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A Mammalian Conserved Circular RNA CircLARP2 Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism (Part 2)

ABSTRACT: Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. Here, we identified a mammalian conserved circRNA circLARP2 that played critical roles in hepatocellular carcinoma (HCC). With clinical specimens, we found that patients with high circLARP2 levels in HCC had advanced prognostic stage and poor overall survival. CircLARP2 facilitated HCC metastasis and lipid accumulation in HCC cell lines. CircLARP2 was one of the rare ones that were identified in HCC metastasis and conserved in mammals, which enabled further studies with animal models. CircLARP2-deficient mice exhibited reduced metastasis and less lipid accumulation in an induced HCC model. We provided lines of evidence at molecular, cellular, and whole organismal levels, to support that circLARP2 functioned as a protein sponge of AUF1. CircLARP2 sequestered AUF1 from binding to LKB1 mRNA, which led to decreased LKB1 mRNA stability and lower LKB1 protein levels. LKB1 as a kinase promoted the phosphorylation of AMPK and then the phosphorylation of ACC, the rate limiting enzyme of fatty acid synthesis. Knockdown of Lkb1 with AAV8-shLkb1 in mice HCC model also proved that Lkb1 was a key element in the regulation. Through this AUF1-LKB1-AMPK-ACC pathway, circLARP2 promoted HCC metastasis and lipid accumulation.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Cancer

SUBMITTER: Jingxin Li

PROVIDER: ST002395 | MetabolomicsWorkbench | Fri Mar 10 00:00:00 GMT 2023

REPOSITORIES: MetabolomicsWorkbench

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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.

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A Mammalian Conserved Circular RNA CircLARP2 Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism (Part 2)

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