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HEDGEHOG IN GLIOMA Shh pathway plays an important role in the migratory
ability of cells derived from CD133 glioblastoma
−
Hedgehog signaling pathway cells. [35] Furthermore, the Hh inhibitor cyclopamine
Hedgehog is a highly conserved signaling pathway and has been shown to improve the effect of radiation on
a key regulator of embryonic development, including GSCs. All of the studies mentioned above suggest that
the processes of cell differentiation, proliferation, and Hh signaling is one of the critical pathways for the
tissue patterning. [33,34] In adults, Hh plays an important maintenance, proliferation, migration, and tumorigenic
role in the maintenance of stem cells, tissue repair, potential of GSCs. Thus, targeting this pathway with
and regeneration. The Hh family consists of three pharmacologic inhibitors may inhibit GSC growth and
secreted proteins, sonic Hedgehog (Shh), Indian improve the efficacy of conventional therapies.
Hedgehog (Ihh) and desert Hedgehog. Two molecules
that are important for Hh signaling are patched (Ptch) The regulatory role of microRNA
and smoothened (Smo). In the absence of Hh, Ptch MicroRNAs (miRNAs) are a class of small noncoding
inhibits the activity of Smo, a receptor-like protein cellular RNAs that bind to cis-regulatory elements
with seven transmembrane domains. In the presence located primarily in the 3’ untranslated regions of
of activated Smo, a complex consisting of the target mRNAs, resulting in their translational inhibition
glioma-associated oncogene family zinc finger (Gli) and or degradation. The function of some miRNAs
the suppressor of fused (Sufu), an important negative has been determined to be important for neural
regulator of Hh signaling, enters the nucleus, leading development. [40] Other studies have indicated that
to nuclear translocation and activation of the Gli1 miRNAs play a potentially important role in glioma
and Gli2 transcription factors, as well as degradation biology. The relationship between the Hh pathway and
of Gli3. Activated Gli subsequently promotes the miRNA is currently being investigated.
transcription of Hh target genes [Figure 1]. Three
types of Gli transcription factors, Gli1, Gli2, and Gli3, It has been shown that stable miR-302-367 cluster
have been identified in mammals. Gli1 and Gli2 are expression is sufficient to suppress the stem cell-like
activators of Hh target genes, while Gli3 mainly appears signature, self-renewal, and infiltration of cells by
to be a repressor. The function of Hh signaling is very inhibition of the CXCR4 pathway. Furthermore,
complicated and critical. Thus, it is important to inhibition of CXCR4 leads to disruption of the
elucidate the function and molecular regulation of Hh Shh-Gli-Nanog network, which is involved in
signaling, especially in GSCs. self-renewal and expression of the embryonic stem cell-
like signature. [41,42] Wu et al. [43] suggested that miR-5 can
Functional studies of Hedgehog in glioma stem cells specifically suppress Hh signaling by directly targeting
Aberrant activation of Hh signaling has been shown to Smo in Drosophila. In addition, miR-125b and miR-326
be associated with the formation of gliomas. Several have been identified as suppressors of Smo, and miR-
studies have investigated the role of Hh-Gli signaling 324-5p targets the downstream transcription factor Gli1.
in GSCs and found that it regulates self-renewal and Down-regulation of these miRNAs allows high levels
tumorigenic potential in GSCs. [22,35-37] Importantly, of Hh-dependent gene expression leading to tumor cell
inhibition of Hh-Gli signaling enhances the ability proliferation. [44] Furthermore, functional analyses have
of TMZ to inhibit GSC proliferation and induce cell shown that miR-326 may be regulated by Shh activation
death. [38] Several studies have demonstrated that and act as a negative modulator of Shh signaling by
inhibition of Hh signaling blocks tumor growth and directly targeting Smo and Gli2. [45] Other studies have
influences both proliferation and malignancy. [39] The
demonstrated that miR-214 can inhibit Sufu, allowing
maximal activation of Gli-mediated transcription, and
[46]
miR-941 targets key components of the Hh-signaling
pathway, including Smo, Sufu, and Gli1. [47] Moreover,
miR-212 was found to be involved in tumorigenesis,
and the oncogenic activity of miR-212 was partly due to
suppression of Ptch1. [48] Although many miRNAs have
been shown to regulate the Hh pathway as upstream
factors, the Hh pathway in turn has been shown to
regulate the mir-29b-1/mir-29a promoter [Table 1 and
Figure 1: The off and on states of the Hedgehog (Hh) signaling pathway. Figure 2]. [49]
Patched (Ptch) inhibits the activity of smoothened, which prevents the suppressor
of fused‑Gli1/2 complex from entering the nucleus and promotes Gli3 nuclear The studies mentioned above show that miRNAs affect
accumulation, leading to low expression of Hh target genes. Hh binding to Ptch
activates the Hh signaling pathway by promoting Gli1/2 expression the expression of numerous genes involved in glioma

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 53