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Title

The EGFR-TMEM167A-p53 axis defines the aggressiveness of gliomas

AuthorsSegura-Collar, Berta; Gargini, Ricardo CSIC ORCID; Tovar-Ambel, E.; Hernández-SanMiguel, Esther; Epifano, Carolina; De Castro, I.P.; Hernández-Laín, Aurelio; Casas-Tinto, S.; Sanchez-Gomez, Pilar
KeywordsEGFR/AKT signaling
Autophagy
glioma
mutant p53
vesicular trafficking
wild-type p53.
Issue Date2020
PublisherMultidisciplinary Digital Publishing Institute
CitationCancers 12 (2020)
AbstractDespite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular traffcking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, a ecting the autophagy process and impairing EGFR traffcking and signaling. This e ect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular traffcking by TMEM167A.
Publisher version (URL)http://dx.doi.org/10.3390/cancers12010208
URIhttp://hdl.handle.net/10261/219602
DOIhttp://dx.doi.org/10.3390/cancers12010208
Identifiersdoi: 10.3390/cancers12010208
issn: 2072-6694
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