Genome-wide gene expression analysis of a murine model of prostate cancer progression: Deciphering the roles of IL-6 and p38 MAPK as potential therapeutic targets
| Autor: | Hisham F. Bahmad, Farah Ballout, Humam Kadara, Reem Daouk, Alissar Monzer, Eman Saleh, Wassim Abou-Kheir |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pyridines Cancer Treatment Gene regulatory network Gene Expression p38 Mitogen-Activated Protein Kinases Metastasis Transcriptome Mice 0302 clinical medicine Cell Movement Basic Cancer Research Breast Tumors Gene expression Medicine and Health Sciences Gene Regulatory Networks Immune Response education.field_of_study Multidisciplinary Prostate Cancer Prostate Diseases Imidazoles Cell migration Gene Expression Regulation Neoplastic Cell Motility Phenotypes Oncology 030220 oncology & carcinogenesis Androgens Disease Progression Medicine Research Article Epithelial-Mesenchymal Transition Science Urology Immunology Population Cell Migration Biology 03 medical and health sciences Signs and Symptoms Cell Line Tumor Breast Cancer Genetics Animals Progenitor cell education Gene Cell Proliferation Inflammation Interleukin-6 Microarray analysis techniques Cancers and Neoplasms Biology and Life Sciences Prostatic Neoplasms Cell Biology Genitourinary Tract Tumors Disease Models Animal 030104 developmental biology Cancer research Clinical Medicine Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 8, p e0237442 (2020) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0237442 |
| Popis: | BACKGROUND:Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among adult males globally. The poor prognosis of PCa is largely due to late diagnosis of the disease when it has already progressed to an advanced stage marked by androgen-independence, thus necessitating new strategies for early detection and treatment. We construe that these direly needed advances are limited by our poor understanding of early events in the progression of PCa and that would thus represent ideal targets for early intervention. To begin to fill this void, we interrogated molecular "oncophenotypes" that embody the transition of PCa from an androgen-dependent (AD) to-independent (AI) state. METHODS:To accomplish this aim, we used our previously established AD and AI murine PCa cell lines, PLum-AD and PLum-AI, respectively, which recapitulate primary and progressive PCa morphologically and molecularly. We statistically surveyed global gene expressions in these cell lines by microarray analysis. Differential profiles were functionally interrogated by pathways, gene set enrichment and topological gene network analyses. RESULTS:Gene expression analysis of PLum-AD and PLum-AI transcriptomes (n = 3 each), revealed 723 differentially expressed genes (392 upregulated and 331 downregulated) in PLum-AI compared to PLum-AD cells. Gene set analysis demonstrated enrichment of biological functions and pathways in PLum-AI cells that are central to tumor aggressiveness including cell migration and invasion facilitated by epithelial-to-mesenchymal transition (EMT). Further analysis demonstrated that the p38 mitogen-activated protein kinase (MAPK) was predicted to be significantly activated in the PLum-AI cells, whereas gene sets previously associated with favorable response to the p38 inhibitor SB203580 were attenuated (i.e., inversely enriched) in the PLum-AI cells, suggesting that these aggressive cells may be therapeutically vulnerable to p38 inhibition. Gene set and gene-network analysis also alluded to activation of other signaling networks particularly those associated with enhanced EMT, inflammation and immune function/response including, but not limited to Tnf, IL-6, Mmp 2, Ctgf, and Ptges. Accordingly, we chose SB203580 and IL-6 to validate their effect on PLum-AD and PLum-AI. Some of the common genes identified in the gene-network analysis were validated at the molecular and functional level. Additionally, the vulnerability to SB203580 and the effect of IL-6 were also validated on the stem/progenitor cell population using the sphere formation assay. CONCLUSIONS:In summary, our study highlights pathways associated with an augmented malignant phenotype in AI cells and presents new high-potential targets to constrain the aggressive malignancy seen in the castration-resistant PCa. |
| Databáze: | OpenAIRE |
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