HMGA1 Regulates the Stem Cell-Like Properties of Circulating Tumor Cells from GIST Patients via Wnt/β-Catenin Pathway

Abstract

Ming Chen,1,2,* Kangjing Xu,1,2,* Bowen Li,1,2,* Nuofan Wang,1,2 Qiang Zhang,3 Liang Chen,4 Diancai Zhang,1,2 Li Yang,1,2 Zekuan Xu,1,2,* Hao Xu1,2,* 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China; 2Jiangsu 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; 3Department of Gastrointestinal Surgery, The Second People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, People’s Republic of China; 4Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, People’s Republic of China*These authors contributed equally to this work.Correspondence: Hao Xu; Zekuan XuDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province 210029, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]; [email protected]: 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.Methods: 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).Results: 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.Conclusion: 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.Keywords: circulating tumor cells, gastrointestinal stromal tumor, stem cell-like properties, heterochronous liver metastasis, HMGA1, Wnt/β-catenin

Keywords

• circulating tumor cells
• gastrointestinal stromal tumor
• stem cell-like properties
• heterochronous liver metastasis
• hmga1
• wnt/β-catenin