Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis

Abstract

Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24-) still retain aggressive phenotypes in vitro and in vivo. Here we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24- cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histological types of cancer. Nuclear-specific expression of CD24 (NLS-CD24) increased anchorage independent growth in vitro and tumor formation in vivo. Immunohistochemistry of patient tumor samples revealed the presence of nucCD24, whose signal intensity correlated positively with the presence of metastatic disease. Analysis of gene expression between cells expressing CD24 and NLS-CD24 revealed a unique nucCD24 transcriptional signature. The median score derived from this signature was able to stratify overall survival in 4 patient datasets from bladder cancer and 5 patient datasets from colorectal cancer. Patients with high scores (more nucCD24-like) had reduced survival. These findings define a novel and functionally important intracellular location of CD24, they explain why surCD24- cells can remain aggressive, and they highlight the need to consider nucCD24 in both fundamental research and therapeutic development.

Heparanase promotes glioma progression via enhancing CD24 expression

“…The CD24 knockout mice also showed reduced metastasis. Together, these findings make CD24 a therapeutic target . Our results discover, for the first time, a similar functional repertoire for CD24 in glioma.…”

“…Likewise, treatment of tumor‐bearing mice with neutralizing anti‐CD24 mAb leads to reduced tumor burden . CD24 knockout mice exposed to chemical carcinogens developed no colorectal tumors and fewer bladder tumors . The CD24 knockout mice also showed reduced metastasis.…”

“…Most studies reported that overexpression of CD24 protein or CD24 positivity is significantly associated with malignant transformation or poor outcome in a variety of carcinomas . Overexpression of CD24 promotes in vitro cell proliferation as well as in vivo tumor growth, invasion and metastasis, whereas its depletion reduces these properties . Likewise, treatment of tumor‐bearing mice with neutralizing anti‐CD24 mAb leads to reduced tumor burden .…”

CD24 is a Potential Biomarker for Prognosis in Human Breast Carcinoma

“…Previous studies have shown that abnormal overexpression of CD24 is an unfavorable prognostic factor during carcinogenesis in various neoplasms [10,15,23,27,28]. Meanwhile, CD24 can upregulate the activity of STAT3 and the expression of prototype STAT3-regulated genes [29].…”

“…High expression levels of CD24 have been identified in various types of cancers-such as breast, prostate, pancreas, ovary, colorectal, and bladder cancers-and indicate poor prognosis [9][10][11][12]. CD24 has also been demonstrated to promote tumor cell proliferation, invasion, and metastasis in many types of cancers [3,13,14].…”