Xu Yu-Jie, Huo Ya-Chang, Zhao Qi-Tai, Liu Jin-Yan, Tian Yi-Jun, Yang Lei-Lei, Zhang Yi
Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, Henan Province, China.
World J Gastrointest Oncol. 2024 Apr 15;16(4):1421-1436. doi: 10.4251/wjgo.v16.i4.1421.
Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood.
To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC.
We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.
We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. , NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. , NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis.
Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.
代谢重编程在癌症进展和临床结局中起关键作用；然而，结直肠癌（CRC）中代谢重编程的模式和主要调节因子尚未完全明确。
探讨烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）在促进CRC进展中的作用。
我们使用基因本体论和京都基因与基因组百科全书评估失调和生存相关代谢基因的表达和功能。基于失调的代谢基因，采用共识聚类对CRC进行聚类。基于生存相关代谢基因构建预测模型。采用成球、迁移、侵袭、增殖、凋亡和克隆形成实验评估NOX4在CRC中的生物学功能。利用mRNA测序探索NOX4过表达肿瘤细胞中基因表达的变化。采用皮下和肺转移小鼠肿瘤模型探索NOX4对肿瘤生长的影响。
我们全面分析了CRC中的3341个代谢基因，并基于失调的代谢基因鉴定出三个聚类。在这些基因中，NOX4在肿瘤组织中高表达，且与较差的生存率相关。此外，NOX4过表达诱导CRC细胞的克隆形成、迁移、侵袭和干性。此外，RNA测序分析显示，NOX4过表达激活了丝裂原活化蛋白激酶-MEK1/2-ERK1/2信号通路。MEK1/2抑制剂曲美替尼消除了NOX4介导的肿瘤进展。此外，NOX4过表达促进皮下肿瘤生长和肺转移，而曲美替尼治疗可逆转转移。
我们的研究全面分析了代谢基因表达，突出了NOX4在促进CRC转移中的重要性，表明曲美替尼可能是针对NOX4的CRC临床治疗的潜在治疗药物。
