Characterisation of mechanisms promoting glioma cell survival and proliferation under hypoxia
The aggressive phenotype associated with Glioblastoma multiforme is thought to be promoted by extensive tumour hypoxia, resulting in rapid tumour cell proliferation and invasion, and the development of chemo- and radiation resistance tumour cells. We hypothesize that hypoxia-responsive miRNA species are involved in this process and may promote resistance to therapy in these patients.
MicroRNAs regulate key molecular processes involved in tumour development. MicroRNAs (miRNAs) are small non-coding RNAs, 20-25 nt in length, that downregulate gene expression in crucial cellular processes, including apoptosis, differentiation and development . miRNAs regulate gene expression by direct cleavage of target mRNA (multiple targets) or by inhibiting translation through perfect or near perfect complementarity to target mRNA at the 3' UTR. miRNAs can act as tumour suppressors (miR-15 and -16) or oncogenes (miR-155), and can themselves be affected by genomic abnormalities, such as chromosomal rearrangements, genomic amplifications, deletions and mutations. More than half of miRNAs are located in cancer-associated genomic regions or fragile sites.
A range of microRNA are reported to be dysregulated in glioma, including miR-21 (antiapoptotic factor and promoter of glioma cell invasion), miR-7 (a regulator of EGFR and Akt signaling), and miR-128 (a regulator of brain cell proliferation). Recently, Srinivasan et al. analysed miRNA expression data of GBM patients (n=222) from the TCGA repository, identifying a 10 miRNA expression signature that could independently predict patient survival, including hsa-miR-20a, -106a, -17-5p, -31, -222, -148a, -221, -146b, -200b and -193a.
A rapidly growing body of evidence points to microRNAs as potential targets for cancer therapy. Recently, Swarbrick et al., demonstrated that a systemically delivered anti-miR in an orthotopic neuroblastoma mouse model was able to inhibit primary tumour growth.
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