Abstract
The acidic tumor microenvironment provides an energy source driving malignant tumor progression. Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells. The expression of the vitamin D receptor (VDR) is closely related to the initiation and development of colorectal carcinoma (CRC), but its regulatory mechanism in CRC stem cells is still unclear. Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta (PPARD) expression. Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis. The nuclear export signal in VDR was sensitive to acidosis, and VDR was exported from the nucleus. Chromatin immunoprecipitation (ChIP) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses showed that VDR transcriptionally repressed SRY-box 2 (SOX2) by binding to the vitamin D response elements in the promoter of SOX2, impairing tumor growth and drug resistance. We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo. These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling, resulting in a lack of efficacy of vitamin D in antineoplastic process.
Highlights
Colorectal carcinoma (CRC) is a common malignancy whose morbidity and mortality rates rank it among the top five malignancies worldwide.[1]
Studies have shown that the vitamin D receptor (VDR) expression level is related to the degree of differentiation of cancer cells, and we have previously found that an acidic environment can suppress the vitamin D signaling pathway to promote the cancer stem cell (CSC) phenotype among glioma cells.[17]
Acidosis inhibits VDR expression, which is negatively correlated with malignant CRC To investigate the effect of the acidic tumor microenvironment on the stemness of CRC cells, we first isolated and identified RKO stem-like cells (RKO-SLCs) and primary CRC cells (CC tissueadherent cells), CRC stem cells (CC tissue CSCs) from tissue samples of CRC patients (Supplementary Fig. S1a–c)
Summary
Colorectal carcinoma (CRC) is a common malignancy whose morbidity and mortality rates rank it among the top five malignancies worldwide.[1]. The tumor microenvironment has an important role in determining the cancer stem cell (CSC) phenotype.[5,6] Low oxygen and low pH are two physicochemical characteristics of the tumor microenvironment These characteristics lead to a series of changes related to cancer cell biological phenotypes, including an induced CSC phenotype and a metabolic reprogramming phenotype.[7] In addition, low oxygen and low pH change the core cell metabolic phenotype, providing the basic conditions required for cancer cells to optimize their metabolism.[8,9] Our recent studies have investigated the roles of metabolic microenvironment reprogramming in promoting gastrointestinal cancer progression.[10,11,12,13] the effects of acidic stress on cancer and the underlying mechanisms need further study. We sought to investigate the effects of the acidic tumor microenvironment on CRC stem cells
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