Abstract
Gastric neuroendocrine carcinoma (GNEC) is a common type of neuroendocrine carcinoma (NEC) with a poor prognosis and limited therapeutic options. The underlying mechanisms of chemoresistance in patients with GNEC and those with NEC are largely unknown, and thus, reliable biomarkers and therapeutic targets that could improve treatment outcomes in patients with NECs are lacking. The aim of this study was to identify specific targets and investigate their roles in GNEC progression and treatment resistance. Differentially expressed genes (DEGs) were identified in GNEC specimens and were further analysed by focusing on their roles in chemoresistance. Gene Ontology (GO) and pathway enrichment analyses of GNEC DEGs revealed that synapse-related function was the most prominent cellular function perturbed in GNEC. SNAP25 was identified as the target gene involved in most of the enriched pathways. In vitro and in vivo experiments showed that SNAP25 plays a role in proliferation and chemoresistance in GNEC cell lines. AKT has been identified as a downstream target, and SNAP25 binds to AKT protein and promotes AKT protein half-life. Further analysis of other types of NEC as well as small cell lung cancer, which resembles NEC on a molecular level, has identified RUNDC3A as an upstream molecule that regulates SNAP25 expression and the associated phenotypes that could enhance chemoresistance in NECs. Our results show that SNAP25 expression in GNEC is mediated by RUNDC3A and promotes GNEC progression and chemoresistance via posttranslational modification of AKT. Thus, our results suggest that the RUNDC3A/SNAP25/Akt axis could be a potential therapeutic target in GNEC. [Abstract copyright: © 2022. The Author(s).]
| Original language | English |
|---|---|
| Article number | 296 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Cell death discovery |
| Volume | 8 |
| Issue number | 1 |
| Early online date | 25 Jun 2022 |
| DOIs | |
| Publication status | Published online - 25 Jun 2022 |
Bibliographical note
Funding Information:We thank the UM-FHS Animal Facility at the University of Macau for experimental and technical support of animal experiments. This study was supported by the Science and Technology Development Fund of Macau SAR (FDCT) [023/2015/AMJ, 0055/2019/A1 and 0010/2021/AFJ]. PC was in receipt of PhD funding from the FDCT and the Faculty of Health Sciences (FHS) University of Macau (UM). SWW, JL and QW were in receipt of the UM PhD Assistantship.
Funding Information:
We thank the UM-FHS Animal Facility at the University of Macau for experimental and technical support of animal experiments. This study was supported by the Science and Technology Development Fund of Macau SAR (FDCT) [023/2015/AMJ, 0055/2019/A1 and 0010/2021/AFJ]. PC was in receipt of PhD funding from the FDCT and the Faculty of Health Sciences (FHS) University of Macau (UM). SWW, JL and QW were in receipt of the UM PhD Assistantship.
Publisher Copyright:
© 2022, The Author(s).
