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Expression profile of shNT and shPTX3 DAOY cells

ABSTRACT: Sonic hedgehog-medulloblastoma (SHH-MB) represents a biologically diverse and clinically challenging subgroup, especially in high-risk variants characterized by metastatic dissemination. Identifying novel oncogenic mechanisms that can be therapeutically exploited is therefore a critical priority. Here, we uncover Pentraxin-3 (PTX3) as a previously unrecognized, SHH-enriched oncogenic mediator that promotes proliferation, migration, clonogenicity, and angiogenesis. Mechanistically, we demonstrate that PTX3 activates a TLR4/IRAK1/PI3K-Akt/GSK-3/β-catenin signaling cascade, establishing a key regulatory axis essential for SHH-MB growth. We used microarrays to detail the global programme of gene expression in DAOY shNT and shPTX3 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311435 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.

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Expression profile of shNT and shPTX3 DAOY cells

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