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Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation.

Wang L, Liu R, Ye P, Wong C, Chen GY, Zhou P, Sakabe K, Zheng X, Wu W, Zhang P, Jiang T, Bassetti MF, Jube S, Sun Y, Zhang Y, Zheng P, Liu Y - Nat Commun (2015)

Bottom Line: CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A.CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen.In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.

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Cd24 promotes onset and progression of prostate cancer in TRAMP mice.(a) Onset of palpable prostate tumour development in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice was observed over 35 weeks. P-value of log-rank tests are Cd24 WT versus Cd24+/−, P=0.0001; Cd24 WT versus Cd24−/−, P=0.0017; Cd24+/− versus Cd24−/−, P=0.51. (b) Representative images of prostates from 30-week-old Cd24+/+ (n=7), Cd24+/− (n=11) and Cd24−/− (n=9) TRAMP mice. (c) Prostate sizes in 30-week-old TRAMP mice in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice. The lower abdominal area was divided into 0.4-mm-thick slices and MRI images were acquired to provide continuous images of the whole prostate. The surface area of the prostate slices was traced by segmenting and summed to estimate the total volume. Analysis of variance (ANOVA) tests revealed an extremely significant Cd24 gene dose effect on the prostate size (P=0.00026). (d) The weights of 35-week-old Cd24+/+ (n=9), Cd24+/− (n=22) and Cd24−/− (n=10) TRAMP prostates. ANOVA tests revealed an extremely significant Cd24 gene-dose effect on the prostate weight (P=0.00011). (e) Representative histology of prostate carcinomas (PCa) that developed in Cd24+/+Cd24+/−, and Cd24−/− TRAMP mice. The data show a difference in the degree of differentiation in tumour morphology. (f) Cd24 promotes progression (left panel) and metastasis (right panel) of prostate cancer in the TRAMP model. The prostate tissue was examined double blind and classified into the following categories: normal prostate, hyperplasia prostate (HP), intraepithelial neoplasia in the prostate (PIN), moderate (mod) to well-differentiated (well diff) PCa and poorly differentiated PCa. Cancer was scored metastatic if one or more distal metastases to either the lungs, kidneys or liver were detected histologically. Examples of tumours at each grade are shown in e, whereas that of normal prostate and hyperplasia are shown in Supplementary Fig. 1. Pearson’s χ2 test was used to determine whether the Cd24 geneotypes affected the progression to poorly differentiated PCa (left panel) or distal metastasis (right panel).
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f1: Cd24 promotes onset and progression of prostate cancer in TRAMP mice.(a) Onset of palpable prostate tumour development in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice was observed over 35 weeks. P-value of log-rank tests are Cd24 WT versus Cd24+/−, P=0.0001; Cd24 WT versus Cd24−/−, P=0.0017; Cd24+/− versus Cd24−/−, P=0.51. (b) Representative images of prostates from 30-week-old Cd24+/+ (n=7), Cd24+/− (n=11) and Cd24−/− (n=9) TRAMP mice. (c) Prostate sizes in 30-week-old TRAMP mice in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice. The lower abdominal area was divided into 0.4-mm-thick slices and MRI images were acquired to provide continuous images of the whole prostate. The surface area of the prostate slices was traced by segmenting and summed to estimate the total volume. Analysis of variance (ANOVA) tests revealed an extremely significant Cd24 gene dose effect on the prostate size (P=0.00026). (d) The weights of 35-week-old Cd24+/+ (n=9), Cd24+/− (n=22) and Cd24−/− (n=10) TRAMP prostates. ANOVA tests revealed an extremely significant Cd24 gene-dose effect on the prostate weight (P=0.00011). (e) Representative histology of prostate carcinomas (PCa) that developed in Cd24+/+Cd24+/−, and Cd24−/− TRAMP mice. The data show a difference in the degree of differentiation in tumour morphology. (f) Cd24 promotes progression (left panel) and metastasis (right panel) of prostate cancer in the TRAMP model. The prostate tissue was examined double blind and classified into the following categories: normal prostate, hyperplasia prostate (HP), intraepithelial neoplasia in the prostate (PIN), moderate (mod) to well-differentiated (well diff) PCa and poorly differentiated PCa. Cancer was scored metastatic if one or more distal metastases to either the lungs, kidneys or liver were detected histologically. Examples of tumours at each grade are shown in e, whereas that of normal prostate and hyperplasia are shown in Supplementary Fig. 1. Pearson’s χ2 test was used to determine whether the Cd24 geneotypes affected the progression to poorly differentiated PCa (left panel) or distal metastasis (right panel).

