Abstract
Hedgehog (Hh) signaling pathway is a valid therapeutic target in a wide range of malignancies. We focus here on glioblastoma multiforme (GBM), a lethal malignancy of the central nervous system (CNS). By analyzing RNA-sequencing based transcriptomics data on 149 clinical cases of TCGA-GBM database we show here a strong correlation (r = 0.7) between GLI1 and PTCH1 mRNA expression—as a hallmark of the canonical Hh-pathway activity in this malignancy. GLI1 mRNA expression varied in 3 orders of magnitude among the GBM patients of the same cohort showing a single continuous distribution—unlike the discrete high/low-GLI1 mRNA expressing clusters of medulloblastoma (MB). When compared with MB as a reference, the median GLI1 mRNA expression in GBM appeared 14.8 fold lower than that of the “high-Hh” cluster of MB but 5.6 fold higher than that of the “low-Hh” cluster of MB. Next, we demonstrated statistically significant up- and down-regulation of GLI1 mRNA expressions in GBM patient-derived low-passage neurospheres in vitro by sonic hedgehog ligand-enriched conditioned media (shh-CM) and by Hh-inhibitor drug vismodegib respectively. We also showed clinically achievable dose (50 μM) of vismodegib alone to be sufficient to induce apoptosis and cell cycle arrest in these low-passage GBM neurospheres in vitro. Vismodegib showed an effect on the neurospheres, both by down-regulating GLI1 mRNA expression and by inducing apoptosis/cell cycle arrest, irrespective of their relative endogenous levels of GLI1 mRNA expression. We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity. That is suggestive of therapies with Hh-pathway inhibitor drugs in this malignancy without a need for further stratification of patients on the basis of relative levels of Hh-pathway activity among them.
Highlights
Hedgehog (Hh) signaling pathway is a developmentally important signaling pathway[1], inactive in normal adult mature cells and found to be aberrantly hyper-activated in a wide range of malignancies [2,3,4,5]
GLI1/PTCH1 correlation confirmed the relevance of Hh-pathway in glioblastoma multiforme (GBM), we sought comparative quantitation of GLI1 mRNA expression in this malignancy—how low is
Unlike MB, GLI1 mRNA expression in GBM to have a single continuous distribution rather than discrete high- or low- Hh expressing clusters
Summary
Hedgehog (Hh) signaling pathway is a developmentally important signaling pathway[1], inactive in normal adult mature cells and found to be aberrantly hyper-activated in a wide range of malignancies [2,3,4,5]. Aberrant hyper-activation of this pathway was first identified in Gorlin’s syndrome [6, 7], where an autosomal dominant mutation in the tumor suppressor gene PTCH1 predisposed patients to basal cell carcinoma (BCC) and/or central nervous system (CNS) malignancy medulloblastoma (MB) [8]. PTCH1 is a 12-pass transmembrane (TM) receptor which in absence of its ligand inhibits the other 7-pass TM receptor SMO, keeping it from transmitting the signal. When PTCH1 binds to the soluble ligand sonic hedgehog (SHH)—or inactivated by loss-of-function mutation, as in Gorlin’s syndrome—this inhibition on SMO is withdrawn and the pathway is turned on. The major intracellular players of this pathway in human are STK36, a serine/threonine kinase known as fused (Fu), suppressor of Fu (SuFu), KIF27, a member of mammalian kinesin family, and the signal is transduced by Hh-transcription factors GLI1, GLI2 and GLI3 [11]. Role of GLI3 is context dependent, shown to play opposing inhibitory roles [13]
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