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. 2015 Mar;13(3):584-91.
doi: 10.1158/1541-7786.MCR-14-0277-T. Epub 2014 Dec 15.

"V体育官网" p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma

Zhen Li  1 , Yin Sun  2 , Xufeng Chen  1 , Jill Squires  1 , Behdokht Nowroozizadeh  1 , Chaozhao Liang  3 , Jiaoti Huang  2
Affiliations

"V体育ios版" p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma

Zhen Li et al. Mol Cancer Res. 2015 Mar.

Abstract

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 VSports手机版. 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. .

Implications: The pathogenesis of prostatic SCNC involves a p53 and Aurora Kinase A signaling mechanism, both potentially targetable pathways. V体育安卓版.

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Conflict of interest statement

Potential conflicts of interest: The authors disclose no potential conflicts of interest.

Figures

Figure 1
Figure 1
p53 regulates miR-25, Fbxw7 and Aurora kinase A. A and B miR-25 expression changes in response to p53 expression and mutation status. Plasmids encoding wild-type p53 (left panel) or mutant p53 (right panel) were transfected into PC-3 or LNCaP cells for 48hrs. RNAs were then isolated for quantification of miR-25 using qRT-PCR. Two independent triplicate experiments were performed, and results are presented as mean ± SD. The ratio of the miR-25 over miR-191 as an internal control was plotted (A). siRNA for p53, or lentiviral vector for dominant negative p53 were introduced into NCI H660 cells for 48hrs, and miR-25 was quantitated as in A (B). Asterisks indicate significant differences (p<0.05). C. Immunoblot analysis results showing the changes of proteins in response to p53 regulation for 48hrs in NCI H660 cells.
Figure 2
Figure 2
Fbxw7 regulates Aurora kinase A expression. Control or Fbxw7 siRNA at 100 nM was transfected into NE1.8, PC-3 or NCI-H660 cells. Aurora kinase A and Fbxw7 were examined via immunoblot analysis. MYCN and MYC are included as known validated targets of Fbxw7.
Figure 3
Figure 3
miR-25-regulated Aurora kinase A is dependent on loss of p53 function. A. Westernblot analysis showing that miR-25 inhibitor eliminate the effect of p53 knockdown on regulation of FBXW7 and AURKA. B. Quantification of the densitometry for western blot bands using ImageJ 1.47t. C. The effects of miR-25 on expressions of AUKUA and FBXW7 proteins. Control or miR-25 mimic at 100 nM was transfected into NE1.8 cells, a variant of LNCaP cells that resemble neuroendocrine cells. Aurora kinase A and Fbxw7 were examined via immunoblot analysis. D. A graphic representation for expression plasmids containing firefly luciferase with wild-type 3′ UTR of human Fbxw7 and the mutant 3′UTR without the target sequence for miR-25 (top). These plasmids were transfected into NE1.8 cells together with control or miR-25 mimic, luciferase activities were measured 48hrs later and plotted (bottom). Three independent experiments were performed, and results are presented as mean ± SD.
Figure 4
Figure 4
Expressions of p53, Aurora kinase A and miR-25 in human prostatic small cell carcinoma. A. Representative images showing the IHC staining with anti-p53 and anti-Aurora kinase A antibodies in human prostatic small cell carcinoma B. Representative images showing the co-expression of nuclear p53 and Aurora kinase A in these human prostatic small cell carcinoma using immunofluorescence double staining. C. miR-25 was quantitated in small cell carcinoma or adenocarcinoma into Box-and-Whisker Plots, the ratio of the miR-25 over miR-191 as an internal control was plotted. D. Differential expression of Aurora kinase A in human prostatic adenocarcinoma or small cell carcinoma. Representative image showing the results for Immunohistochemistry staining with antibody for Aurora kinase A in these different types of prostate cancers. E. Semi-quantitation of AURKA IHC staining were performed using Quick score method.
Figure 5
Figure 5
A diagram depicting multiple pathways that leads to overexpression of Aurora kinase A in human prostatic small cell carcinoma.
See this image and copyright information in PMC

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