Mentions: To test Cd24 function in a spontaneous cancer model, we crossed the Cd24- allele45 into TRAMP mice, a transgenic model that develops spontaneous prostate adenocarcinoma due to the expression of the SV40 T antigen under control of the rat probasin promoter46. As shown in Fig. 1a, the onset of palpable tumour development in the prostate of TRAMP mice was significantly delayed by deletion of either one or two alleles of the Cd24 gene. When the prostate size was measured at 30 weeks by magnetic resonance imaging (MRI), the prostate volume was significantly reduced in a gene dose-dependent manner (P=0.0026, analysis of variance trend test; Fig. 1b,c). At 35 weeks, the mice were killed and their prostates were weighted. CD24 deficiency also decreased the prostate weight at 35 weeks (Fig. 1d). As shown in Fig. 1e and Supplementary Fig. 1 and summarized in Fig. 1f, the majority of cancer in wild-type (WT) TRAMP mice had progressed to poorly differentiated adenocarcinomas (7/12) and distal metastases (8/12) into the kidneys, lungs and liver. In contrast, only 1 mouse in the Cd24−/− (1/9) and Cd24+/− (1/12) cohorts developed poorly differentiated adenocarcinomas, whereas 1/12 Cd24+/− and 0/9 Cd24−/− mice had metastasis. Therefore, in addition to reduced tumour size, inactivation of a single allele of Cd24 significantly reduced the malignancy of the tumours.


Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation.

Wang L, Liu R, Ye P, Wong C, Chen GY, Zhou P, Sakabe K, Zheng X, Wu W, Zhang P, Jiang T, Bassetti MF, Jube S, Sun Y, Zhang Y, Zheng P, Liu Y - Nat Commun (2015)

