Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Ohio State University, College of Pharmacy, Columbus, OH, USA.
Oncogene. 2014 Jan 9;33(2):173-80. doi: 10.1038/onc.2012.579. Epub 2013 Jan 14.
Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.
恶性外周神经鞘瘤(MPNST)可散发性发生,也可发生于神经纤维瘤病 1 型背景下。表皮生长因子受体(EGFR)过表达与 MPNST 的形成有关,但确切作用及其相关信号通路仍不清楚。我们发现 EGFR 过表达可促进小鼠神经纤维瘤向侵袭性 MPNST(GEM-PNST)转化。免疫组化显示,人类 MPNST 和小鼠 GEM-PNST 中均存在磷酸化 STAT3(Tyr705)。特异性 JAK2/STAT3 抑制剂 FLLL32 可延迟 MPNST 异种移植裸鼠模型中的 MPNST 形成。shRNA 敲低 STAT3 可防止体内 MPNST 的形成。最后,降低 EGFR 活性可显著减少体内的 pSTAT3。因此,EGFR-STAT3 通路对于 MPNST 的转化和建立 MPNST 异种移植物的生长是必需的,但对于肿瘤的维持不是必需的。FLLL32 药理学抑制剂在延迟 MPNST 生长方面的疗效表明,针对 JAK/STAT3 的联合治疗可能是一种有用的治疗方法。