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.
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.
Cell Rep. 2024 Jul 23;43(7):114446. doi: 10.1016/j.celrep.2024.114446. Epub 2024 Jul 10.
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.
NUAK 家族激酶 1（NUAK1）基因编码频繁扩增，其表达上调，在多种癌症中激活致癌信号。然而，其在胃癌（GC）中的作用知之甚少。我们研究了 GC 中 NUAK1、Hedgehog 信号和肿瘤发生之间的机制联系。NUAK1 过表达在局部和公共 GC 队列中得到验证。患者来源的异种移植和转基因小鼠模型表明，NUAK1 耗竭或抑制可显著改善胃肿瘤发生。NUAK1 通过激活 STAT5 介导的转录和稳定 GLI1 蛋白来上调 GLI1 表达。NUAK1 耗竭或抑制可损害体外和体内模型中的癌细胞增殖、肿瘤形成和化疗耐药性。临床病理分析证实，上调的 NUAK1 表达与人类 GC 的不良预后和化疗耐药性相关。我们的研究结果表明，NUAK1/STAT5/GLI1 信号轴促进癌细胞增殖和肿瘤发生，并表明 NUAK1 是 GC 中一种有吸引力的治疗靶点和预后因素。
