Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate
| Autor: | Vijaya Pooja Vaikari, Lauren A. Geary, Pei-Chuan Li, Tzu-Ping Lin, Jean C. Shih, Chi Hung Lin, Chun-Peng Liao, Jason Boyang Wu, Mitchell E. Gross, Kevin Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Homeobox protein NANOG Male Cancer Research Carcinogenesis Adenocarcinoma medicine.disease_cause Article Epithelium 03 medical and health sciences Prostate cancer Gene Knockout Techniques Mice 0302 clinical medicine Cancer stem cell Cell Line Tumor Genetics medicine PTEN Animals Humans Phosphorylation Molecular Biology Monoamine Oxidase Cell Proliferation biology CD44 PTEN Phosphohydrolase Prostate Prostatic Neoplasms medicine.disease 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Disease Progression Neoplastic Stem Cells Monoamine oxidase A Stem cell Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncogene |
| Popis: | Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters and dietary amines and produces H(2)O(2). Recent studies have shown increased MAOA expression in prostate cancer (PCa), glioma, and classical Hodgkin lymphoma. However, the biological function of MAOA in cancer development remains unknown. In this study, we investigated the role of MAOA in the development of prostate adenocarcinoma by creating a prostate-specific Pten/MAOA knockout (KO) mouse model, in which MAOA-floxP mouse was crossed with the conditional Pten KO PCa mouse that develops invasive PCa. In contrast to Pten KO mice, age-matched Pten/MAOA KO mice exhibited a significant decrease in both prostate size and the incidence of invasive cancer. We observed a significant decline in AKT phosphorylation and Ki67 expression in Pten/MAOA KO mice, which reduced epithelial cell growth and proliferation. As cancer stem cells (CSCs) are required for tumor initiation and growth, we investigated expression of OCT4 and NANOG in the setting of decreased MAOA expression. We found that both OCT4 and NANOG were significantly attenuated in the prostate epithelia of Pten/MAOA KO mice compared to Pten KO mice, which was confirmed with targeted knockdown of MAOA with a short-hairpin(sh) vector targeting MAOA compared to cells transfected with a control vector. Expression of other markers associated with the a stem cell phenotype, including CD44, α2β1, and CD133 as well as HIF-1α(+)CD44(+) stem cells were all decreased in shMAOA PCa cells compared with empty vector-transfected control cells. We also found spheroid formation ability in PCa cells was decreased when endogenous MAOA was suppressed by siRNA or MAOA inhibitor clorgyline in a colony formation assay. Using the TCGA database, elevated MAOA expression was associated with reduced Pten levels in high Gleason grade in patient samples. Further, we found that Pten-positive PCa cells were more resistant to clorgyline treatments than Pten-null cells in tumorigenicity and stemness. Taken together, these studies suggest that MAOA expression promotes PCa development by increasing cell proliferation and CSCs and highlights the potential use of MAOA inhibitors for the treatment of PCa. |
| Databáze: | OpenAIRE |
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