NUAK1 activates STAT5/GLI1/SOX2 signaling to enhance cancer cell expansion and drives chemoresistance in gastric cancer
Longlong Cao,
Guangtan Lin,
Denghui Fan,
Kai Weng,
Yujing Chen,
Jiabin Wang,
Ping Li,
Chaohui Zheng,
Changming Huang,
Jianwei Xie
Affiliations
Longlong Cao
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China; Corresponding author
Guangtan Lin
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Denghui Fan
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Kai Weng
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Yujing Chen
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Jiabin Wang
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Ping Li
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Chaohui Zheng
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China
Changming Huang
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China; Corresponding author
Jianwei Xie
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, China; Corresponding author
Summary: The gene encoding the NUAK family kinase 1 (NUAK1) is frequently amplified and its expression is upregulated, activating oncogenic signaling in various cancers. However, little is known about its role in gastric cancer (GC). We investigate the mechanistic links among NUAK1, Hedgehog signaling, and tumorigenesis in GC. NUAK1 overexpression is validated in local and public GC cohorts. Patient-derived xenograft and transgenic mouse models demonstrate that NUAK1 depletion or inhibition dramatically ameliorates gastric tumorigenesis. NUAK1 upregulates GLI1 expression by activating STAT5-mediated transcription and stabilizing GLI1 protein. NUAK1 depletion or inhibition impairs cancer cell expansion, tumor formation, and chemotherapy resistance in in vitro and in vivo models. Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.
