The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors

Abstract

Brain tumors in children and adults are challenging tumors to treat. Malignant primary brain tumors (MPBTs) such as glioblastoma have very poor outcomes, emphasizing the need to better understand their pathogenesis. Developing novel strategies to slow down or even stop the growth of brain tumors remains one of the major clinical challenges. Modern treatment strategies for MPBTs are based on open surgery, chemotherapy, and radiation therapy. However, none of these treatments, alone or in combination, are considered effective in controlling tumor progression. MicroRNAs (miRNAs) are 18-22 nucleotide long endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level by interacting with 3'-untranslated regions (3'-UTR) of mRNA-targets. It has been proven that miRNAs play a significant role in various biological processes, including the cell cycle, apoptosis, proliferation, differentiation, etc. Over the last decade, there has been an emergence of a large number of studies devoted to the role of miRNAs in the oncogenesis of brain tumors and the development of resistance to radio- and chemotherapy. Wherein, among the variety of molecules secreted by tumor cells into the external environment, extracellular vesicles (EVs) (exosomes and microvesicles) play a special role. Various elements were found in the EVs, including miRNAs, which can be transported as part of these EVs both between neighboring cells and between remotely located cells of different tissues using biological fluids. Some of these miRNAs in EVs can contribute to the development of resistance to radio- and chemotherapy in MPBTs, including multidrug resistance (MDR). This comprehensive review examines the role of miRNAs in the resistance of MPBTs (e.g., high-grade meningiomas, medulloblastoma (MB), pituitary adenomas (PAs) with aggressive behavior, and glioblastoma) to chemoradiotherapy and pharmacological treatment. It is believed that miRNAs are future therapeutic targets in MPBTs and such the role of miRNAs needs to be critically evaluated to focus on solving the problems of resistance to therapy this kind of human tumors.

Keywords: exosomes; malignant primary brain tumors; miRNAs; oncogenesis; resistance; therapy.

FIGURE 1

MiRNA biogenesis pathway. Overview schematic representation of canonical miRNA biogenesis pathway.

FIGURE 2

MiR-21 involved in radio- and chemoresistance in glioblastoma. This figure shows through which signaling pathways miR-21 may be involved in resistance to therapy in glioblastoma.

FIGURE 3

Secretion of miRNAs into the extracellular environment. Primary microRNA (pri-miRNAs) are transcribed by RNA polymerase II and then processed by Drosha into precursor-miRNAs (pre-miRNAs). Exportin5 transfers these pre-miRNAs from the nucleus to the cytoplasm, where Dicer converts them into mature miRNAs. Mature miRNAs can be selectively incorporated into extracellular vesicles (EVs) (exosomes and microvesicles) or linked to the Argonaute 2 (Ago2) protein and released into the extracellular environment. Alternatively, they can be attached to high-density lipoprotein (HDL) or contained in apoptotic bodies and then released into the extracellular environment.

FIGURE 4

Biogenesis of exosomes. The exosome membrane is formed as a result of the invagination of the early endosome into the membrane. Proteins, lipids, RNA, DNA enter the exosome from the cell cytoplasm. The fate of an endosome depends on the marking of its membrane with certain lipids: if it is labeled with lysobisphosphatidic acid, then its contents will be destroyed, and if ceramides, it will be pushed out of the cell. These processes are controlled by the GTPases of the Rab (G-protein) family, whose various members perform different functions: Rab5 directs the formation of the endosome, Rab7 organizes the degradation of the contents of the multivesicular body (late endosome) in the lysosome, and Rab11, Rab27, and Rab35 are necessary for the secretion of exosomes into the extracellular space. It has been shown that exosomes contain about 4,000 different proteins, more than 1,500 different miRNAs and mRNAs, as well as DNA. Bottom right – enlarged “generalized” exosome.