of this pathway is therefore frequently observed in cancers from epithelial origin. For instance, colorectal and hepatic cancers display activating mutations in the CTNNB1 gene encoding β-catenin, or inactivating APC and AXIN gene mutations. However, these mutations are uncommon in breast and pancreatic cancers despite nuclear β-catenin localization, indicative of pathway activation. Notably, the low-density lipoprotein receptor-related protein 6 (LRP6), an indispensable co-receptor for WNT, is frequently overexpressed in colorectal, liver, breast and pancreatic adenocarcinomas in association with increased WNT/β -catenin signaling. Moreover, LRP6 is hyperphosphorylated in KRAS-mutated cells and in patient-derived colorectal tumours. Polymorphisms in the LRP6 gene are also associated with different susceptibility to developing specific types of lung, bladder and colorectal cancers. Additionally, recent observations suggest that LRP6 dysfunction may be involved in carcinogenesis. Indeed, reducing LRP6 expression and/or activity inhibits cancer cell proliferation and delays tumour growth in vivo. This review summarizes current knowledge regarding the biological function and regulation of LRP6 in the development of epithelial cancers—especially colorectal, liver, breast and pancreatic cancers.
Highlights
Cell proliferation and differentiation are finely regulated during epithelial tissue development and renewal
Single-cell analyses performed in isogenic human colonic epithelial cell lines confirmed that total and nuclear levels of β-catenin were increased upon lipoprotein receptor-related protein 6 (LRP6) silencing, confirming an important role for LRP6 in WNT signaling of adenomatous polyposis coli (APC)-mutated cells [69]
It is clear that LRP6 is a key player in the activation of the WNT/β-catenin signaling pathway and, in the regulation of tissue homeostasis under physiological and pathological conditions
Summary
Cell proliferation and differentiation are finely regulated during epithelial tissue development and renewal. That includes casein kinase 1 (CK1α), glycogen synthase kinase 3 (GSK3), AXIN and adenomatous polyposis coli (APC) proteins Within this complex, β-catenin is phosphorylated by CK1α at serine. Cancers 2019, 11, 1162 recruitment of more AXIN and GSK3, acting as an inhibitor of this kinase, amplifying WNT signal activation and allowing sustained activation of the pathway [6]. Mutations in WNT/β-catenin pathway coding genes such as CTNNB1, AXIN and APC are found in colorectal and hepatic cancers, as described below, and are known to drive tumorigenesis. Overexpression of these genes is not reported in all carcinomas, suggesting the involvement of other key components of this pathway in carcinogenesis. We focus on the specific roles of LRP6 in the control of the WNT/β-catenin pathway and in the regulation of tissue homeostasis and carcinoma development
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