Vitamin D receptor prevents tumour development by regulating the Wnt/β-catenin signalling pathway in human colorectal cancer

Abstract

Background Colorectal cancer (CRC) is a common disease threatening human lives worldwide, and vitamin D receptor (VDR) contributes protective roles in this disease. However, the molecular mechanisms underlying VDR protection in CRC progression require further investigation. Methods In this study, we statistically analyzed the relationship between VDR expression and CRC development in patients and detected invasion and apoptosis in CRC cells with VDR overexpression and interference. We also detected the expression of key genes involved in Wnt/β-catenin signalling (β-catenin, lymphoid enhancer factor (LEF)-1 and cyclin D1) in SW480 cells and nude mice injected with VDR-overexpressing SW480 cells and observed tumour development. Additionally, we performed Co-immunoprecipitation (Co-IP) and glutathione-S-transferase (GST) pull-down assays to identify the protein interactions of VDR with β-catenin, dual luciferase (LUC) and chromatin immunoprecipitation (ChIP) to detect the activation of LEF-1 by VDR. Results The VDR level was closely related to the development and prognosis of CRC patients. VDR overexpression inhibited invasion but promoted apoptosis in cancer cells. β-catenin shRNA contributed oppositely to cancer cell activity with VDR shRNA. Additionally, VDR interacted with β-catenin at the protein level and blocked its nuclear accumulation. VDR regulated the expression of β-catenin, cyclin D1 and LEF-1 and directly activated LEF-1 transcription in vitro. Furthermore, nude mice injected with VDR-overexpressing SW480 cells revealed suppression of tumour growth and decreased expression of β-catenin, cyclin D1 and LEF-1. Conclusions This study indicated that VDR protected against CRC disease in humans by inhibiting Wnt/β-catenin signalling to control cancer cell invasion and apoptosis, providing new evidence to explore VDR biomarkers or agonists for CRC patient diagnosis and treatment.

Calcitriol Treatment Decreases Cell Migration, Viability and β-Catenin Signaling in Oral Dysplasia

“…Similarly, in colorectal cancer, low VDR expression is predominantly observed in patients with advanced cancer stages (III and IV), and interestingly, overexpression of VDR reduced β-catenin and Cyclin D1 levels, suggesting that the Wnt/β-catenin pathway is active during colorectal cancer because of reduced VDR [36]. In fact, tumor growth of the colon adenocarcinoma cell line SW480 in mice is impaired when cells overexpress VDR, indicating that VDR acts as a tumor suppressor in colorectal cancer [36]. Nuclear VDR expression has also been associated with better overall survival in lung and urothelial bladder cancer patients [20,23].…”

“…By comparing VDR expression levels in normal, benign, and malignant tissues of skin, breast, ovarian and prostate, it was described a negative correlation between VDR expression and tumor malignancy [17,18]. Similarly, in colorectal cancer, low VDR expression is predominantly observed in patients with advanced cancer stages (III and IV), and interestingly, overexpression of VDR reduced β-catenin and Cyclin D1 levels, suggesting that the Wnt/β-catenin pathway is active during colorectal cancer because of reduced VDR [36]. In fact, tumor growth of the colon adenocarcinoma cell line SW480 in mice is impaired when cells overexpress VDR, indicating that VDR acts as a tumor suppressor in colorectal cancer [36].…”

A comprehensive AI‐driven analysis of large‐scale omic datasets reveals novel dual‐purpose targets for the treatment of cancer and aging

“…Antagonism, for most of the selected targets (Figure 5b–c , genes in purple), and agonism, for PGR, PPARA, and VDR (genes in red), were proposed as potential approaches for anti‐aging and anti‐cancer treatment. Of note, while VDR was mostly upregulated among cancer types, higher expression of VDR is suggested to exert an anti‐tumorigenic effect and associated with favorable prognosis in multiple types of cancer (Campbell & Trump, 2017 ; Yu et al., 2023 ). As such, agonism was proposed as a putative therapeutic approach.…”

Vitamin D improves autoimmune diseases by inhibiting Wnt signaling pathway

“…14 Recent studies have shown that the activated Wnt/βcatenin pathway is opposite to the effect of VitD on the development and phenotypic changes of cancer cells, and the antagonism between Wnt/β-catenin pathway and VitD further affects the normal physiological processes of the body. 15,16 However, VitD exerts a negative regulatory effect on the Wnt signaling pathway, thus impacting the progression of SLE, an aspect that has not been previously reported. To further study the development of SLE mediated by VitD through the Wnt signaling pathway, we conducted this study to breakthrough approaches for clinical treatment.…”

“…Recent studies have shown that the activated Wnt/β‐catenin pathway is opposite to the effect of VitD on the development and phenotypic changes of cancer cells, and the antagonism between Wnt/β‐catenin pathway and VitD further affects the normal physiological processes of the body. 15 , 16 …”