RCC2 and CD24 Cooperate to Modulate Prostate Cancer Progression Through Vimentin Ubiquitination and β-Catenin Pathway Activation
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ABSTRACT:
PROVIDER: PRJNA1164812 | ENA |
REPOSITORIES: ENA
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Project description:CD24 plays a crucial role in tumor growth and metastasis, including in prostate cancer. While CD24 stimulates prostate cancer cell growth by controlling the ARF-NPM interaction and p53 inactivation, the mechanism of CD24-mediated metastasis remains elusive. This study identifies a direct interaction between CD24 and RCC2 with roles in prostate cancer cell proliferation and migration. Immunohistochemical analysis of primary prostate cancer samples showed expression of CD24 in 49% of samples and RCC2 in 82%, with a positive correlation between their protein levels. Their co-expression, particularly the binding of CD24 to the C-terminal domain of RCC2, supports their direct interaction, which may regulate cell motility and adhesion. Functional assays revealed that knockout (KO) of RCC2 in DU145 and PC3 prostate cancer cells inhibited cell proliferation but unexpectedly enhanced cell migration and invasion, while CD24 KO reduced proliferation and migration. Notably, dual KOs of CD24 and RCC2 led to a significant decrease in cell proliferation but showed mixed effects on migration, indicating a complex interplay between these proteins. In vivo, RCC2 KO in prostate cancer cells promoted spontaneous lung metastasis without significantly altering primary tumor growth, contrasting with CD24 KO, which reduced tumor growth and metastasis. Mechanistically, RCC2 was shown to ubiquitinate and degrade Vimentin, influencing cytoskeletal dynamics and migratory behavior. Furthermore, CD24 was found to ubiquitinate and degrade RCC2, leading to modulation of the β-catenin signaling pathway. RCC2 KO increased β-catenin activation and decreased the expression of its inhibitors AXIN2 and APC, while CD24 KO led to β-catenin inactivation. This opposing regulation of β-catenin signaling by CD24 and RCC2 underscores their differential roles in prostate cancer cell migration. These findings provide new insights into the molecular mechanisms underlying prostate cancer growth and metastasis and identify the CD24-RCC2 axis as a potential therapeutic target for controlling tumor growth and metastasis in prostate cancer.
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Project description:Being involved in adhesion, migration, and invasion, the highly glycosylated signal transducer CD24 (cluster of differentiation 24) has been implicated to play an essential role during carcinogenesis. Previously, the molecular and (epi)genetic regulation of CD24 has been characterized in testicular germ cell tumors (GCT). Here, CD24 was exclusively found in embryonal carcinoma (EC), which represents the stem cell like population of GCT (see project PXD025110). For a better understanding of the molecular function of CD24, this study aimed at the identification of the direct interaction partners of CD24 not only in GCTs, but also in other urologic malignancies, such as urothelial- (UC), prostate- (PC), and renal cell carcinoma (RCC). For this purpose, co-immunoprecipitations of CD24 were performed in GCT, UC, PC, and RCC cell lines, while CD24-deficient EC cells as well as IgG2a controls were included for high validity. Extracted proteome was measured by liquid-chromatography coupled with mass spectrometry (LS-MS).
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Project description:The intermediate filament vimentin is present in immune cells. It provides structural support to cells and functions in macrophages to coordinate inflammatory responses. Neutrophils are an abundance innate immune cell that function by distinct mechanisms from macrophages to mediate antimicrobial activities. The role of vimentin in neutrophils is not established. Here, we developed an immortalized neutrophil model to examine the requirement of vimentin. We demonstrate that vimentin restricts proinflammatory cytokine production and reactive oxygen species production, but enhances phagocytosis and swarming. We observe that vimentin is dispensable for neutrophil extracellular trap (NET) formation, degranulation, and for inflammasome activation. Moreover, gene expression analysis defined vimentin presence was associated with expression changes in multiple genes required for mitochondrial function and ROS overproduction in the absence of vimentin. By treatment of cells producing vimentin with rotenone, an inhibitor for complex I of the electron transport chain, or by treatment of cells lacking vimentin with mitoTEMPO, a SOD mimetic, we complement the changes in ROS levels through manipulation of mitochondrial function. Together, we suggest vimentin regulates neutrophil antimicrobial functions and alters ROS levels through regulation of mitochondrial activity.
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