Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D

Abstract

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.

Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis

“…Baik et al found that ZBP1 mediated necroptosis of breast cancer induced by GS [ 21 ]. RHOF also acts as a protector of hepatocellular carcinoma and promotes metabolic reprogramming under glucose deprivation conditions [ 22 ]. However, cancer cells tend to rob nutrition from the human body to adapt to their highly proliferative states.…”

Identification and Validation of Four Novel Biomarkers Involved in Docetaxel Resistant Prostate Cancer

“…RHOF is a member of the Rho GTPase family, an oncogene that plays an important role in tumor cell invasion and migration. High expression of RHOF is closely associated with tumor progression and poor survival of patients [48,49]. Yang et al found that targeting RHOF could improve the sensitivity of pancreatic cells to gemcitabine treatment through the EMT pathway [49].…”

Current perspectives on exosomes in the diagnosis and treatment of hepatocellular carcinoma (review)

“…Recent studies have demonstrated the role of exosomes in EMT progression in different types of cancer, including HCC. 69 Chen et al 70 revealed that HCC-derived exosomes promoted HCC progression and recurrence by activating EMT through the MAPK/ERK signaling pathway. Rab27a, a small GTPase, regulates exosome secretion by mediating multivesicular endosome docking at the plasma membrane.…”