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

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Abstract

Golgi phosphoprotein 73 (GP73), encoded by GOLM1, is a highly expressed factor in hepatocellular carcinoma (HCC) cells and has been regarded for several years as a remarkable serum biomarker for the diagnosis of HCC. Recently, it was found that upregulation of GP73 promotes cancer metastasis, but the mechanism is complex, and it is even unclear how the gene is transactivated in HCC cells. In this study, it was discovered that c-Myc transactivated GP73 in a mildly hypoxic microenvironment and that the activation of c-Myc upregulated the expression of matrix metalloproteinase-7 (MMP-7). Moreover, it is shown that GP73 interacted with intracellular MMP-7 in the region of the cytoplasmic domain and facilitated the trafficking and secretion of MMP-7, resulting in cell metastasis. This study indicates that GP73 is transactivated by c-Myc and serves as a transporter in the trafficking of intracellular MMP-7 in HCC cells. These findings suggest that GP73 is a potential target for combating metastatic HCC.

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Is there new hope for therapeutic matrix metalloproteinase inhibition?

Roosmarijn Vandenbroucke, Claude Libert (2014)

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.

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Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis.

Long-Yun Ye, Wei-Wei Chen, Xue-Li Bai … (2016)

Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1α induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDO-expressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network.

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Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α

Qirui Wang, Zhenqiang He, Menggui Huang … (2018)

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as one of the major sources for interleukin-6 (IL-6) expression in GBM microenvironment. Furthermore, we reveal that colony-stimulating factor-1 and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor-γ-dependent transcriptional activation of hypoxia-inducible factor-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors.

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Author and article information

Contributors

Zhi Chen: +86-571-8723-6579 , chenzhi@zju.edu.cn

Linfu Zhou: +86-571-8820-8239 , 239zlf@zju.edu.cn

Journal

Journal ID (nlm-ta): Oncogenesis

Journal ID (iso-abbrev): Oncogenesis

Title: Oncogenesis

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2157-9024

Publication date (Electronic): 7 October 2019

Publication date PMC-release: 7 October 2019

Publication date Collection: October 2019

Volume: 8

Issue: 10

Electronic Location Identifier: 58

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, 310003 China

[2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Biochemistry and Molecular Biology, , Zhejiang University School of Medicine, ; Hangzhou, 310058 China

[3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of the First Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310003 China

[4 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, College of Pharmaceutical Sciences, , Zhejiang University, ; Hangzhou, 310058 China

Article

Publisher ID: 166

DOI: 10.1038/s41389-019-0166-7

PMC ID: 6779757

PubMed ID: 31591387

SO-VID: d9fb2f0a-4039-47c1-880b-34ce6ae3820a

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 March 2019

Date accepted : 18 September 2019

Funding

Funded by: The Project of the Department of Science and Technology of Zhejiang Province (2013C14011),the Project of National Essential Drug Research and Development of China (2013ZX09102051).

Funded by: the National Science and Technology Major Project of China (2012ZX10002007).

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer microenvironment,cell migration

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer microenvironment, cell migration

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

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Karger: Oncology

Most cited references 14

Is there new hope for therapeutic matrix metalloproteinase inhibition?

Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis.

Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α

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Cited by 16

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