Myers Amy L, Lin Lin, Nancarrow Derek J, Wang Zhuwen, Ferrer-Torres Daysha, Thomas Dafydd G, Orringer Mark B, Lin Jules, Reddy Rishindra M, Beer David G, Chang Andrew C
Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Oncotarget. 2015 Sep 22;6(28):25897-916. doi: 10.18632/oncotarget.4532.
Esophageal adenocarcinoma (EAC) patients commonly present with advanced stage disease and demonstrate resistance to therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for improvement of clinical outcomes. IGFBP2 is a member of the IGFBP family of proteins that has been reported to modulate both IGF and integrin signaling and is a mediator of cell growth, invasion and resistance in other tumor types. In this study, high IGFBP2 expression was observed in a subset of primary EACs and was found to be significantly higher in patients with shorter disease-free intervals as well as in treatment-resistant EACs as compared to chemonaive EACs. Modulation of IGFBP2 expression in EAC cell lines promoted cell proliferation, migration and invasion, implicating a role in the metastatic potential of these cells. Additionally, knockdown of IGFBP2 sensitized EAC cells to cisplatin in a serum-dependent manner. Further in vitro exploration into this chemosensitization implicated both the AKT and ERK pathways. Silencing of IGFBP2 enhanced IGF1-induced immediate activation of AKT and reduced cisplatin-induced ERK activation. Addition of MEK1/2 (selumetinib or trametinib) or AKT (AKT Inhibitor VIII) inhibitors enhanced siIGFBP2-induced sensitization of EAC cells to cisplatin. These results suggest that targeted inhibition of IGFBP2 alone or together with either the MAPK or PI3K/AKT signaling pathway in IGFBP2-overexpressing EAC tumors may be an effective approach for sensitizing resistant EACs to standard neoadjuvant chemotherapy.
食管腺癌（EAC）患者通常表现为疾病晚期，且对治疗耐药，缓解率低于40%。了解耐药的分子机制对于改善临床结局至关重要。胰岛素样生长因子结合蛋白2（IGFBP2）是胰岛素样生长因子结合蛋白家族的成员，据报道可调节胰岛素样生长因子（IGF）和整合素信号传导，并且是其他肿瘤类型中细胞生长、侵袭和耐药的介质。在本研究中，在一部分原发性EAC中观察到高IGFBP2表达，并且发现与未经化疗的EAC相比，无病间期较短的患者以及耐药EAC中的IGFBP2表达明显更高。EAC细胞系中IGFBP2表达的调节促进了细胞增殖、迁移和侵袭，提示其在这些细胞的转移潜能中发挥作用。此外，敲低IGFBP2以血清依赖的方式使EAC细胞对顺铂敏感。对这种化学增敏作用的进一步体外研究涉及AKT和ERK途径。IGFBP2的沉默增强了IGF1诱导的AKT立即激活，并降低了顺铂诱导的ERK激活。添加MEK1/2（司美替尼或曲美替尼）或AKT（AKT抑制剂VIII）抑制剂增强了siIGFBP2诱导的EAC细胞对顺铂的敏感性。这些结果表明，在IGFBP2过表达的EAC肿瘤中单独靶向抑制IGFBP2或与MAPK或PI3K/AKT信号通路一起靶向抑制，可能是使耐药EAC对标准新辅助化疗敏感的有效方法。
