DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Effects of CD24/RCC2/p53 Signaling on Prostate Cancer Metastasis

Posted September 1, 2021

Runhua Liu, Ph.D., University of Alabama at Birmingham

Dr. Runhua Liu
Dr. Runhua Liu

Prostate cancer (PCa) is the most common type of cancer in men in the United States. Although a majority of prostate tumors are slow-growing and harmless, some tumors become more aggressive and metastatic with no reliable treatment options. In fact, PCa is the second leading cause of cancer-related deaths in American men. As the mechanisms that cause PCa metastasis are not fully understood, there is a critical need to identify the genes involved in this process and develop targeted therapies to prevent it. One potential gene candidate is signal transducer protein 24 (CD24). While CD24 expression is undetected in normal prostates, it is expressed at high levels in nearly 50% of PCa tumors, especially in metastatic and African-American (AA) tumors, suggesting that CD24 may play a role in tumor metastasis. It has been shown that deletion of CD24 reduces tumor metastasis of PCa in mice, but the mechanism by which CD24 regulates metastasis has yet to be established.

With funding from an FY14 Idea Development Award (New Investigator), Dr. Runhua Liu and her team at the University of Alabama at Birmingham investigated the mechanism by which CD24 contributes to PCa metastasis. Through this work, they found that CD24 regulates PCa metastasis through interactions with two other genes known to be important in PCa progression and metastasis, RCC2 and p53. Based on this novel observation, they tested the effects of targeting these genes in PCa cells and clinically relevant animal models and found that preventing the interaction of CD24 with RCC2 effectively inhibits cell migration in the tumor cells. Additional studies also determined that CD24-dependent inactivation of p53 occurs through disrupting the interaction between two other genes involved in cancer progression called ARF and NPM.

These findings help to contribute to understanding PCa metastasis and highlight an important role for CD24 signaling. Furthermore, this work has shown that the CD24/RCC2 interaction is critical for prostate tumor metastasis and has further elucidated the mechanism by which p53 contributes to PCa metastasis. Dr. Liu recently received an FY19 Idea Expansion Award to continue studying how CD24 promotes metastasis by regulating RCC2 and p53 gene signaling, and to explore novel ways to target this signaling pathway in order to prevent metastasis in men with PCa, which, if successful, may help translate these discoveries into the clinic in the future.;

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Publications:

Wang, L., Liu, R., Ye, P., Wong, C., Chen, G.Y., Zhou, P., Sakabe, K., Zheng, X., Wu, W., Zhang, P., Jiang, T., Bassetti, M.F., Jube, S., Sun, Y., Zhang, Y., Zheng, P., and Liu, Y. (2015). Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation. Nat Commun 6, 5909.

Zhang, W., Yi, B., Wang, C., Chen, D., Bae, S., Wei, S., Guo, R.J., Lu, C., Nguyen, L.L., Yang, W.H., Lillard, J.W., Zhang, X., Wang, L., and Liu, R. (2016). Silencing of CD24 Enhances the PRIMA-1-Induced Restoration of Mutant p53 in Prostate Cancer Cells. Clin Cancer Res 22, 2545-2554.

Zhang, Y., Li, B., Zhang, X., Sonpavde, G.P., Jiao, K., Zhang, A., Zhang, G., Sun, M., Chu, C., Li, F., Wang, L., Cui, R., and Liu, R. (2017). CD24 is a genetic modifier for risk and progression of prostate cancer. Mol Carcinog 56, 641-650.

Liu W, Zhang Y, Wei S, Bae S, Yang WH, Smith GJ, Mohler JL, Fontham ETH, Bensen JT, Sonpavde GP, Chen GY, Liu R, Wang L. (2020) A CD24-p53 axis contributes to African American prostate cancer disparities. Prostate 80, 609-618.

Links:

Effects of CD24-RCC2 Signaling on Prostate Cancer Metastasis

Targeting CD24 Signaling for Lethal Metastatic Prostate Cancer Therapy

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Last updated Wednesday, September 1, 2021