DLL4 overexpression increases gastric cancer stem/progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation.
DLL4 overexpression increases gastric cancer stem/progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation.
复制标题
DLL4 过表达增加胃癌干/祖细胞自我更新能力，并通过 Notch-1 信号通路激活与不良临床结果相关
作者：
Miao ZF;Xu H;Xu HM;Wang ZN;Zhao TT;Song YX;Xu YY
胃癌是最常见的恶性肿瘤之一，严重威胁着人类的生活质量。胃癌干/祖细胞（GCSPC）在肿瘤形成中具有关键作用，影响自我更新和分化的特定特征，并在转移中起关键作用。Notch-1通路对GCSPC至关重要，并受DLL 4调节。在这项研究中，DLL 4和巢蛋白水平通过免疫组织化学方法在383例胃癌组织样本中进行了测量，并评估了患者的临床病理特征。在选定的胃癌细胞系中DLL 4沉默后，分析GCSPC标志物的表达和集落形成能力，并评价细胞的自我更新和分化能力。DLL 4水平和Notch-1信号通路效应物量之间的关系通过蛋白质印迹和免疫荧光进行评估。最后，在体内用不同浓度的DLL 4和多种细胞密度评价胃癌细胞的成瘤能力。我们的研究结果表明，DLL 4表达与TNM分期和癌症转移相关，DLL 4的高表达量导致预后不良。DLL 4沉默抑制GCSPC的自我更新能力，并增加其多分化能力，导致GCSPC比率降低。DLL 4敲除还阻断了Notch-1通路，削弱了侵袭能力和对5-FU化疗的耐药性。在体内，DLL 4沉默抑制GCSPC的肿瘤形成能力。总之，DLL 4影响GCSPC的干性，改变其病理行为。DLL 4沉默通过阻碍Notch-1信号通路激活在体外和体内抑制GCSPC转移潜力，表明DLL 4可能是一个新的潜在治疗靶点。
Gastric cancer is one of the most common malignant diseases, and poses a serious threat to the quality of human life. Gastric cancer stem/progenitor cells (GCSPCs) have critical effects on tumor formation, affecting specific features of self‐renewal and differentiation and playing a critical role in metastasis. The Notch‐1 pathway is crucially important to GCSPCs and is regulated by DLL4. In this study, DLL4 and Nestin levels were measured in 383 gastric cancer tissue samples by immunohistochemistry, and the clinico‐pathological features of patients assessed. After DLL4 silencing in selected gastric cancer cell lines, the expression of GCSPC markers and colony formation ability were analyzed and the self‐renewal and differentiation capacities of the cells were evaluated. The relationship between DLL4 levels and Notch‐1 signaling pathway effector amounts was assessed via Western blotting and immunofluorescence. Finally, the tumor formation ability of the gastric cancer cells was evaluated with different levels of DLL4 and multiple cell densities in vivo. Our results indicate that DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self‐renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch‐1 pathway, weakening invasion ability and resistance to 5‐FU chemotherapy. In vivo, DLL4 silencing inhibited the tumor formation ability of GCSPCs. In conclusion, DLL4 affects GCSPC stemness, altering their pathological behavior. DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch‐1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target.