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. 2023 Oct 2;14(17):3285-3294.
doi: 10.7150/jca.81034. eCollection 2023.

Molecular Mechanism of Vitamin D Receptor Modulating Wnt/β-catenin Signaling Pathway in Gastric Cancer

Ying Zhang  1 , Yan Li  2 , Yuzheng Wei  2 , Lei Cong  2   3
Affiliations

Molecular Mechanism of Vitamin D Receptor Modulating Wnt/β-catenin Signaling Pathway in Gastric Cancer

Ying Zhang et al. J Cancer. .

Abstract

Background: Gastric cancer is the most common gastrointestinal cancer worldwide. The latest data showed that it was the fourth leading cause of cancer-related death. The unobvious symptom and the difficulties lying in the early diagnosis largely affect the effect of the treatment. Therefore, it becomes particularly important to investigate the related genes and signal transduction pathways in gastric cancer. Our previous study found that the vitamin D receptor (VDR) gene FokI polymorphism may be associated with susceptibility to gastric cancer in the Chinese Han population. However, the mechanism of VDR affecting gastric cancer is unknown. In this study, we explored the molecular mechanism and the possible signaling pathway of VDR modulating carcinogenesis and progression of gastric cancer. Methods: The expression of VDR in gastric cancer cell lines was interfered by plasmid transfection and RNA interference technology. And then we analyzed the cell viability and invasive ability by MTT assay, colony formation assay, and transwell migration assay, and detected the expression of VDR and several signaling proteins in gastric cancer cells by SDS-PAGE and Western blotting. Results: The overexpression of VDR can significantly inhibit the viability and invasive ability of gastric cancer cells; on the contrary, when VDR siRNA inhibits the expression of VDR, the viability and invasive ability of gastric cancer cells enhanced. VDR expression levels in gastric cancer cells treated with 1,25 (OH) 2D3 showed a time-dependent increased expression; and with the increase of the VDR expression, the expression of β-catenin decreased gradually, but the expression of E-cadherin showed a time-dependent increase (P < 0.05). Compared with the mutant-type VDR gene(ff) cells, the degree of β-catenin decline was significantly enhanced after transfected with homozygous wild-type VDR gene (FF) plasmids (p<0.05). Conclusions: The results of this study indicate that VDR FokI polymorphism plays an important role in the malignant phenotype of gastric cancer cells, such as proliferation, invasion, and clone formation. When the VDR is activated by its ligand, it can prevent the nuclear import of β-catenin, affect the E-cadherin level, inhibit the proliferation of gastric cancer cells, which suggested that VDR FokI gene may play a role of cancer suppressor via Wnt/β-catenin signaling pathway.

Keywords: FokI polymorphism; Wnt/β-catenin signaling pathway; carcinogenesis; gastric cancer; vitamin D receptor.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Expression of VDR in different tumor types from TIMER.
Figure 2
Figure 2
Expression of VDR in five gastric carcinoma cell lines.
Figure 3
Figure 3
Function changes of gastric cancer cells induced by interference on expression of VDR. a. Cell viability affected by VDR were analyzed by MTT assay. b. Cell proliferation capability affected by VDR were analyzed by colony formation assay. c. Cell invasive and migration ability affected by VDR were analyzed.
Figure 3
Figure 3
Function changes of gastric cancer cells induced by interference on expression of VDR. a. Cell viability affected by VDR were analyzed by MTT assay. b. Cell proliferation capability affected by VDR were analyzed by colony formation assay. c. Cell invasive and migration ability affected by VDR were analyzed.
Figure 4
Figure 4
Changes of VDR and related signaling proteins after 1,25 (OH) 2D3 stimulation.
Figure 5
Figure 5
Variation of Wnt/β-catenin pathway signal proteins in different VDR genotypes with ligand stimulation.
Figure 6
Figure 6
Effects of different VDR states on β-catenin expression and cell proliferation. a. Effects of different VDR states on β-catenin expression. b. Effects of different VDR states on cell proliferation.
See this image and copyright information in PMC

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