CD24

Official Full Name

CD24 molecule

Organism

Homo sapiens

GeneID

100133941

Background

This gene encodes a sialoglycoprotein that is expressed on mature granulocytes and B cells and modulates growth and differentiation signals to these cells. The precursor protein is cleaved to a short 32 amino acid mature peptide which is anchored via a glycosyl phosphatidylinositol (GPI) link to the cell surface. This gene was missing from previous genome assemblies, but is properly located on chromosome 6. Non-transcribed pseudogenes have been designated on chromosomes 1, 15, 20, and Y. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

Synonyms

CD24A;

Protein Sequence

MGRAMVARLGLGLLLLALLLPTQIYSSETTTGTSSNSSQSTSNSGLAPNPTNATTKAAGGALQSTASLFVVSLSLLHLYS

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

Expressed mostly on mature granulocytes and B cells, the CD24 gene codes a sialoglycoprotein. It is essential in controlling signals of development and differentiation to these immune cells. Derived from a short precursor peptide, the mature 32 amino acid peptide is linked to the cell surface by a glycosylphosphatidylinositol (GPI) bond after cleavage. Fascinatingly, prior genome assemblies lacked CD24, yet now it is precisely localized to chromosome 6. On chromosomes 1, 15, 20, and Y non-transcribed pseudogenes have been found. Different splicing by the gene generates many transcript variants.

Pathophysiological Role of CD24

Multiple elements control CD24 expression in tumor cells; hypoxia-inducible factors (HIFs) are especially important. Low-oxygen conditions are common for tumor cells, which depend on HIFs to adapt to hypoxia. The key transcriptional target of HIF-1α, CD24 is promoted by the functional hypoxia response element in its promoter. Bladder, prostate, and stomach tumors have shown this elevation of CD24 when hypoxic circumstances greatly raise CD24 mRNA and protein levels.

Non-coding RNAs (ncRNAs) also contribute to the regulation of CD24 expression, influencing tumor growth, metabolism, and migration. For instance, the long non-coding RNA H19 has been shown to reduce CD24 levels on the cell surface, while its downregulation helps maintain CD24 expression. H19-mediated modulation of CD24 expression is thought to enhance tumor cell invasion and promote immune evasion.

Secreted frizzled-related protein 1 (SFRP1) and T-cell factor-4 (TCF-4), both engaged in the Wnt signaling pathway, further, affect CD24 regulation. These proteins reduce Wnt signaling in breast tissue; their downregulation activates the Wnt pathway. While TCF-4 knockdown does not have the same impact in cells expressing Wnt-1, CD24 levels rise with SFRP1 knockdown. These results imply that many signaling channels underlie complicated control of CD24 transcription.

Moreover connected to the control of CD24 is the NF2-YAP signaling pathway. Inhibition of NF2-YAP signaling may lower the expression of CD24 and ferroptosis suppressor protein 1 (FSP1), therefore encouraging ferroptosis and increasing macrophage-mediated phagocytosis of tumor cells. This implies that CD24 protects cancer cells against ferroptosis, a kind of controlled cell death, and avoids immune surveillance.

CD24 Signaling Mechanisms

Without a transmembrane domain, CD24 hooks itself to the cell membrane via a GPI connection and interacts with signaling molecules found in lipid rafts. Using these connections, CD24 communicates control over tumor cell adhesion, proliferation, invasion, and metastases as well as suppressive death. One of the main glycan structures on CD24 is the highly fucosylated glycol Sialyl-Lewis (x), which is very essential for the metastases of breast and lung cancer cells. Expressed on activated endothelial cells and platelets, Sialyl-Lewis (x) is required for CD24's interaction with P-selectin, therefore enabling the spread of malignant cells throughout the circulation.

