Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats
| Autor: | Kay Huebner, Oliver Fiehn, Zi-Xuan Wang, Sili Fan, Karl J. Smalley, Hongping Chen, Carlo M. Croce, Ruiyan Jing, John L. Farber, Louise Y.Y. Fong, Hansjuerg Alder, Cristian Taccioli |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Aging Transcription Genetic Untargeted miRNA profiling Wistar Prostatic Hyperplasia Rats Sprague-Dawley Prostate cancer 0302 clinical medicine Prostate Tumor Cells Cultured 2.1 Biological and endogenous factors Aetiology Cation Transport Proteins Cancer Dietary Zn intake Prostate cancer metabolic phenotype Prostate cancer risk Untargeted metabolomics profiling Adenocarcinoma Animals Cell Proliferation Citric Acid Diet Disease Models Animal Gene Expression Regulation Neoplastic Humans MicroRNAs Prostatic Neoplasms Rats Rats Wistar Signal Transduction Zinc Multidisciplinary Cultured Chemistry Prostate Cancer untargeted metabolomics profiling Biological Sciences 3. Good health Tumor Cells medicine.anatomical_structure PNAS Plus 030220 oncology & carcinogenesis prostate cancer metabolic phenotype Transcription Urologic Diseases prostate cancer risk 03 medical and health sciences untargeted miRNA profiling Genetic microRNA medicine Carcinoma Genetics dietary Zn intake Nutrition Neoplastic Cell growth Animal Prevention medicine.disease Fold change 030104 developmental biology Gene Expression Regulation Disease Models Cancer research Sprague-Dawley |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 115, iss 47 Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance Prostate cancer in man is associated with Zn loss, citrate metabolite reduction, overexpression of the miR-183-96-182 cluster, and regulation of Zn homeostasis through Zn transporter suppression. Our mechanistic study shows that a low-Zn diet upregulates this miR cluster in Zn-deficient middle-aged rat prostate, with ZIP1 mRNA/protein downregulation and a citrate-oxidizing metabolic phenotype, linking citrate reduction directly to prostatic Zn loss. The findings of this study show that the transcriptional and metabolic signal pathways induced by Zn deficiency in rats and almost certainly in men are critical for the development of human and rat prostate cancer and provide a strong rationale for including Zn supplementation in clinical trials to reduce the prostate cancer burden in the human population. Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis–regulating miR-183-96-182 cluster (fold change = 1.41–2.38; P = 0.029–0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention. |
| Databáze: | OpenAIRE |
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