Another One Bites the Gut: Nuclear Receptor LRH-1 in Intestinal Regeneration and Cancer

The process of self-renewal in normal intestinal epithelium is characterized by a fine balance between proliferation, differentiation, migration, and cell death. When even one of these aspects escapes the normal control, cellular proliferation and differentiation are impaired, with consequent onset of tumorigenesis. In humans, colorectal cancer (CRC) is the main pathological manifestation of this derangement. Nowadays, CRC is the world's fourth most deadly cancer with a limited survival after treatment. Several conditions can predispose to CRC development, including dietary habits and pre-existing inflammatory bowel diseases. Given their extraordinary ability to interact with DNA, it is widely known that nuclear receptors play a key role in the regulation of intestinal epithelium, orchestrating the expression of a series of genes involved in developmental and homeostatic pathways. In particular, the nuclear receptor Liver Receptor Homolog-1 (LRH-1), highly expressed in the stem cells localized in the crypts, promotes intestine cell proliferation and renewal in both direct and indirect DNA-binding manner. Furthermore, LRH-1 is extensively correlated with diverse intestinal inflammatory pathways. These evidence shed a light in the dynamic intestinal microenvironment in which increased regenerative epithelial cell turnover, mutagenic insults, and chronic DNA damages triggered by factors within an inflammatory cell-rich microenvironment act synergistically to favor cancer onset and progression.