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Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion.

ABSTRACT: Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase-2 (MMP-2) in HCC-related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP-2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP73 induces the accumulation of intracellular MMP-2, which inhibits the phosphorylation of Src at Y416 and triggers the inhibition of SAPK/JNK and p53-p21 signalling pathways through a negative feedback loop. Finally, the transactivation of MMP2 was inhibited by the reduction in E2F1. This study reveals that GP73 plays functional roles in the trafficking and equilibrium of epithelial-mesenchymal transition (EMT)-related secretory proteins and that GP73 serves as a new potential target for combating the metastasis of HCC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6433683 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion.

Liu Yiming Y Zhang Xiaodi X Zhou Sining S Shi Jieyao J Xu Yun Y He Jia J Lin Feng F Wei Anbang A Zhou Linfu L Chen Zhi Z

Journal of cellular and molecular medicine 20190124 4

Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase-2 (MMP-2) in HCC-related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP-2 trafficking and sec ...[more]

PMID: 30677226

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Project description:BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC.MethodsFirstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway.ResultsData showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P < 0.05). Correlation analyses showed that GOLPH3 expression was positively correlated with serum alpha-fetoprotein level (AFP, P = 0.006). Knockdown GOLPH3 expression inhibited proliferation and promoted apoptosis in HCC cell lines. What's more, knockdown GOLPH3 expression led to tumor growth restriction in xenograft tumor model. The expression of phosphorylated mTOR, AKT and S6 K1 were significantly higher in HCC tumor tissue and cell lines compared with those in normal liver tissues (p < 0.05). While the phosphorylated mTOR, AKT and S6 K1 were much lower when diminished GOLPH3 expression in HCC cell lines both in vitro and in vivo.ConclusionThe current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway. GOLPH3 is a promising diagnose biomarker and therapeutic target for HCC. Our study may provide a scientific basis for developing effective approaches to treat the HCC patients with GOLPH3 overexpression.

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.

Dataset Information

Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion.

Publications

Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion.

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