CD24 promoted cancer cell angiogenesis via Hsp90-mediated STAT3/VEGF signaling pathway in colorectal cancer

Abstract

CD24 is involved in tumor progression of various cancers, but the effects of CD24 on tumor angiogenesis in colorectal cancer are still unknown. We aimed to investigate the underlying mechanism and role of CD24 on colorectal cancer (CRC) angiogenesis. Our data showed that the microvessal density (MVD) was related to the expression of CD24 in primary and metastasis CRC. Silencing of CD24 could dramatically decrease human umbilical vein endothelial cell (HUVEC) migration, invasion and tubule formation, but trivially affected cell proliferation. We also mechanically showed that silencing CD24 could downregulate the expression of VEGF via inhibiting the phosphorylation and translocation of STAT3. Moreover, Hsp90 was identified as the down-interaction protein of CD24 with co-immunoprecipitation assay and systematic mass spectrometry. Immunofluorescence results showed Hsp90 partly co-localized with CD24 in CRC cell membrane and there was a positive correlation between CD24 and Hsp90 expression in CRC tissues. We gradually evidenced that Hsp90 modulated the stability and degradation of CD24 in a proteasome-depended manner, and transferred the signal transmission from CD24 to STAT3. 17-AAG, a specific Hsp90, could abrogate the CD24 induce- HUVEC migration, invasion and tubule formation in vitro and in vivo. Collectively, our results suggested that CD24 induced CRC angiogenesis in Hsp90-dependent manner and activated STAT3-mediated transcription of VEGF. We provided a new insight into the regulation mechanism of tumor angiogenesis by exploring the role of CD24 in angiogenesis.

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

“…25 The authors suggested that Src was the kinase linking CD24 to the activation of STAT3. 48 We show that early activation of STAT3 is required to obtain an increased expression of SOX2. 47 In contrast, in our experiments, we did not observe any effect of the Src kinase inhibitors PP2 or dasatinib on the vem-mediated phosphorylation of STAT3.…”

“…A recent study on colorectal cancer has shown that Hsp90 can serve as a signaltransmitting link between CD24 and STAT3. 48 We show that early activation of STAT3 is required to obtain an increased expression of SOX2. This initial STAT3 activation might be due to secreted factors as suggested by Ohanna et al showing that the secretome of senescent melanoma cells drives basal melanoma cells toward a mesenchymal phenotype and activates the STAT3 pathway.…”

CD24: A Rheostat That Modulates Cell Surface Receptor Signaling of Diverse Receptors

“…In addition, hypoxia in solid tumors induced CD24 expression via Hypoxia Inducible Factor-1 leading to increased tumor cell survival (Thomas et al, 2012). Finally, CD24 has been shown to regulate angiogenesis through Heat Shock Protein 90 and modulation of the STAT3/VEGF pathway (Wang et al, 2016). Therefore, CD24 is also important for modulating the sensitivity or cellular response to extracellular stresses.…”

Therapeutic potency of heat-shock protein-90 pharmacological inhibitors in the treatment of gastrointestinal cancer, current status and perspectives

“…They showed that HSP90 regulates angiogenesis at least partially by modulating stability of CD24 in colorectal cancer cells. [8,9] Consistently, it has been shown that HSP90 inhibitors elicit anti-angiogenic properties in tumour cells. [10] In line with this, Lang et al showed that inhibition of HSP90 by 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) exerts anti-angiogenic effect by inhibiting the growth and vascularization of gastric tumours in tumour models.…”