The gene encoding NUAK family kinase 1(NUAK1) is frequently amplified and its expression is upregulated, activating oncogenic signals in various cancers. However, little is known about its role in gastric cancer (GC).
On July 23, 2024, Xie Jianwei, Huang Changming and Cao Longlong (first author) of Fujian Medical University jointly communicated inCell Reports Published online entitled“NUAK1 activates STAT5/GLI1/SOX2 signaling to enhance cancer cell expansion and drives chemoresistance in gastric cancer”The research paper,This article investigates the mechanistic link between NUAK1, Hedgehog signaling, and tumorigenesis in GC.
NUAK1 overexpression was validated in local and public GC cohorts.Patient-derived xenograft and transgenic mouse models have shown that NUAK1 depletion or inhibition significantly 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 confirmed that upregulation of NUAK1 expression was associated with poor prognosis and chemoresistance in human GC.The authors' findings show that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis, and suggest that NUAK1 is an attractive therapeutic target and prognostic factor in GC.
More than one million cases of gastric cancer (GC) are diagnosed each year.GC is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Helicobacter pylori is a class I carcinogen and a major risk factor for GC.Chronic gastric mucosaHelicobacter pylori infectionIt can lead to atrophic gastritis, intestinal metaplasia and malignant tumor formation. In addition, it has been implicated in the genetic and epigenetic mechanisms of induction of oncogenes and suppression of tumor suppressor genes.Due to tumor heterogeneity and drug resistance, GC patients may not benefit from current treatment strategies. Therefore, there is an urgent need for precise therapeutic targets for GC therapy.
Cancer stem cells (CSCs) are self-renewing, tumorigenic, and confer chemoresistance to certain cancers. CSCs are associated with tumor progression, metastasis, and drug resistance.Abnormalities of Notch, Hedgehog and Wnt signaling pathways are associated with tumorigenicity of CSC. Hedgehog signaling pathway is an important pathway in embryonic development and tissue pattern formation. GLI family zinc finger 1(GLI1) is a key transcriptional activator that translocates into the nucleus to control the expression of CCND1, BCL2, SNAI1 and SOX2. Constitutive Hedgehog signaling pathway activation can lead to the development and progression of various malignancies, including GC.Therefore, the Hedgehog pathway may be an important therapeutic target for blocking CSC function.
NUAK family kinase 1(NUAK1), a member of the AMP-activated protein kinase (AMPK) catalytic subunit family, has been implicated in tumor development and progression.NUAK1-targeted therapy may be a therapeutic strategy to block CSCs in colorectal and hepatocellular carcinoma. In addition, clinical studies strongly suggest that NUAK1 is a marker for predicting the prognosis of patients with GC, but its mechanism and therapeutic value have not been elucidated.In the present study, the authors empirically demonstrated the oncogenic function of NUAK1 in GC and revealed the mechanism by which NUAK1 enhances gastric cancer cell expansion and chemoresistance by activating STAT5/GLI1/SOX2 signaling.
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