p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma.
p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma.
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DOI：
10.1158/1541-7786.mcr-14-0277-t
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发表时间：
2015-03
期刊：
影响因子：
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通讯作者：
Huang J
中科院分区：
文献类型：
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作者：
Li Z;Sun Y;Chen X;Squires J;Nowroozizadeh B;Liang C;Huang J
前列腺小细胞神经内分泌癌（SCNC）是一种罕见但侵袭性的前列腺癌（PCa），雄激素受体（AR）阴性，对激素治疗无反应。这种PCa变异体的分子病因学尚不清楚;然而，前列腺神经内分泌细胞中p53（TP 53）肿瘤抑制因子的突变使通常抑制细胞增殖的IL 8-CXCR 2-p53通路失活，导致SCNC的发展。SCNC还过表达极光激酶A（AURKA），其被认为是可行的治疗靶点。因此，研究了这两个分子事件的关系，我们发现p53突变导致miR-25表达增加和E3泛素连接酶FBXW 7下调，导致Aurora激酶A水平升高。本研究证实了p53突变导致Aurora激酶A表达的细胞内途径，这对前列腺SCNC的快速增殖和侵袭行为至关重要。
Prostatic small cell neuroendocrine carcinoma (SCNC) is a rare but aggressive form of prostate cancer (PCa) that is negative for androgen receptor (AR) and not responsive to hormonal therapy. The molecular etiology of this PCa 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 down-regulation 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.