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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 in non-haematopoietic cells contributes to tumour growth.(a) Overexpression of CD24 mRNA in human prostate cancer tissue based on analysis of two data cohort deposited in Oncomine.com. Two reported cohorts with a sufficient number of matched cancer and normal tissue were analysed. P-values were calculated by Student’s t-tests6970. (b) Expression of Cd24 in Cd24+/+ PCa but not Cd24−/− PCa or normal Cd24+/+ prostate epithelia. Data shown are representative images and have been reproduced three times. (c) Cd24 levels in TRAMP prostate are gene-dose dependent. Age-matched Cd24+/+ and Cd24+/− prostate were analysed for Cd24 levels by western blot. (d) Diagram of experimental design. Eight-week-old Cd24+/+ TRAMP mice were lethally irradiated and transplanted with 5 × 106 bone marrow cells at 1 day after irradiation. The prostate size was measured by MRI at 30 weeks of age. (e) Successful replacement of haematopoietic cells from the donor bone marrow based on Cd24 expression. (f) Means and s.d. of the prostate volume in the bone marrow chimera mice.
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f2: Cd24 in non-haematopoietic cells contributes to tumour growth.(a) Overexpression of CD24 mRNA in human prostate cancer tissue based on analysis of two data cohort deposited in Oncomine.com. Two reported cohorts with a sufficient number of matched cancer and normal tissue were analysed. P-values were calculated by Student’s t-tests6970. (b) Expression of Cd24 in Cd24+/+ PCa but not Cd24−/− PCa or normal Cd24+/+ prostate epithelia. Data shown are representative images and have been reproduced three times. (c) Cd24 levels in TRAMP prostate are gene-dose dependent. Age-matched Cd24+/+ and Cd24+/− prostate were analysed for Cd24 levels by western blot. (d) Diagram of experimental design. Eight-week-old Cd24+/+ TRAMP mice were lethally irradiated and transplanted with 5 × 106 bone marrow cells at 1 day after irradiation. The prostate size was measured by MRI at 30 weeks of age. (e) Successful replacement of haematopoietic cells from the donor bone marrow based on Cd24 expression. (f) Means and s.d. of the prostate volume in the bone marrow chimera mice.

Mentions: Probing Oncomine.com database revealed that CD24 mRNA is overexpressed in prostate cancer tissues (Fig. 2a). In the TRAMP model, Cd24 was expressed in cancer cells but not in the normal prostate gland (Fig. 2b). Heterozygous deletion of Cd24 resulted in a quantitative reduction of Cd24 protein (Fig. 2c). As Cd24 is highly expressed in haematopoietic cells and plays important roles in both adaptive and innate immunity, we sought to determine whether the Cd24 status in the haematopoietic cells contributes to tumorigenicity. To achieve this goal, we lethally irradiated Cd24+/+ TRAMP mice and transplanted them with bone marrow from either Cd24−/− or Cd24+/+ mice (Fig. 2d). Tumour development in the prostate was measured by MRI at 30 weeks and confirmed by histology. In the chimera mice, all leukocytes expressed Cd24 according to the genotype of donor cells (Fig. 2e), confirming complete replacement of the haematopoietic system. However, in two independent experiments, the genotype of bone marrow-derived cells had no impact on prostate size (Fig. 2f). Thus, prostate tumorigenesis was independent of Cd24 status in the haematopoietic cells.


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 in non-haematopoietic cells contributes to tumour growth.(a) Overexpression of CD24 mRNA in human prostate cancer tissue based on analysis of two data cohort deposited in Oncomine.com. Two reported cohorts with a sufficient number of matched cancer and normal tissue were analysed. P-values were calculated by Student’s t-tests6970. (b) Expression of Cd24 in Cd24+/+ PCa but not Cd24−/− PCa or normal Cd24+/+ prostate epithelia. Data shown are representative images and have been reproduced three times. (c) Cd24 levels in TRAMP prostate are gene-dose dependent. Age-matched Cd24+/+ and Cd24+/− prostate were analysed for Cd24 levels by western blot. (d) Diagram of experimental design. Eight-week-old Cd24+/+ TRAMP mice were lethally irradiated and transplanted with 5 × 106 bone marrow cells at 1 day after irradiation. The prostate size was measured by MRI at 30 weeks of age. (e) Successful replacement of haematopoietic cells from the donor bone marrow based on Cd24 expression. (f) Means and s.d. of the prostate volume in the bone marrow chimera mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300525&req=5

f2: Cd24 in non-haematopoietic cells contributes to tumour growth.(a) Overexpression of CD24 mRNA in human prostate cancer tissue based on analysis of two data cohort deposited in Oncomine.com. Two reported cohorts with a sufficient number of matched cancer and normal tissue were analysed. P-values were calculated by Student’s t-tests6970. (b) Expression of Cd24 in Cd24+/+ PCa but not Cd24−/− PCa or normal Cd24+/+ prostate epithelia. Data shown are representative images and have been reproduced three times. (c) Cd24 levels in TRAMP prostate are gene-dose dependent. Age-matched Cd24+/+ and Cd24+/− prostate were analysed for Cd24 levels by western blot. (d) Diagram of experimental design. Eight-week-old Cd24+/+ TRAMP mice were lethally irradiated and transplanted with 5 × 106 bone marrow cells at 1 day after irradiation. The prostate size was measured by MRI at 30 weeks of age. (e) Successful replacement of haematopoietic cells from the donor bone marrow based on Cd24 expression. (f) Means and s.d. of the prostate volume in the bone marrow chimera mice.
Mentions: Probing Oncomine.com database revealed that CD24 mRNA is overexpressed in prostate cancer tissues (Fig. 2a). In the TRAMP model, Cd24 was expressed in cancer cells but not in the normal prostate gland (Fig. 2b). Heterozygous deletion of Cd24 resulted in a quantitative reduction of Cd24 protein (Fig. 2c). As Cd24 is highly expressed in haematopoietic cells and plays important roles in both adaptive and innate immunity, we sought to determine whether the Cd24 status in the haematopoietic cells contributes to tumorigenicity. To achieve this goal, we lethally irradiated Cd24+/+ TRAMP mice and transplanted them with bone marrow from either Cd24−/− or Cd24+/+ mice (Fig. 2d). Tumour development in the prostate was measured by MRI at 30 weeks and confirmed by histology. In the chimera mice, all leukocytes expressed Cd24 according to the genotype of donor cells (Fig. 2e), confirming complete replacement of the haematopoietic system. However, in two independent experiments, the genotype of bone marrow-derived cells had no impact on prostate size (Fig. 2f). Thus, prostate tumorigenesis was independent of Cd24 status in the haematopoietic cells.

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