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

Abstract

Golgi phosphoprotein 73 ( GP 73) 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 GP 73 may promote the carcinogenesis and metastasis of HCC ; however, the mechanisms remain poorly understood. In this study, GP 73 correlates positively with matrix metalloproteinase‐2 ( MMP ‐2) in HCC ‐related cells and tissues. Further studies indicate that the knockdown of GP 73 blocks MMP ‐2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP 73 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 MMP 2 was inhibited by the reduction in E2F1. This study reveals that GP 73 plays functional roles in the trafficking and equilibrium of epithelial‐mesenchymal transition ( EMT )‐related secretory proteins and that GP 73 serves as a new potential target for combating the metastasis of HCC .

Stimulation of cell invasion by the Golgi Ion Channel GAAP/TMBIM4 via an H2O2-Dependent Mechanism

“…Emerging evidence suggests that the Golgi apparatus (GA) can directly or indirectly affect intracellular Ca 2+ fluxes, ROS, metabolism, intra-organelle pH, protein and membrane trafficking and thereby contribute to cell migration/invasion [[21], [22], [23], [24], [25]]. Although these roles have been ascribed to the GA, the intricate molecular mechanisms involved in the control of such processes are still mostly unidentified.…”

Evaluation of Golgi Protein-73 as a Tumor Marker in Patients with Hepatocellular Carcinoma

“…GP73 is a biomarker in advanced liver disease. GP73 levels are associated with various liver diseases such as hepatic fibrosis, liver cirrhosis [10], HCC [11] and HBV mediated acute on top of chronic liver failure [12 & 13] and tumor metastasis prediction [14]. This study aimed to assess the value of serum GP73 in diagnosis of HCC patients.…”

c-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment

“…Inhibition of GP73 blocks the trafficking of intracellular MMP-7 and leads to repression of cancer cell invasion. Furthermore, in our recent study, it has been proved that GP73 is involved in the trafficking of intracellular MMP-2, a factor playing comparable functional roles to MMP-7 19 . Both of the two factors interact with GP73 in the region of cytoplasmic domain, therefore MMPs might act as potential substrates for GP73-mediated protein trafficking and facilitate HCC metastasis.…”

“…As previously reported, GP73 is highly expressed in most types of cancers, especially in HCC, and it has been adopted clinically as a cancer biomarker for decades 15,16 . In most recent studies, it was discovered that high expression of GP73 facilitates cancer metastasis by promoting epithelial-mesenchymal transition (EMT), and evidence has implicated that GP73 is not only a serum biomarker but also an important player in carcinogenesis and metastasis 17–19 . Viral infection is reportedly to activate the expression of GP73 in HCC cells; however, it has also been indicated that GP73 is upregulated in cancer cells without viral infection, such as non-viral-related HCC, bladder cancer and prostate cancer 20–22 .…”