PDF(Pubmed)
Abstract：
To address the increased energy demand, tumor cells undergo metabolic reprogramming, including oxidative phosphorylation (OXPHOS) and aerobic glycolysis. This study investigates the role of Kruppel-like factor 4 (KLF4), a transcription factor, as a tumor suppressor in hepatocellular carcinoma (HCC) by regulating ATP synthesis. Immunohistochemistry was performed to assess KLF4 expression in HCC tissues. Functional assays, such as CCK-8, EdU, and colony formation, as well as in vivo assays, including subcutaneous tumor formation and liver orthotopic xenograft mouse models, were conducted to determine the impact of KLF4 on HCC proliferation. Luciferase reporter assay and chromatin immunoprecipitation assay were utilized to evaluate the interaction between KLF4, miR-206, and RICTOR. The findings reveal low KLF4 expression in HCC, which is associated with poor prognosis. Both in vitro and in vivo functional assays demonstrate that KLF4 inhibits HCC cell proliferation. Mechanistically, it was demonstrated that KLF4 reduces ATP synthesis in HCC by suppressing the expression of RICTOR, a core component of mTORC2. This suppression promotes glutaminolysis to replenish the TCA cycle and increase ATP levels, facilitated by the promotion of miR-206 transcription. In conclusion, this study enhances the understanding of KLF4\'s role in HCC ATP synthesis and suggests that targeting the KLF4/miR-206/RICTOR axis could be a promising therapeutic approach for anti-HCC therapeutics.
摘要：
为了解决日益增长的能源需求，肿瘤细胞经历代谢重编程，包括氧化磷酸化（OXPHOS）和有氧糖酵解。本研究调查了Kruppel样因子4(KLF4)的作用，转录因子，通过调节ATP合成在肝细胞癌（HCC）中作为肿瘤抑制因子。进行免疫组织化学以评估HCC组织中的KLF4表达。功能测定，如CCK-8，EdU，和殖民地的形成，以及体内测定，包括皮下肿瘤形成和肝脏原位异种移植小鼠模型，进行以确定KLF4对HCC增殖的影响。荧光素酶报告基因测定和染色质免疫沉淀测定用于评估KLF4、miR-206和RICTOR之间的相互作用。研究结果表明，肝癌中KLF4表达较低，这与不良预后有关。体外和体内功能测定均表明KLF4抑制HCC细胞增殖。机械上,研究表明，KLF4通过抑制RICTOR的表达来减少HCC中的ATP合成，mTORC2的核心组件。这种抑制促进谷氨酰胺分解以补充TCA循环并增加ATP水平，促进miR-206转录。总之,这项研究增强了对KLF4在HCCATP合成中作用的理解,并提示靶向KLF4/miR-206/RICTOR轴可能是一种有前景的抗HCC治疗方法.
