1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

Abstract

The aim of this study was to highlight the role of 1a,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQOinduced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D 3 may be a promising strategy for the prevention and treatment of esophageal SCC.

Inflammation‐induced myeloid‐derived suppressor cells associated with squamous cell carcinoma of the head and neck

“…The suppressive function of MDSC to T‐cell proliferation may be central to tumor formation . The suppressive function was measured in the following suppression assay, as described previously . The isolated CD8 + T cells among PBMCs from patients were carboxyfluorescein succinimidyl ester‐labeled (3 μM) (Sigma), and seeded in 96‐well plates (at 2 × 10 5 cells/well) with MDSC isolated from PBMCs and/or cancer cells with 5:1 ratio.…”

Suppression of Oxidative Stress and NFκB/MAPK Signaling by Lyophilized Black Raspberries for Esophageal Cancer Prevention in Rats

“…In rodent models of ESCC, the elevated iNOS can lead to oxidative stress [16,17]. In 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model, an increased level of ROS was observed [18]. DNA damage is the major outcomes from ROS [19].…”

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

“…Calcitriol treatment of esophageal squamous cell carcinoma cell lines suppressed IL-6 induced STAT3 phosphorylation. 15 When mice with experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, were treated with calcitriol, they showed decreased STAT1 phosphorylation in microglia and decreased phosphorylation of JAK2, TYK2, STAT3 and STAT4 in T-cells. 16 In addition, the clinical severity and duration of EAE was significantly decreased in mice treated with calcitriol, and importantly was associated with decreased IFN-g production and T-cell proliferation.…”