Role of VDR-signalling in colorectal tumourigenesis

Acknowledgement

We are grateful to Quantace, suppliers of SensiMix qPCR reagents, and Bioline, suppliers of the human reference gene panel, for  supporting one of our PhD students.

Introduction

There is some experimental and epidemiological evidence that points to a link between environmental factors such as diet or exposure to sunshine and the development of colorectal cancer. Vitamin D and sodium butyrate are two factors proposed as having a protective effect on colorectal cancer risk. Vitamin D, derived from sunlight exposure and food, is a regulator of essential cell regulatory processes, such as differentiation, proliferation and apoptosis. The human colon expresses both enzymes required for the synthesis of active vitamin D as well as its inactivation. NaB is produced by bacterial fermentation of short chain fatty acids and is a primary energy source for normal colonocytes. It has a proliferative effect on normal colonic epithelium but has anti-proliferative and differentiation-inducing effects on colorectal carcinoma cell. These properties have generated considerable interest in using these compounds or derivatives thereof for colon cancer chemoprevention.

RXR regulates nuclear import of unliganded VDR. VitD affects numerous genes and some main targets are shown here, with activities that are upregulated shown in green, and those that are down regulated shown in red. Clearly, these effects provide a rationale for the protective effect of vitD, but the detailed molecular mechanisms underlying this effect are not well understood.

The effects of vitD are not absolute. Antiproliferative effects of VitD are incomplete and the percentage of cells accumulating in G1 phase rarely exceeds 80%.

The genomic effects of vitD are effected through the VDR, a nuclear hormone receptor that also acts as a receptor for a secondary bile acid, another pathway through which it is believed to exerta protective effect. IHC reveals that in normal tissue VDR expression is localised mainly in the epithelial cells and that its expression is more sporadic in cancers. qRT-PCR of LCM epithelium and stroma shows that VDR mRNA is expressed in the stroma.

Project: Molecular mechanisms: Identification of Vitamin D receptor-mediated signalling pathways involved in colorectal tumourigenesis

Aim: to identify the molecular mechanisms underlying the tumour-preventative effects of vitamin D.

Vitamin D, whose biological effects are mediated by the vitamin D receptor (VDR) has been postulated to play a role in CRC prevention. Its function has been linked to the inhibition of cancer cell growth and stimulation of cellular differentiation. Therefore, the VDR is viewed as an important target for cancer prevention and therapy by specific VDR modulators. We have discovered a molecular mechanism that accounts for the dysregulation of the vitamin D signalling pathway in colorectal cancers. Moreover, we have identified numerous vitamin D-dependent genes whose expression is co-regulated with VDR in normal colon, but becomes dysregulated in colorectal cancers. Some of these genes have previously been identified as vitamin D-responsive, but the majority have never been linked to vitamin D. A significant number of these novel vitamin D-regulated genes are negative regulators of the wnt pathway and positive regulators of the TGF-beta; pathway, the two prime signalling pathways implicated in colorectal cancer development. The elucidation of the mechanisms by which vitamin D modifies the occurrence or progression of colorectal cancer is of prime relevance for the design of chemopreventative protocols for colorectal cancer. Our research is identifying vitamin D as a central coordinator of pathways that are critical for maintaining homeostasis in the normal colon.