Cd24 promotes onset and progression of prostate cancer in TRAMP mice.(a) Onset of palpable prostate tumour development in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice was observed over 35 weeks. P-value of log-rank tests are Cd24 WT versus Cd24+/−, P=0.0001; Cd24 WT versus Cd24−/−, P=0.0017; Cd24+/− versus Cd24−/−, P=0.51. (b) Representative images of prostates from 30-week-old Cd24+/+ (n=7), Cd24+/− (n=11) and Cd24−/− (n=9) TRAMP mice. (c) Prostate sizes in 30-week-old TRAMP mice in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice. The lower abdominal area was divided into 0.4-mm-thick slices and MRI images were acquired to provide continuous images of the whole prostate. The surface area of the prostate slices was traced by segmenting and summed to estimate the total volume. Analysis of variance (ANOVA) tests revealed an extremely significant Cd24 gene dose effect on the prostate size (P=0.00026). (d) The weights of 35-week-old Cd24+/+ (n=9), Cd24+/− (n=22) and Cd24−/− (n=10) TRAMP prostates. ANOVA tests revealed an extremely significant Cd24 gene-dose effect on the prostate weight (P=0.00011). (e) Representative histology of prostate carcinomas (PCa) that developed in Cd24+/+Cd24+/−, and Cd24−/− TRAMP mice. The data show a difference in the degree of differentiation in tumour morphology. (f) Cd24 promotes progression (left panel) and metastasis (right panel) of prostate cancer in the TRAMP model. The prostate tissue was examined double blind and classified into the following categories: normal prostate, hyperplasia prostate (HP), intraepithelial neoplasia in the prostate (PIN), moderate (mod) to well-differentiated (well diff) PCa and poorly differentiated PCa. Cancer was scored metastatic if one or more distal metastases to either the lungs, kidneys or liver were detected histologically. Examples of tumours at each grade are shown in e, whereas that of normal prostate and hyperplasia are shown in Supplementary Fig. 1. Pearson’s χ2 test was used to determine whether the Cd24 geneotypes affected the progression to poorly differentiated PCa (left panel) or distal metastasis (right panel).
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f1: Cd24 promotes onset and progression of prostate cancer in TRAMP mice.(a) Onset of palpable prostate tumour development in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice was observed over 35 weeks. P-value of log-rank tests are Cd24 WT versus Cd24+/−, P=0.0001; Cd24 WT versus Cd24−/−, P=0.0017; Cd24+/− versus Cd24−/−, P=0.51. (b) Representative images of prostates from 30-week-old Cd24+/+ (n=7), Cd24+/− (n=11) and Cd24−/− (n=9) TRAMP mice. (c) Prostate sizes in 30-week-old TRAMP mice in Cd24+/+, Cd24+/− and Cd24−/− TRAMP mice. The lower abdominal area was divided into 0.4-mm-thick slices and MRI images were acquired to provide continuous images of the whole prostate. The surface area of the prostate slices was traced by segmenting and summed to estimate the total volume. Analysis of variance (ANOVA) tests revealed an extremely significant Cd24 gene dose effect on the prostate size (P=0.00026). (d) The weights of 35-week-old Cd24+/+ (n=9), Cd24+/− (n=22) and Cd24−/− (n=10) TRAMP prostates. ANOVA tests revealed an extremely significant Cd24 gene-dose effect on the prostate weight (P=0.00011). (e) Representative histology of prostate carcinomas (PCa) that developed in Cd24+/+Cd24+/−, and Cd24−/− TRAMP mice. The data show a difference in the degree of differentiation in tumour morphology. (f) Cd24 promotes progression (left panel) and metastasis (right panel) of prostate cancer in the TRAMP model. The prostate tissue was examined double blind and classified into the following categories: normal prostate, hyperplasia prostate (HP), intraepithelial neoplasia in the prostate (PIN), moderate (mod) to well-differentiated (well diff) PCa and poorly differentiated PCa. Cancer was scored metastatic if one or more distal metastases to either the lungs, kidneys or liver were detected histologically. Examples of tumours at each grade are shown in e, whereas that of normal prostate and hyperplasia are shown in Supplementary Fig. 1. Pearson’s χ2 test was used to determine whether the Cd24 geneotypes affected the progression to poorly differentiated PCa (left panel) or distal metastasis (right panel).
Mentions: To test Cd24 function in a spontaneous cancer model, we crossed the Cd24- allele45 into TRAMP mice, a transgenic model that develops spontaneous prostate adenocarcinoma due to the expression of the SV40 T antigen under control of the rat probasin promoter46. As shown in Fig. 1a, the onset of palpable tumour development in the prostate of TRAMP mice was significantly delayed by deletion of either one or two alleles of the Cd24 gene. When the prostate size was measured at 30 weeks by magnetic resonance imaging (MRI), the prostate volume was significantly reduced in a gene dose-dependent manner (P=0.0026, analysis of variance trend test; Fig. 1b,c). At 35 weeks, the mice were killed and their prostates were weighted. CD24 deficiency also decreased the prostate weight at 35 weeks (Fig. 1d). As shown in Fig. 1e and Supplementary Fig. 1 and summarized in Fig. 1f, the majority of cancer in wild-type (WT) TRAMP mice had progressed to poorly differentiated adenocarcinomas (7/12) and distal metastases (8/12) into the kidneys, lungs and liver. In contrast, only 1 mouse in the Cd24−/− (1/9) and Cd24+/− (1/12) cohorts developed poorly differentiated adenocarcinomas, whereas 1/12 Cd24+/− and 0/9 Cd24−/− mice had metastasis. Therefore, in addition to reduced tumour size, inactivation of a single allele of Cd24 significantly reduced the malignancy of the tumours.

Bottom Line: CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A.CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen.In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.

Show MeSH
Related in: MedlinePlus