Chen Pengchen, Wang Wei, Wong Sin Wa, Li Junnan, Wu Qiushaung, Zhang Shu-Dong, Lin Yao, Kwok Hang Fai
Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China.
MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.
Cell Death Discov. 2022 Jun 25;8(1):296. doi: 10.1038/s41420-022-01084-4.
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.
胃神经内分泌癌（GNEC）是神经内分泌癌（NEC）的一种常见类型，预后较差且治疗选择有限。GNEC患者和NEC患者化疗耐药的潜在机制在很大程度上尚不清楚，因此，缺乏可改善NEC患者治疗效果的可靠生物标志物和治疗靶点。本研究的目的是确定特定靶点，并研究它们在GNEC进展和治疗耐药中的作用。在GNEC标本中鉴定出差异表达基因（DEG），并通过关注它们在化疗耐药中的作用进行进一步分析。对GNEC的DEG进行基因本体论（GO）和通路富集分析发现，突触相关功能是GNEC中最突出的受干扰细胞功能。SNAP25被确定为参与大多数富集通路的靶基因。体外和体内实验表明，SNAP25在GNEC细胞系的增殖和化疗耐药中起作用。AKT已被确定为下游靶点，SNAP25与AKT蛋白结合并促进AKT蛋白半衰期。对其他类型的NEC以及在分子水平上与NEC相似的小细胞肺癌的进一步分析，已确定RUNDC3A为调节SNAP25表达及相关表型的上游分子，这些表型可增强NEC的化疗耐药性。我们的结果表明，GNEC中SNAP25的表达由RUNDC3A介导，并通过AKT的翻译后修饰促进GNEC进展和化疗耐药。因此，我们的结果表明RUNDC3A/SNAP25/Akt轴可能是GNEC的潜在治疗靶点。
