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Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study.

ABSTRACT: We have demonstrated that zinc exposure induces apoptosis in human prostate cancer cells (PC-3) and benign hyperplasia cells (BPH), but not in normal prostate cells (HPR-1). However, the mechanisms underlying the effects of zinc on prostate cancer cell growth and zinc homeostasis remain unclear. To explore the zinc effect on gene expression profiles in normal (HPR-1) and malignant prostate cells (PC-3), we conducted a time course study of Zn treatment with microarray analysis. Microarray data were evaluated and profiled using computational approach for the primary and secondary data analyses. Final analyses were focused on the genes (1) highly sensitive to zinc; (2) associated with zinc homeostasis, i.e., metallothioneins (MTs), solute zinc carriers (ZIPs) and zinc exporters (ZnTs); (3) relevant to several oncogenic pathways. Zinc-mediated mRNA levels of MT isotypes were further validated by semi-quantitative RT-PCR. Results showed that zinc effect on genome-wide expression patterns was cell-type specific, and zinc appeared to have mainly down-regulatory effects on thousands of genes (1953 in HPR-1; 3534 in PC-3) with a threshold of +/-2.5-fold, while fewer genes were up-regulated (872 in HPR-1; 571 in PC-3). The patterns of zinc effect on functional MT genes' expression provided evidence for the cell type-dependent zinc accumulation and zinc-induced apoptosis in prostate cells. In PC-3 cells, zinc significantly up-regulated the expression of MT-1 isotypes MT-1J and MT-1M, denoted previously as "nonfunctional" MT genes, and now a depictive molecular structure of MT-1J was proposed. Examination of genes involved in oncogenic pathways indicated that certain genes, e.g., Fos, Akt1, Jak3 and PI3K, were highly regulated by zinc with cell-type specificity. This work provided an extensive database on zinc-related prostate cancer research. The strategy of data analysis was devoted to finding genes highly sensitive to Zn, and the genes associated with zinc accumulation and zinc-induced apoptosis. The results indicate that zinc regulation of gene expression is cell-type specific, and MT genes play important roles in prostate malignancy.

SUBMITTER: Lin SF

PROVIDER: S-EPMC2821158 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study.

Lin Shu-Fei SF Wei Hua H Maeder Dennis D Franklin Renty B RB Feng Pei P

The Journal of nutritional biochemistry 20081213 12

We have demonstrated that zinc exposure induces apoptosis in human prostate cancer cells (PC-3) and benign hyperplasia cells (BPH), but not in normal prostate cells (HPR-1). However, the mechanisms underlying the effects of zinc on prostate cancer cell growth and zinc homeostasis remain unclear. To explore the zinc effect on gene expression profiles in normal (HPR-1) and malignant prostate cells (PC-3), we conducted a time course study of Zn treatment with microarray analysis. Microarray data we ...[more]

PMID: 19071009

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Project description:BACKGROUND: Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months. CONCLUSIONS: E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways.

Project description:Graphical abstract The cGAS-STING pathway, orchestrating complicated transcriptome-wide immune responses, is essential for host antiviral defense but can also drive immunopathology in severe COVID-19. Here, we performed time-course RNA-Seq experiments to dissect the transcriptome expression dynamics at the gene-isoform level after cGAS-STING pathway activation. The in-depth time-course transcriptome after cGAS-STING pathway activation within 12 h enabled quantification of 48,685 gene isoforms. By employing regression models, we obtained 13,232 gene isoforms with expression patterns significantly associated with the process of cGAS-STING pathway activation, which were named activation-associated isoforms. The combination of hierarchical and k-means clustering algorithms revealed four major expression patterns of activation-associated isoforms, including two clusters with increased expression patterns enriched in cell cycle, autophagy, antiviral innate-immune functions, and COVID-19 coronavirus disease pathway, and two clusters showing decreased expression pattern that mainly involved in ncRNA metabolism, translation process, and mRNA processing. Importantly, by merging four clusters of activation-associated isoforms, we identified three types of genes that underwent isoform usage alteration during the cGAS-STING pathway activation. We further found that genes exhibiting protein-coding and non-protein-coding gene isoform usage alteration were strongly enriched for the factors involved in innate immunity and RNA splicing. Notably, overexpression of an enriched splicing factor, EFTUD2, shifted transcriptome towards the cGAS-STING pathway activated status and promoted protein-coding isoform abundance of several key regulators of the cGAS-STING pathway. Taken together, our results revealed the isoform-level gene expression dynamics of the cGAS-STING pathway and uncovered novel roles of splicing factors in regulating cGAS-STING pathway mediated immune responses.

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Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study.

Publications

Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study.

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