Li Ting, Wang Jin, Liu Pengfei, Chi Jiadong, Yan Han, Lei Lei, Li Zexing, Yang Bing, Wang Xi
Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
Department of Lymphoma, Sino-Us Center of Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Oncotarget. 2017 Jul 18;8(29):47269-47283. doi: 10.18632/oncotarget.17617.
Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.
恶性横纹肌样瘤（MRTs）是一种罕见的、致命的儿科肿瘤，主要发生于肾脏、脑和软组织。MRTs是由肿瘤抑制因子SNF5/INI1/SMARCB1/BAF47缺失驱动的。使用目前可用的治疗方法，MRT的预后很差，因此需要确定新的治疗靶点，以扩大对化疗耐药患者的治疗选择。生长激素胰岛素样生长因子2（IGF2）信号通路是克服许多癌症耐药性的一个有前景的靶点。在这里，我们评估了IGF2轴在MRT细胞增殖中的作用。我们发现，包括饥饿处理和化疗暴露在内的微环境应激，会导致SNF5缺陷的MRT细胞系中IGF2表达升高。自分泌的IGF2反过来会激活胰岛素样生长因子1受体（IGF1R）、胰岛素受体（INSR），随后激活PI3K/AKT通路和RAS/ERK通路，以促进癌细胞增殖和存活。我们进一步证明，用IGF2中和抗体、IGF1R抑制剂NVP-AEW541或AKT抑制剂MK-2206 2HCl处理来阻断IGF2信号，可在体外阻止MRT细胞生长。综上所述，我们对该轴的表征确定了应激微环境中MRT细胞生长的一种新机制。我们的结果还证明了在未来研究中测试针对该轴的治疗效果的必要性。
