Abstract 1021: CD24 dependent inactivation of mutant p53 in metastatic castration resistant prostate cancer
Authors: Yi Baozhu , Li Xin , Xu Zhifang , Bae Sejong , Wei Shi , Liu Runhua , Lillard James , Wang Lizhong 
Published: August 2019

CD24 is not expressed in normal prostate epithelial cells but is overexpressed in high-stage prostate cancer (PC) and metastases, especially in African American (AA) men, and serves as a marker for poor prognosis. The oncogenic function of CD24 has been demonstrated by ectopic and/or inducible expression, targeted mutations, gene silencing, and antibody blockade. Recently, we found CD24-dependent inactivation of mutant p53 in PC cells. CD24 silencing prevents functional inactivation of mutant p53, a gene frequently mutated in about 30% of PCs. TP53 mutation or loss of function promotes the invasion and metastasis of castration-resistant PC (CRPC) cells. Mutant p53 expression is associated with an increased risk of disease-specific death as well as the development of distant metastasis. In the present study, we assesed the protein expression levels of CD24 and mutant p53 by immunohistochemical staining in 150 formalin-fixed paraffin-embedded CRPC tissue specimens from 78 White and 78 AA patients. The frequency of CD24 expression showed a significant difference (p=0.023) between CRPCs of 66.7% AAs and 48.7% Whites. Likewise, the frequency of mutant p53 expression was significantly higher (p=0.014) in CRPCs of 38.5% AAs compared with 20.5% Whites. These results suggest that overexpression of CD24 and mutant p53 is a frequent event in AA CRPCs. Furthmore, we created CD24-/- p53-null PC3 CRPC cell models by use of CRISPR/Cas9 technology. Next, we transfected the TP53R273H or TP53R175H into CD24+/+ and CD24-/- PC3-luc cells to create TP53R273H or TP53R175H CD24+/+ and CD24-/- PC3-luc cell models. Uisng these cell models, we found that CD24 promotes PC3 cell migration and invasion in TP53R273H cells but not in TP53R175H PC3 cells. The p53 target genes, including p21/CDKN1A, VDR, and TP53INP1, were downregulated after CD24 overexpression in TP53R273H cells but not in TP53R175H PC3 cells, supporting the effect of CD24-dependent inactivation of mutant p53R273H. To address the effect of CD24-dependent inactivation of mutant p53 on CRPC cell colonization in vivo, we intravenously injected NOD-SCID (NSG) male mice with TP53R273H or TP53R175H transfected CD24+/+ and CD24-/- PC3-luc cells. After implantation, the numbers and burden of lung and liver metastases were higher in the mice with TP53R273H CD24+/+ cells compared with TP53R273H CD24-/- cells, but no difference was found between the mice with TP53R175H CD24+/+ cells and TP53R175H CD24-/- cells, further supporting the effect of CD24-dependent inactivation of mutant p53R273H.

Citation Format: Baozhu Yi, Xin Li, Zhifang Xu, Sejong Bae, Shi Wei, Runhua Liu, James Lillard, Lizhong Wang. CD24 dependent inactivation of mutant p53 in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1021.