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Golgi Protein 73 Promotes Angiogenesis in Hepatocellular Carcinoma.

ABSTRACT: Golgi protein 73 (GP73), a resident protein of the Golgi apparatus, is notably elevated in hepatocellular carcinoma (HCC). While its critical role in remodeling the tumor microenvironment (TME) is recognized, the intricate mechanisms are not fully understood. This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2 (PHD-2) in a competitive manner, thereby impeding the hydroxylation of hypoxia-induced factor-1α (HIF-1α). The effect above promotes the production and secretion of vascular endothelial growth factor A (VEGFA). Moreover, exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells (HUVECs) and competitively interact with HECTD1, an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2 (GRB2). This interaction stabilizes GRB2, thereby activating the Ras-mitogen-activated protein kinase (MAPK) signaling pathway. Consequently, escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells, fostering angiogenesis in the TME. Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC11251733 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Golgi Protein 73 Promotes Angiogenesis in Hepatocellular Carcinoma.

Liu Yiming Y Hu Xinyang X Zhou Sining S Sun Ting T Shen Feiyan F Zeng Linghui L

Research (Washington, D.C.) 20240717

Golgi protein 73 (GP73), a resident protein of the Golgi apparatus, is notably elevated in hepatocellular carcinoma (HCC). While its critical role in remodeling the tumor microenvironment (TME) is recognized, the intricate mechanisms are not fully understood. This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2 (PHD-2) in a competitive manner, thereby impeding the hydroxylation of hypoxia-induced factor-1α (HIF-1α). The effect above promotes the production and secretion ...[more]

PMID: 39022745

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Project description:BackgroundScreening of early hepatocellular carcinoma (HCC) diagnosis is the greatest challenge for hepatologists. Alpha?-fetoprotein (AFP) is the most common non-invasive biomarker used in HCC diagnosis.Objectives and AimsTo make a comparison between the new biomarker Golgi protein 73 (GP73) versus the standard biomarker AFP in the diagnosis of HCC.MethodsOur study was a case–control study, and 60 patients were included in the study. They were divided into two groups: ?1) HCC patients with either chronic HBV or HCV infection (n=30); and ?2) ?non-HCC patients with HBV or HCV infection who had either chronic hepatitis or liver cirrhosis (n=30). In addition, 30 healthy volunteers were included as a control group. Patients were subjected to liver function tests, kidney function tests, serum Golgi protein 73 and AFP levels. Imaging diagnosis of HCC was done by ?computed ?tomography (CT) or ?magnetic ?resonance ?imaging (MRI) based on American Association for the Study of Liver Diseases (AASLD) ?practice ?guidelines.ResultsStatistically significant differences between groups in terms of serum AFP (p<0.001) and GP73 (p<0.001) were found. Non-HCC patients (chronic hepatitis and liver cirrhosis) and HCC patients had significantly higher AFP and GP73 than the control group. In addition, patients with HCC had significantly higher AFP and GP73 than chronic hepatitis and cirrhotic patients. GP73 had higher diagnostic performance than AFP. At a cut-off value of ?8.4 ng/mL, GP73 yielded a sensitivity of 86.7% and specificity of 89% for the discrimination between HCC and normal populations. Similarly, at a cut-off value of ?8.45 ng/mL, GP73 yielded a sensitivity of 83.3% and specificity of 84% for the discrimination between HCC patients and non?-HCC patients. On the other hand, AFP at a cut-off value of ?2.4 ng/mL yielded a sensitivity of 75.4% and specificity of 90% for the discrimination between HCC and normal populations?; and at a cut-off value of ?20.85 ng/mL, AFP yielded a sensitivity of 72.2% and specificity of 86.2% for the discrimination between HCC and non-HCC patients.ConclusionGolgi protein 73 is a promising and accurate biomarker for early detection of HCC.

Project description:BackgroundAlpha-fetoprotein (AFP) has been extensively applied in clinical practice to detect and predict postoperative outcomes of patients with hepatocellular carcinoma (HCC). However, due to its low sensitivity and specificity, its efficacy has been questioned. Recently, novel serum biomarkers including Golgi protein 73 (GP73) and glypican-3 (GPC-3) have shown a better discriminatory ability than AFP in detecting early HCC. The results of the combined use of GP73, GPC-3 and AFP in the diagnosis of HCC remain inconclusive. This investigation aimed to evaluate the discriminatory ability of GP73, GPC-3 and AFP to jointly identify HCC using the statistical methods of meta-analysis.MethodsComprehensive database searches of, Web of Science, the Cochrane Library, Embase, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure were performed for literature dated up to 1 November, 2019. Studies relating to the diagnostic accuracy of the combination of GP73, GPC-3 and AFP in the identification of HCC were included. A random-effects model was used to pool sensitivity, specificity, the positive and negative likelihood ratios [positive likelihood ratio (PLR) and negative likelihood ratio (NLR), respectively], and the diagnostic odds ratio (DOR). We applied the Fagan nomogram to assess the clinical utility of joint detection. The overall detection accuracy was determined using summary receiver operating characteristic curve (SROC) analysis. Meta-regression analysis of heterogeneity publication bias was analyzed with Stata (version 12.0).ResultsOur meta-analysis focused on 12 studies involving 919 patients with HCC and 1,549 non-HCC patients. Sensitivity, specificity, PLR, NLR and DOR for joint detection, were 0.91 (95% CI: 0.87-0.94), 0.84 (95% CI: 0.77-0.89), 5.83 (95% CI: 4.05-8.40), 0.10 (95% CI: 0.07-0.15), 57.51 (95% CI: 35.92-92.08), respectively, when pooled, and the area under the SROC curve was 0.95.ConclusionsCurrent evidence indicates that GP73, GPC-3 and AFP exhibit much better accuracy for the diagnosis of HCC when used in combination rather than alone or in pairs.

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Golgi Protein 73 Promotes Angiogenesis in Hepatocellular Carcinoma.

Publications

Golgi Protein 73 Promotes Angiogenesis in Hepatocellular Carcinoma.

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