化疗仍然是胃癌(GC)的主要治疗策略。然而,大多数患者最终获得多药耐药(MDR)。EGFR信号通路的过度激活通过促进癌细胞增殖和抑制凋亡而促进MDR。我们先前将分泌蛋白CGA鉴定为EGFR的新型配体,并揭示了CGA/EGFR/GATA2正反馈电路,可在GC中赋予MDR。在这里,我们概述了一种靶向CGA和GATA2的基于microRNA的MDR逆转治疗方法.我们观察到GC样品中CGA和GATA2的表达增加以及EGFR的活化增加。生物信息学分析显示miR-107可同时靶向CGA和GATA2,miR-107的低表达与GC患者预后不良相关。miR-107与CGA或GATA2之间的直接相互作用通过荧光素酶报告基因测定和蛋白质印迹分析进行验证。miR-107在MDRGC细胞中的过表达增加了它们对化疗药物的敏感性,包括氟尿嘧啶,阿霉素和长春新碱,在体外。值得注意的是,瘤内注射miR-107前药增强MDR异种移植对体内化疗的敏感性.分子上,用miR-107靶向CGA和GATA2抑制EGFR下游信号,如ERK和AKT的磷酸化降低所证明的。这些结果表明,miR-107可能有助于开发一种有前途的治疗方法来治疗GC中的MDR。
Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/
GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and
GATA2. We observed increased expression of CGA and
GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or
GATA2 were validated by luciferase reporter assays and western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and
GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.