Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D
Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D
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Ras 同源家族成员 F，Filopodia Associated 通过 RAB3D 改变癌细胞的代谢状态，促进肝细胞癌转移
DOI：
10.1002/hep.31641
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发表时间：
2021-06-01
期刊：
影响因子：
13.5
通讯作者：
Xia, Jianling
中科院分区：
文献类型：
--
作者：
Li, Shi;Liu, Yu;Xia, Jianling
背景和目的肿瘤细胞抵抗代谢应激的机制尚不清楚，但已知许多癌基因调控这一过程。因此，代谢应激与肿瘤转移密切相关。本研究利用基因芯片技术发现Ras同源基因家族成员F，filopodia associated（RHOF）是Rho鸟苷三磷酸酶家族的一员，是一个与肝细胞癌（HCC）转移显著相关的癌基因，但在肿瘤中的报道很少。我们的目的是确定的临床病理意义和作用，RHOF在肝癌进展和调查的相关mechanism.Approach和结果-结果表明，在邻近的非癌组织中的表达相比，RHOF经常上调肝癌肿瘤样本和升高的条件下，葡萄糖剥夺。RHOF表达与HCC的肿瘤淋巴结转移分期、T分级、转移状态、复发和生存相关。RHOF还影响细胞形态，促进HCC细胞系的迁移、侵袭和上皮-间质转化（EMT）。其机制分析表明，RHOF通过上调肝癌细胞中几种糖酵解酶的表达和功能，促进了瓦尔堡效应。这种代谢转移增强了HCC细胞的迁移和侵袭。具体而言，RHOF通过直接与AMPK相互作用并增加AMPK的磷酸化而发挥促肿瘤作用。结论RHOF通过调节瓦尔堡效应，帮助肿瘤细胞抵抗代谢应激，在促进肝癌细胞迁移、侵袭和EMT中发挥重要作用，在重塑转移微环境、调节肿瘤转移中发挥重要作用。RHOF显示出作为HCC的治疗靶点和预后生物标志物的潜力。
Background and Aims The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that Ras homolog family member F, filopodia associated (RHOF), a member of the Rho guanosine triphosphatase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. Our aim was to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms.Approach and Results The results showed that compared to expression in adjacent noncancerous tissues, RHOF was frequently up-regulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with tumor-node-metastasis stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by up-regulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted a tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells.Conclusions RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a therapeutic target and prognostic biomarker for HCC.