Abstract：
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.
摘要：
编码NUAK家族激酶1（NUAK1）的基因经常被扩增，其表达上调，在各种癌症中激活致癌信号。然而,对其在胃癌（GC）中的作用知之甚少。我们调查了NUAK1、刺猬信号、和GC的肿瘤发生。NUAK1过表达在本地和公共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证明NUAK1消耗或抑制显著改善胃肿瘤发生。NUAK1通过激活STAT5介导的转录和稳定GLI1蛋白上调GLI1表达。NUAK1消耗或抑制损害癌细胞扩增，肿瘤形成，和体外和体内模型中的化疗抗性。临床病理分析证实，NUAK1表达上调与人GC预后不良和化疗耐药相关。我们的发现表明信号轴NUAK1/STAT5/GLI1促进癌细胞扩增和肿瘤发生，并表明NUAK1是GC中一个有吸引力的治疗靶标和预后因素。
