Hypoxic Glioma Cell-Secreted Exosomal miR-301a Activates Wnt/β-catenin Signaling and Promotes Radiation Resistance by Targeting TCEAL7

Abstract

Recent evidence suggests that microRNAs (miRNAs) can be released to the extracellular microenvironment and mediate cell-cell communication through exosomes. The aim of this study was to identify exosomal miR-301a (exo-miR-301a) involved in glioblastoma (GBM) radioresistance and reveal the possible mechanisms. The exo-miR-301a specifically secreted by hypoxic GBM cells could transfer to corresponding normoxia-cultured cells and promote radiation resistance. Hypoxic exo-miR-301a directly targeted TCEAL7 genes, which were identified as a tumor suppressor in GBM malignancy and actively repressed its' expression in normoxic glioma cells. Our studies indicated that TCEAL7 negatively regulated the Wnt/ b-catenin pathway by blocking b-catenin translocation from cytoplasm to nucleus. Interestingly, we clarified that the Wnt/ b-catenin signaling was activated by miR-301a and TCEAL7 mediated the important procession. The exo-miR-301a was involved in the resistance to radiotherapy, and the effects would be reversed by miR-301a inhibition or TCEAL7 overexpression to regulate the Wnt/b-catenin axis. Here we show that exo-miR-301a, which is characteristically expressed and secreted by hypoxic glioma cells, is a potent regulator of Wnt/b-catenin and then depresses radiation sensitivity through targeting anti-oncogene TCEAL7. The newly identified exo-miR-301a/ TCEAL7-signaling axis could present a novel target for cellular resistance to cancer therapeutic radiation in GBM patients.

Long non-coding RNA HAND2-AS1 inhibits gastric cancer progression by suppressing TCEAL7 expression via targeting miR-769–5p

“…Moreover, silencing of TCEAL7 was revealed to promote the expression of Cylin D1 and in the end promotes non-small cell lung cancer progression [18] . Another work indicated TCEAL7 could be regulated by miR-301a to regulate glioma cell radiation resistance [19] . In GC, TCEAL7 was revealed to be decreased expression and correlated with prognosis of cancer patients [20] .…”

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

“…Exosomal ncRNAs released by glioma cells can also interfere with the sensitivity to radiotherapy and thus affect the treatment efficiency. Yang et al reported that exosomal miR-301a specifically secreted by hypoxic GBM cells could transfer to corresponding normoxiacultured cells and promote radiation resistance by targeting TCEAL7 genes [79]. In addition, a recent study demonstrated that circRNA-ATP8B4 from radioresistant GBM derived EVs could also promote glioma radioresistance by sponging miR-766 [78].…”

Non-Coding RNAs in Cancer Radiosensitivity: MicroRNAs and lncRNAs as Regulators of Radiation-Induced Signaling Pathways

“…In contrast, miR-301a-mediated TCEAL7 inhibition increased transcriptional activity of β-catenin. Moreover, inhibition of miR-301a and overexpression of TCEAL7 reversed the radioresistant miR-301a phenotype in GMB cells in vitro and in vivo [93]. These opposite effects could be attributed to a cell-line specific miR-301a function.…”

“…Contradictory effects of miR-301a on Wnt/β-catenin signaling pathway and radiosensitivity were demonstrated. miR-301a was shown to directly target Wnt that activates and TCEAL7 that suppress β-catenin signaling [58,93]. Upregulation of miR-301a directly inhibited Wnt and indirectly β-catenin and cyclin D1 in ESCC cells and this led to increased radiosensitivity, reduced proliferation and migration of ESCC cells [58].…”