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of cells in gliomas with properties of stem cells, known as also contribute to radioresistance in classical-GBM. Thus,
[43]
glioma-initiating cells (GICs). These cells express neural inhibiting TGF-β has been proposed as a treatment since
stem cell markers such as NESTIN, OLIG2, sex determining it induces radiosensitivity in gliomas through decreasing
region Y-box 2 (SOX2) and fucosyltransferase 4. [20,24,25] the expression of miR-1 and -125a. [23,39,44] Additionally,
The classification of GICs is based on the expression of miR-221/222 downregulate PTEN, leading to activation
prominin-1 (CD133); the CD133 GICs are more invasive of proteins that promote cell proliferation or prevent cell
+
than those that do not express the antigen, and constitute death, such as: AKT, B-cell lymphoma 2 (Bcl-2), Cyclin-D,
3-29% of the glioma mass. [26,27] Also, GICs from secondary matrix metallopeptidase 2 and 9, [41,45,46] Interestingly,
cultures conserve the characteristics of the original tumor, the phosphorylation of AKT is the main mechanism for
even after several passages. Self-renewal, aggressiveness developing radioresistance, regardless of the activity of
[28]
and stemness of GICs are associated with the expression of its negative regulator PTEN. [40,41] In summary, molecular
Cyclin E and proteins of the family of inhibitor of DNA- analysis could help to reconsider whether conventional
binding/differentiation proteins, increased activity of treatments are suitable, or therapeutic modifications should
several signaling pathways including: transforming growth be adapted to the requirements of the patient.
factor (TGF)-β; protein kinase A and jagged-NOTCH; [26,29]
as well as the activation of the receptors for PDGF, epidermal GROWTH-ARREST-SPECIFIC 1
growth factor (EGF) and fibroblast growth factor (FGF).
[26]
Surprisingly, CD133 GICs also contribute to malignant The balance between proliferation or growth arrest is
+
transformation of the adjacent normal glial cells through regulated by several extrinsic and intrinsic factors. Cells
paracrine activity of PDGF-α and stimulate angiogenesis by can exit the cell cycle and enter in the non-proliferative
activation of the NOTCH signaling pathway on endothelial phase, known as the G0 phase. Particularly, in the this
tissue. [26,28,30] phase six genes named growth-arrest-specific (Gas) genes
are expressed, from 1 to 6. The gas1 transcript is the
[47]
It is noteworthy that CD133 GICs are predisposed to most abundant in NIH3T3 cells arrested in the G0 phase by
+
become resistant to chemo- and radiotherapy with respect deprivation of serum or high cell density. [47-49] Gas1 induces
to non-GICs cells, implicating the activation of extracellular growth arrest by inhibiting DNA synthesis in NIH3T3 cells
signal-regulated kinases 1 and 2 (ERK1/2). [20,31,32] In this when it is ectopically expressed. [49]
context, the use of classical therapies against gliomas,
facilitate the selection of multi-resistant GICs, leading TRANSCRIPTIONAL AND
to the formation of more aggressive tumors, resistant to TRANSLATIONAL REGULATION
chemo- and radiotherapy. Moreover, in vitro and in vivo
[33]
studies have shown that with the adequate stimulus, GICs Human and mouse gas1 genes are located in the long arms
[52]
differentiate to either neuronal or astrocytic cells, however of chromosome 9 (9q21.3-q22) [50,51] and chromosome 13
many of these responses are deregulated in gliomas. [31] respectively, with 77.04% of homology between them.
Gas1 is an intronless gene, suggesting that it probably
Currently, the analysis of protein expression and of the originated from a retrotransposon. [53]
transcriptome, including micro-RNAs (miRNAs), has helped
to uncover molecular markers involved in the susceptibility There are few studies about the regulation of the gas1 gene,
or resistance to treatments. Indeed, differential expression however it has been reported that Menin and Myb-like
patterns of miRNAs have been reported in high-grade (coded by the men1 and dmp1 genes respectively), induce the
gliomas. Even now, the association of miRNAs with the transcriptional repression of gas1. [54,55] Also, c-Myc and Src
[34]
methylation of the MGMT promoter is still controversial repress gas1 transcription, since they facilitate re-entering to the
since miRNAs are not considered as direct epigenetic cell cycle. [56,57] c-Myc protein requires the Myc-Box2 domain
regulators. [21,35] However, overexpression of miR-222, to be present on the N-terminus to repress the transcription of
-145 and -132 is related with TMZ resistance coupled with gas1. Furthermore, the basic Helix-loop-Helix leucine zipper
MGMT promoter methylation. Additionally, miR-181b domain located at the C-terminus of c-Myc is also necessary
[35]
and -181c are downregulated in patients that responded to to induce the transcriptional repression of gas1, perhaps
radiotherapy and concomitant TMZ. However, sensibility together with an accessory protein not yet identified. [56,58]
[36]
to chemotherapy is not only dependent of the presence of Both c-Myc and Src are key components for the proliferation,
MGMT. [37,38] growth, and survival of glioma cells. The expression of c-Myc
closely correlates both with cellular dedifferentiation and the
Screening of molecular changes after radiotherapy showed grade of malignancy, [59-61] since its activity induces the
overexpression of miR-1, -125a, -144, -150, -151-5p, transcripcion of cyclin D1 and repression of the p21 WAF1/
-221/22, -425 and -1285. [39-42] The ectopic expression of CIP1 cyclin-dependent kinase inhibitor. Interestingly, the
[62]
miR-1, -125a, -150 and -425 increases cell survival and histone chaperone, Facilitate Chromatin Transcription
confers radioresistance through the induction of the cell- protein complex (FACT) increases the transcription of Myc,
cycle. On the other hand, TGF-α and -β, and the EGFR a recent report showed that the downregulation or inhibition
[39]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 103