期刊
MOLECULAR CANCER RESEARCH
卷 13, 期 3, 页码 584-591出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-14-0277-T
关键词
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资金
- Stand Up to Cancer-Prostate Cancer Foundation-Prostate Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0812]
- Movember Foundation
- Stand Up To Cancer is a program of the Entertainment Industry Foundation
- UCLA SPORE in Prostate Cancer
- Department of Defense Prostate Cancer Research Program [W81XWH-11-1-0227, W81XWH-12-1-0206]
- NIH [1R01CA158627-01, 1R01CA172603-01A1]
- Prostate Cancer Foundation Honorable A. David Mazzone Special Challenge Award
- Stand-up-to-Cancer Dream Team Award
- NATIONAL CANCER INSTITUTE [R01CA158627, R01CA172603] Funding Source: NIH RePORTER
Prostatic small cell neuroendocrine carcinoma (SCNC) is a rare but aggressive form of prostate cancer that is negative for androgen receptor (AR) and not responsive to hormonal therapy. The molecular etiology of this prostate cancer variant is not well understood; however, mutation of the p53 (TP53) tumor suppressor in prostate neuroendocrine cells inactivates the IL8-CXCR2-p53 pathway that normally inhibits cellular proliferation, leading to the development of SCNC. SCNC also overexpresses Aurora kinase A (AURKA) which is considered to be a viable therapeutic target. Therefore, the relationship of these two molecular events was studied, and we show that p53 mutation leads to increased expression of miR-25 and downregulation of the E3 ubiquitin ligase FBXW7, resulting in elevated levels of Aurora kinase A. This study demonstrates an intracellular pathway by which p53 mutation leads to Aurora kinase A expression, which is critically important for the rapid proliferation and aggressive behavior of prostatic SCNC.
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