Chen Ming, Xu Kangjing, Li Bowen, Wang Nuofan, Zhang Qiang, Chen Liang, Zhang Diancai, Yang Li, Xu Zekuan, Xu Hao
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.
Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
Onco Targets Ther. 2020 Jun 11;13:4943-4956. doi: 10.2147/OTT.S249063. eCollection 2020.
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the digestive system. Circulating tumor cells (CTCs) have been proven to be critical in the recurrence and metastasis of diseases; however, the characteristics of CTCs of GIST are still unclear.
We sorted out and verified the validity of CTCs from peripheral blood of gastrointestinal stromal tumor (GIST) patients with or without heterochronous liver metastasis using flow cytometry (FCM). Differential genes were analyzed between the GIST patients with and without liver metastasis using next-generation sequencing (NGS).
The preliminary study on the characteristics of CTCs revealed that CTCs of GIST patients with heterochronous liver metastasis had stronger stem cell-like properties (SC-like properties) than CTCs of those without liver metastasis. Furthermore, NGS followed with a series of assays revealed that HMGA1 played a critical role in regulating the SC-like properties of CTCs. Mechanistically, HMGA1 could activate Wnt/β-catenin pathway in vitro and vivo. Moreover, we found that the expression level of HMGA1 in CTCs was an independent risk factor probably influencing the prognosis of GIST patients.
Our findings indicate the significant role of HMGA1 in SC-like properties, IM resistance and eventually hepatic metastasis formation of CTCs. Targeting HMGA1 in CTCs may be a therapeutic strategy for GIST patients with hepatic metastasis.
胃肠道间质瘤（GIST）是消化系统最常见的肉瘤。循环肿瘤细胞（CTC）已被证明在疾病的复发和转移中起关键作用；然而，GIST的CTC特征仍不清楚。
我们使用流式细胞术（FCM）从有或无异时性肝转移的胃肠道间质瘤（GIST）患者外周血中筛选并验证CTC的有效性。使用下一代测序（NGS）分析有肝转移和无肝转移的GIST患者之间的差异基因。
对CTC特征的初步研究表明，有异时性肝转移的GIST患者的CTC比无肝转移患者的CTC具有更强的干细胞样特性（SC样特性）。此外，NGS及一系列检测表明，HMGA1在调节CTC的SC样特性中起关键作用。机制上，HMGA1在体外和体内均可激活Wnt/β-连环蛋白通路。此外，我们发现CTC中HMGA1的表达水平可能是影响GIST患者预后的独立危险因素。
我们的研究结果表明HMGA1在CTC的SC样特性、伊马替尼耐药及最终肝转移形成中起重要作用。靶向CTC中的HMGA1可能是肝转移GIST患者的一种治疗策略。
