Abstract
EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies.
Highlights
Recent data showed that the key NMD factor UPF1 is downregulated during the epRecent data showed that the key NMD factor UPF1 is downregulated during the ithelial to mesenchymal transition (EMT) [21]
We confirmed these data in a cohort epithelial to mesenchymal transition (EMT) [21]
We confirmed these data in a cohort (n = 42) of non-small cell lung carcinomas (NSCLCs) in which the tissue samples were (n = 42) of non-small cell lung carcinomas (NSCLCs) in which the tissue samples were sorted according to their Vimentin status: epithelial-to-mesenchymal transition (EMT)+ tumors that exhibit high percentages of sorted according to their Vimentin status: EMT+ tumors that exhibit high percentages of malignant cells expressing this biomarker and EMT− tumors with a complete absence of malignant cells expressing this biomarker and EMT− tumors with a complete absence of expression for this protein by the cancer cells [22]
Summary
Licensee MDPI, Basel, Switzerland.Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).The epithelial-to-mesenchymal transition (EMT) is a physiological process in which epithelial cells lose their cell polarity and acquire mesenchymal properties; it occurs during embryogenesis or tissue remodeling (EMT I and II). During cancer progression, the EMT (type III) [1] plays a key role in metastasis formation by promoting cellular invasion, dissemination and tissue colonization. Specific morphological changes observed in cells undergoing the EMT are controlled at different levels of gene expression, including epigenetics, transcriptional and post-transcriptional levels, or translation [2]. It was reported that the EMT has an impact on autophagy, and conversely, the induction of Biomedicines 2021, 9, 1302. https://doi.org/10.3390/biomedicines9101302 https://www.mdpi.com/journal/biomedicines
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