Use of microRNAs as Diagnostic, Prognostic, and Therapeutic Tools for Glioblastoma

Abstract

Glioblastoma (GB) is the most aggressive and common type of cancer within the central nervous system (CNS). Despite the vast knowledge of its physiopathology and histology, its etiology at the molecular level has not been completely understood. Thus, attaining a cure has not been possible yet and it remains one of the deadliest types of cancer. Usually, GB is diagnosed when some symptoms have already been presented by the patient. This diagnosis is commonly based on a physical exam and imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), together with or followed by a surgical biopsy. As these diagnostic procedures are very invasive and often result only in the confirmation of GB presence, it is necessary to develop less invasive diagnostic and prognostic tools that lead to earlier treatment to increase GB patients' quality of life. Therefore, blood-based biomarkers (BBBs) represent excellent candidates in this context. microRNAs (miRNAs) are small, non-coding RNAs that have been demonstrated to be very stable in almost all body fluids, including saliva, serum, plasma, urine, cerebrospinal fluid (CFS), semen, and breast milk. In addition, serum-circulating and exosome-contained miRNAs have been successfully used to better classify subtypes of cancer at the molecular level and make better choices regarding the best treatment for specific cases. Moreover, as miRNAs regulate multiple target genes and can also act as tumor suppressors and oncogenes, they are involved in the appearance, progression, and even chemoresistance of most tumors. Thus, in this review, we discuss how dysregulated miRNAs in GB can be used as early diagnosis and prognosis biomarkers as well as molecular markers to subclassify GB cases and provide more personalized treatments, which may have a better response against GB. In addition, we discuss the therapeutic potential of miRNAs, the current challenges to their clinical application, and future directions in the field.

Keywords: GBM; RNA therapy; glioblastoma; glioblastoma multiforme; glioma; glioma treatment; miRNAs; microRNAs; non-coding RNAs.

Figure 1

miRNA biogenesis pathway. miRNA biogenesis begins with the transcription of a miRNA gene by RNA polymerase II (POLII), which results in the production of a long transcript called primary miRNA (pri-miRNA) that is recognized by the microprocessor complex consisting of the type III RNAse, DROSHA, and the DiGeorge syndrome critical region gene 8 (DGCR8) protein. The pri-miRNA is then processed to generate a precursor miRNA (pre-miRNA) with a size of 70−100 nucleotides (nts). The pre-miRNA has a stem–loop structure and it is transported from the nucleus to the cytoplasm by the GTPase, EXPORTIN 5. Once in the cytosol, the loop region of the pre-miRNA is removed by another type III RNAse named DICER, resulting in the generation of an RNA duplex with an approximate size of 21–23 nt. One strand of the duplex will constitute the mature miRNA, while the other one will be degraded. Once the mature miRNA is released, it recruits the RNA-induced silencing complex (RISC) and, depending on the degree of sequence complementarity and the recognized region within the miRNA target messenger RNA (mRNA), gene expression will be either positively or negatively regulated by different mechanisms of action: transcriptional or translational induction (if the miRNA binds to the 5′ untranslated region (UTR) of the mRNA with imperfect sequence complementarity), mRNA degradation (if the miRNA binds to the 3′ UTR of the mRNA with perfect/almost perfect sequence complementarity), and translational repression (if the miRNA binds to the 3′ UTR of the mRNA with imperfect sequence complementarity).

Figure 2

Downregulated (left) and upregulated (right) miRNAs in GB. Their related functions are depicted in boxes. Enhanced cellular functions are labeled with an upward-pointing arrow, while reduced cellular functions are labeled with a downward-pointing arrow.