Alpha‐2‐glycoprotein 1, zinc‐binding (AZGP1), known as zinc‐alpha‐2‐glycoprotein (ZAG), is a multifunctional secretory glycoprotein and relevant to cancer metastasis. Little is known regarding the underlying mechanisms of AZGP1 in prostate cancer (PCa). In the present study, we report that AZGP1 is an androgen‐responsive gene, which is involved in AR‐induced PCa cell proliferation and metastasis. In clinical specimens, the expression of AZGP1 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of AZGP1 is upregulated by the androgen‐AR axis at both messenger RNA and protein levels. Furthermore, Chip‐Seq assay identifies canonical androgen‐responsive elements (AREs) at AZGP1 enhancer; and dual‐luciferase reporter assays reveal that the AREs is highly responsive to androgen whereas mutations of the AREs abolish the reporter activity. In addition, AZGP1 promotes G1/S phase transition and cell cycle progress by increasing cyclin D1 levels in PCa cells. Functional studies demonstrate that knocking down endogenous AZGP1 expression in LNCaP and CWR22Rv1 cells largely weaken androgen/AR axis‐induced cell migration and invasion. In vivo xenotransplantation tumor experiments also show that AZGP1 involves in androgen/AR axis‐mediated PCa cell proliferation. Taken together, our study implicates for the first time that AZGP1 is an AR target gene and is involved in androgen/AR axis‐mediated cell proliferation and metastasis in primary PCa.
Background Tumor metastasis is the main cause of death of cancer patients, and cancer stem cells (CSCs) is the basis of tumor metastasis. However, systematic analysis of the stemness of prostate cancer cells is still not abundant. In this study, we explore the effective factors related to the stemness of prostate cancer cells by comprehensively mining the multi-omics data from TCGA database. Methods Based on the prostate cancer transcriptome data in TCGA, gene expression modules that strongly relate to the stemness of prostate cancer cells are obtained with WGCNA and stemness scores. Copy number variation of stemness genes of prostate cancer is calculated and the difference of transcription factors between prostate cancer and normal tissues is evaluated by using CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes in prostate cancer is constructed using the STRING database. Meanwhile, the correlation between stemness genes of prostate cancer and immune cells is analyzed. Results Prostate cancer with higher Gleason grade possesses higher cell stemness. The gene set highly related to prostate cancer stemness has higher CNV in prostate cancer samples than that in normal samples. Although the transcription factors of stemness genes have similar expressions, they have different contributions between normal and prostate cancer tissues; and particular transcription factors enhance the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. In addition, the lower tumor immune microenvironment is conducive to the stemness of prostate cancer. CD8 + T cells and M1 macrophages may play more important role in the stemness of prostate cancer than other immune cells in the tumor microenvironment. Finally, EZH2 is found to play a central role in stemness genes and is negatively correlated with resting mast cells and positively correlated with activated memory CD4 + T cells. Conclusions Based on the systematic and combined analysis of multi-omics data, we find that high copy number variation, specific transcription factors, and low immune microenvironment jointly contribute to the stemness of prostate cancer cells. These findings may provide us new clues and directions for the future research on stemness of prostate cancer.
Background: Tumor metastasis is the main cause of death of cancer patients, and the existence of cancer stem cells is the basis of tumor metastasis. However, the systematic analysis of the stemness of prostate cancer cells is still not abundant. This article explores the effective factors that lead to the stemness of prostate cancer cells with multi-omics data mining.Methods: Gene expression modules that were strongly related to the stemness of prostate cancer cells were obtained with WGCNA and stemness scores, based on the prostate cancer transcriptome data in TCGA. Calculated the copy number variation of stemness genes of prostate cancer and evaluated the difference of transcription factors in prostate cancer and normal tissues, based on CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes of prostate cancer was constructed with the STRING database. At the same time, the correlation between stemness genes of prostate cancer and immune cells was analyzed.Results: Prostate cancer with high Gleason grade was more stemness. The gene set highly related to prostate cancer stemness had higher CNV in prostate cancer samples than normal samples. The transcription factors of stemness genes had similar expressions but had different contributions in normal and prostate cancer tissues. And particular transcription factors enhanced the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. The lower tumor immune microenvironment was conducive to the stemness of prostate cancer, and CD8+ T cells and M1 macrophages might play an important role than other immune cells in the tumor microenvironment. We also found that EZH2 played a central role in stemness genes and was negatively correlated with resting mast cells and positively correlated with activated memory CD4+ T cells.Conclusions: This study found that high copy number variation, specific transcription factors, and low immune microenvironment contributed to the stemness of prostate cancer cells through systematic multi-omics analysis. These findings would provide new clues and directions for future research of prostate cancer stem cells.
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