Project description: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 RHOF, a member of the Rho GTPase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. This study was aimed to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms. The results showed that compared to expression in adjacent non-cancerous tissues, RHOF was frequently upregulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with TNM 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 upregulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted 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. Therefore, 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 new therapeutic target and prognostic biomarker for HCC. We used microarrays to detail the global programme of gene expression associated with hepatocellular carcinoma metastasis and identified distinct classes of deregulated genes during this process.

Project description:Epithelial-mesenchymal transition (EMT) is a diverse and dynamic biological process which is involved in cancer progression. It is important for carcinoma cells during invasion and metastasis. EMT has been in the spotlight for cancer cells to disseminate to distant organs by gaining partial EMT phenotype. Cancer cells with partial EMT are believed to be more cancerogenic/invasive than cells that have undergone complete EMT. The proteomic changes that occur following EMT in breast epithelial cells and how these relate to changes in cellular metabolism are incompletely understood. To study metabolic reprogramming in different mesenchymal states, we analyzed proteomic changes following EMT in the breast epithelial cell model D492, with single-shot LFQ supported by SILAC proteomic approach. The D492 EMT cell model contains three isogenic cell lines: epithelial D492 cells, mesenchymal D492M cells, and partial mesenchymal, HER2 overexpressing, tumorigenic D492HER2 cells. Proteomic analysis positioned the D492 and D492M cells as basal-like while D492HER2 as claudin-low. Further comparison of the non-tumorigenic D492 and D492M cells to tumorigenic D492HER2 differentiated the metabolic EMT markers of migration from those of invasion. Among these were markers of glycan metabolism. We identified glutamine-fructose-6-phosphate transaminase [isomerizing] 2 (GFPT2) as the top dysregulated enzyme in glycan metabolism and found increased GFPT2 expression was a characteristic of claudin-low breast cancer. siRNA knockdown of GFPT2 influenced both cell growth and invasion in vitro and was accompanied by lowered flux through the hexosamine biosynthesis pathway (HBP). Knockdown of GFPT2 decreased cystathionine and sulfide:quinone oxidoreductase (SQOR) in the transsulfuration pathway which regulates H2S production and mitochondrial homeostasis. Moreover, GFPT2 expression was regulated by the level of reduced glutathione (GSH) and suppressed by the oxidative stress regulator, GSK3-β. Our results demonstrate that GFPT2 is a marker for oxidative stress. It is upregulated and controls growth and invasion in the D492 EMT model and is associated with claudin-low and poor prognosis in breast cancer.

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Cytoplasmic localization of SETDB1 induced Warburg effect via c-MYC/ LDHA axis to enhance migration and invasion in breast carcinoma

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