AHIF promotes glioblastoma progression and radioresistance via exosomes

Abstract

Glioblastoma multiforme (GBM) has the highest mortality rate among patients with brain tumors, and radiotherapy forms an important part of its treatment. Thus, there is an urgent requirement to elucidate the mechanisms conferring GBM progression and radioresistance. In the present study, it was identified that antisense transcript of hypoxia-inducible factor-1α (AHIF) was significantly upregulated in GBM cancerous tissues, as well as in radioresistant GBM cells. The expression of AHIF was also upregulated in response to radiation. Knockdown of AHIF in GBM cells decreased viability and invasive capacities, and increased the proportion of apoptotic cells. By contrast, overexpression of AHIF in GBM cells increased viability and invasive capacities, and decreased the proportion of apoptotic cells. Furthermore, exosomes derived from AHIF-knockdown GBM cells inhibited viability, invasion and radioresistance, whereas exosomes derived from AHIF-overexpressing GBM cells promoted viability, invasion and radioresistance. Further biochemical analysis identified that AHIF regulates factors associated with migration and angiogenesis in exosomes. To the best of our knowledge, the present study is the first to establish that AHIF promotes glioblastoma progression and radioresistance via exosomes, which suggests that AHIF is a potential therapeutic target for GBM.

Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications

“…Interestingly, lncRNAs can also be selectively sorted into exosomes and contribute to intercellular communication in the tumor microenvironment [47]. Exosomal lncRNAs can participate in the onset and progression of gliomas, such as proliferation, invasion, angiogenesis and drug resistance, which may act as attractive therapeutic targets [6,48,49]. Furthermore, exosomal lncRNAs have potential for diagnostic and prognostic biomarkers [47].…”

“…Increasing evidence shows that ncRNAs play important roles in glioma progression [35]. Glioma-derived exosomes carrying a broad range of ncRNAs are reported to exert significant functions in glioma proliferation and invasion through regulating intercellular communication in local and distant microenvironments [6,48,[63][64][65]71] (Fig. 4a).…”

“…CADM1 was proved to be a tumor suppressor which was downregulated in glioma tissues and most glioma cell lines [63]. Besides miRNAs, some exosomal lncRNAs, such as lncRNA-ATB [6] and lncRNA-AHIF [48], were reported to regulate cell proliferation and invasion in glioma. Bian and colleagues found that glioma cell-derived exosomes had the ability to shuttle lncRNA-ATB to astrocytes and promoted the activation of astrocytes, which could in turn promote the invasion and migration of glioma cells.…”

Extracellular Vesicles in Glioblastoma Tumor Microenvironment

“…Hypoxic environments stimulate glioma cells to secrete EVs that contain proteins involved in the actin cytoskeleton regulation, extracellular matrix-receptor interactions, focal adhesion and leukocyte trans-endothelial migration suggesting that hypoxic glioma derived EVs promote a migratory phenotype in glioma cells (33, 53). Glioma EV mediated transfer of HIF-1α promotes invasive capacity along with inducing radioresistance in sensitive glioma cells (116). Glioma EVs containing immunoglobulin superfamily protein L1CAM were shown to promote cell motility, proliferation and invasiveness in glioma cells in vitro (117).…”

The Role of Macrophage Migration Inhibitory Factor (MIF) in Acute Kidney Injury

“…MIF was considered to be the early prediction of tissue rejection in experimental and clinical transplantation [68]. MIF is increased in many kidney diseases as: acute kidney injury, lipid-induced glomerular injury [69], rat crescentic glomerulonephritis [66], anti-GBM diseases [70], ANCN-vasculitis, experimental murine MRL/ lpr lupus nephritis [71], and unilateral ureteral obstruction (UUO) obstructive nephropathy[72], acute renal allograft rejection[73], acute urate nephropathy[74], aristolochic acid nephropathy[75] and IgA nephropathy[76].In human kidney diseases, dramatic increase in MIF expression is detected in both glomerular and tubular MIF neutralizing antibody treatment or MIF deficiency may protect mice from kidney diseases. Blocking MIF activity with anti-neutralizing antibody can partially reverse mice crescentic glomerulonephritis, suggesting that MIF would enhance the cellular immune response[80].…”