Across tissues, CD24's glycosylation patterns are very varied; the molecule interacts with P-selectin, L-selectin, E-selectin, HMGB1, L1CAM, NCAM1, and SigleC-10 among other ligands. Different signals sent by CD24's binding to various ligands control cell activity and function. For instance, CD24 in a Ca²⁺-dependent manner moderates the binding and rolling of MCF-7 breast cancer cells on E-selectin. In hepatocellular carcinoma (HCC), where it helps immune evasion by reducing natural killer (NK) cell activity, CD24 also interacts with L1CAM (CD171) to control neurite outgrowth.

Crucially important in membrane receptor signaling, CD24 interacts with non-receptor tyrosine kinase Src. CD24 stimulates Src in lipid raft domains, which phosphorizes important proteins like paxillin and focal adhesion kinase (FAK), therefore influencing cell adhesion and migration. These connections encourage tumor cells' invading and metastatic activity. Further increasing tumor cell invasiveness, CD24 also reduces the expression of tissue factor pathway inhibitor-2 (TFPI-2) in an SRC-dependent manner. Additionally activating Src via CD24 causes STAT3 to phosphorize, hence encouraging tumor development and metastases.

Through changes in Rho GTPase protein RhoA, CD24 modulates the expression and function of the epidermal growth factor receptor (EGFR). Extensive activation of the ERK pathway is promoted by CD24-mediated activation of RhoA sustaining EGFR expression and restricting internalizing of the molecule. This extends downstream signaling and stimulates cancer and cell proliferation. Moreover, CD24 triggers the Akt pathway, which is well-recognized for controlling cell survival and development. Utilizing these channels, CD24 maintains the malignant phenotype of tumor cells, therefore fostering their resistance to death and hence their metastases potential.

CD24 in Cancer

In recent years, CD24 has garnered attention for its overexpression in several human malignancies, including breast, lung, and colorectal cancers. It is typically observed as a diffuse cytoplasmic accumulation in cancer cells. Elevated CD24 levels are especially prominent in aggressive cancers, such as triple-negative breast cancer (TNBC) and ovarian cancer. Additionally, CD24 overexpression has been correlated with poor prognosis in prostate cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and bladder cancer, where cytoplasmic CD24 levels have been linked to increased tumor invasiveness and recurrence.

Figure 1 describes the role of CD24 in activating various signaling pathways and integrins in cancer cells, leading to processes such as cancer development and gene regulation. Figure 1. CD24 activates αβ integrins to bind extracellular components and activates Src kinase in various cancer cells. (Eyvazi S, et al., 2018)

Emerging as a useful prognostic biomarker across many cancer types is CD24. For prostate cancer, for instance, CD24 expression may differentiate individuals at either low or high risk of recurrence. Cytoplasmic CD24 expression independently predicts patient survival in colorectal cancer and non-small cell lung cancer. Higher risk of tumor recurrence and a more aggressive disease course linked to CD24 expression in bladder cancer.

CD24 is also a key marker of cancer stem cells (CSCs), which are a subset of tumor cells capable of generating all the cell types within a tumor. CSCs are critical for tumor initiation and progression, and CD24 has been identified as an important marker of CSCs in several cancers, including ovarian, colorectal, pancreatic, and nasopharyngeal cancers. This highlights CD24's role in promoting tumorigenesis and tumor cell heterogeneity.

References:

Eyvazi S, Kazemi B, Dastmalchi S, et al. Involvement of CD24 in Multiple Cancer Related Pathways Makes It an Interesting New Target for Cancer Therapy. Curr Cancer Drug Targets. 2018;18(4):328-336.
Li W, Wang F, Guo R, Bian Z, Song Y. Targeting macrophages in hematological malignancies: recent advances and future directions. J Hematol Oncol. 2022;15(1):110. Published 2022 Aug 17.
Jiang KY, Qi LL, Kang FB, Wang L. The intriguing roles of Siglec family members in the tumor microenvironment. Biomark Res. 2022;10(1):22. Published 2022 Apr 13.
Wang X, Liu M, Zhang J, et al. CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder. Cell Metab. 2022;34(8):1088-1103.e6.

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