**12. miRNAs as therapeutic targets**

**Figure 11.** Diverse mechanisms which alter the expression and functionality of miRNAs in human cancer.

*Defects in biogenesis* of miRNAs. Proteins which participate in the biogenesis of miRNAs may find themselves altered in cancer. In a study that spanned 67 lung cancer patients, a low expression on Dicer1 levels was determined, associated with a poor differentiation of tumour cells and short post-surgery survival [65]. The Argonaut proteins, components of the RISC complex, are in chromosome 1 and are deleted frequently in Wilms' tumours; in

**Figure 10.** Epigenetic mechanisms regulate the transcription of miRNAs. (A) A CpG island regulates the transcription of an intergenic miRNA. (B) A CpG island regulates the transcription of a gene that harbours an miRNA. (C) An intronic miRNA has its own transcriptional starting point, which is regulated through CpGs. (D) A factor of transcription recruits DNA-modifying enzymes and histones so as to epigenetically regulate a gene that harbours an miRNA which

is surrounded by CpGs.

72 Glioma - Contemporary Diagnostic and Therapeutic Approaches

Currently, miRNAs are categorised as oncogenes and tumour suppressants in such a manner that a future therapeutic strategy must be headed to inhibiting or activating the altered miRNA, in this sense, in recent years, a therapy of re-expression of microRNAs. The main advantage of miRNA therapy is that its re-expression may influence the expression of hundreds of genes involved in several cell strands and routes. The main obstacle for an effective therapy is the insertion of miRNAs within the cell, because they are molecules that do not freely enter, they are unstable and therefore they may degrade after crossing the membrane of plasma. Another important part is controlling the levels of re-expression of miRNAs to avoid their expression beyond the physiological levels. Another challenge is achieving the antineoplastic agents to cross the haematoma-encephalic barrier. To overcome this inconvenience, different strategies are being developed, such as the intranasal application of oligonucleotides, which is a non-invasive method for the transport of therapeutic agents; unites nucleic acids to cationic lipids, introducing the therapeutic agent by a conjugation with membrane lipids. The *in vitro* studies done with cell strands, antagomiRs, are introduced to cells uniting to their region 5′ a cholesterol molecule; in this way, antagomiR crosses the cell membrane and inhibits the action of the miRNA, sequestering it and uniting by a complementarity of bases, avoiding the inhibition of the target RNAm. Nevertheless, cancer is a complex illness and patients with the same diagnosis may have different genetic and epigenetic alterations and polymorphic variations; therefore, the incorporation of customised medicine is necessary.

In the development of the brain, several microRNAs have been identified with a differential expression profile, for which the differentiation strategy in cancers represents a new approach. There are two focuses on this regard: on one side, there are miRs which favour the growth of the tumour through the inhibition of the cell differentiation, and the maintenance of a small population of tumour stem cells (cells which retain properties of stem cells). In this case, therapies must be directed to these cell under-populations, introducing molecules which block the functions of the miR (antagomiR) [49]. On the contrary, it is known that the overexpression of some miRs such as miR-451 stimulates the CD133+ cells of GBM to differentiate themselves and lose their character of stem cells [67]. MiR-21 regulates several oncogenic routes and strands, for which it participates in the development and progress of gliomas. This makes it a potential therapeutic target in order to treat these tumours. In the same manner, the therapy headed to restore the levels of miR-34a may achieve anti-tumour effects by inducing their differentiation [66]. MiR-124 and 137 inhibit the expression of the RNAm of CDK6, protein CDK6, and they phosphorylate RB in GBM cells, which demonstrate their potential value in treating this illness. Besides, miR-124 and miR-137 have a potent anti-proliferation effect and pro-differentiation effect in GBM CD133+ and CD133− cells [40] (**Figure 12**).

In the following figure, the re-expression of miR-124 is described as a differentiation therapy in GBM.

It is also important to highlight the role that miRNAs undertake in the stem cell, in the differentiation and in cell identity. MiRNAs involved in neural development have also been found deregulated in GBM, which implies that certain miRs allow the growth of the tumour by suppressing the differentiation and maintaining the characteristics of stem cells. Several miRNAs have been identified as having a functional importance in neural development. In particular, miR-7 and miR-124 participate in neural differentiation and are little expressed in GBM. MiR-128 is also altered, but its function in normal cells is unknown. In GBM, the suppression of miR-128 may have severe effects because it may keep the self-renewal of glioma stem cells [42].

The determination and validation of target RNAm will help understand the development of the tumour and will provide potential targets to reduce its growth. In such manner, one of the goals to pursue is to identify a group of miRNAs, whose expression is significantly correlated

Little is known about the role of miRNAs as prognosticating indicators. Nevertheless, in astrocytomas, it has been observed that some miRNAs are expressed in a differential manner as miR-221 which is over-expressed in high-grade gliomas, and miR-124 has a lower level of expression in the anaplastic astrocytoma and in the GBM by comparison with low-grade astrocytomas such as the pilocytic and the diffuse astrocytoma. The low expression of miR-137 in astrocytomas is associated with a more advanced clinical phase. The low expression of miR-181b or the high expression of miR-21 was significantly associated with a poor survival of the patient [43].

The miRNAs may have important therapeutic implications, given that they may be function-

MiRNAs are less susceptible to chemical modifications and degradement by ribonucleases by comparison with RNAm. These features of miRNAs allow their detection not only from frozen tissue but also in bodily fluids such as plasma and serum, and even in samples fixed in formol and included in paraffin. This allows for the development of retrospective studies, including a greater number of cases. Particularly speaking, the level of expression starting from bodily fluids represents the most promising advance for a non-invasive diagnosis and allows for their use as biomarkers to detect tumours in early stages and correlating them with clinical development.

and Fernando Chico Ponce de León3

Astrocytomas and miRNAs: Are They Useful? http://dx.doi.org/10.5772/intechopen.77419 75

\*, Pilar Eguía-Aguilar2

1 Department of Pathology, Hospital Infantil de México Federico Gómez, México City,

2 Molecular Biology Laboratory of the Department of Pathology, Hospital Infantil de México

3 Department of Neurosurgery, Hospital Infantil de México Federico Gómez, México City,

\*Address all correspondence to: mpdiazconti@gmail.com

with clinical parameters and which may be used to classify different degrees of

ally antagonised or restored.

**Author details**

Mexico

Mexico

Mario Perezpeña-Diazconti1

Federico Gómez, México City, Mexico

**Figure 12.** Mature miRNA does not unite to its target RNAm because it is blocked by a complementary therapeutic miRNA.
