Abstract

The overall survival of patients with the advanced and recurrent gastric cancer (GC) remains unfavorable. In particular, this is due to cancer spreading and resistance to chemotherapy associated with the epithelial-mesenchymal transition (EMT) of tumor cells. EMT can be identified by the transcriptome profiling of GC for EMT markers. Indeed, analysis of the TCGA and GTEx databases (n = 408) and a cohort of GC patients (n = 43) revealed that expression of the CDH2 gene was significantly decreased in the tumors vs. non-tumor tissues and correlated with the overall survival of GC patients. Expression of the EMT-promoting transcription factors SNAIL and ZEB1 was significantly increased in GC. These data suggest that targeting the EMT might be an attractive therapeutic approach for patients with GC. Previously, we demonstrated a potent anti-cancer activity of the olive leaf extract (OLE). However, its effect on the EMT regulation in GC remained unknown. Here, we showed that OLE efficiently potentiated the inhibitory effect of the chemotherapeutic agents 5-fluorouracil (5-FU) and cisplatin (Cis) on the EMT and their pro-apoptotic activity, as was demonstrated by changes in the expression of the EMT markers (E- and N-cadherins, vimentin, claudin-1) in GC cells treated with the aforementioned chemotherapeutic agents in the presence of OLE. Thus, culturing GC cells with 5-FU + OLE or Cis + OLE attenuated the invasive properties of cancer cells. Importantly, upregulation of expression of the apoptotic markers (PARP cleaved form) and increase in the number of cells undergoing apoptosis (annexin V-positive) were observed for GC cells treated with a combination of OLE and 5-FU or Cis. Collectively, our data illustrate that OLE efficiently interferes with the EMT in GC cells and potentiates the pro-apoptotic activity of certain chemotherapeutic agents used for GC therapy.

中文翻译：

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欧洲橄榄 (Olea europaea L.) 叶提取物在转录后抑制上皮-间质转化并使胃癌细胞对化疗敏感

摘要

晚期和复发性胃癌（GC）患者的总生存率仍然不利。特别是，这是由于癌症扩散和与肿瘤细胞上皮间质转化（EMT）相关的化疗耐药所致。 EMT 可以通过 GC 的转录组分析来鉴定 EMT 标记。事实上，对 TCGA 和 GTEx 数据库 ( n  = 408) 以及一组 GC 患者 ( n  = 43) 的分析表明，与非肿瘤组织相比，肿瘤组织中CDH2基因的表达显着降低，并且与总生存期相关GC 患者。 GC 中促进 EMT 的转录因子 SNAIL 和 ZEB1 的表达显着增加。这些数据表明，针对 GC 患者，针对 EMT 可能是一种有吸引力的治疗方法。此前，我们证明了橄榄叶提取物 (OLE) 具有强大的抗癌活性。然而，其对GC中EMT调节的影响仍不清楚。在这里，我们发现 OLE 有效增强了化疗药物 5-氟尿嘧啶 (5-FU) 和顺铂 (Cis) 对 EMT 的抑制作用及其促凋亡活性，这一点通过 EMT 标记物表达的变化得到了证明。 (E-和N-钙粘蛋白、波形蛋白、claudin-1)在 OLE 存在下用上述化疗剂处理的 GC 细胞中。因此，用 5-FU + OLE 或 Cis + OLE 培养 GC 细胞减弱了癌细胞的侵袭特性。重要的是，对于用 OLE 和 5-FU 或 Cis 组合处理的 GC 细胞，观察到凋亡标记物（PARP 裂解形式）表达上调和经历凋亡的细胞数量（膜联蛋白 V 阳性）增加。总的来说，我们的数据表明，OLE 有效干扰 GC 细胞的 EMT，并增强用于 GC 治疗的某些化疗药物的促凋亡活性。