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Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma.

ABSTRACT: Heparanase (HPSE) is a kind of multifunctional extracellular hydrolase, and related to metastasis of hepatocellular carcinoma (HCC). Endothelial necroptosis promotes the metastasis of cancer cells. It is not clear whether HPSE could mediate necroptosis of microvascular endothelial cells (MVECs) to promote HCC metastasis. Here we found HPSE expression was up-regulated in HCC tissues and its over-expression was correlated with multiple tumor foci, microvascular invasion, and poor outcome of HCC patients. Non-contact co-culture experiments showed high-expressed HPSE in HCC cells mediated the necroptosis of human umbilical vein endothelial cells (HUVECs) and elevated the expression levels of syndecan-1 (SDC-1) and tumor necrosis factor-? (TNF-?) in vitro. As a result of necroptosis, trans-endothelial migration (TEM) of HCC cells was increased. Conversely, both HPSE and SDC-1 knockdowns reversed necroptosis and decreased TNF-? expression level, while HPSE over-expression increased SDC-1 and TNF-? expression and aggravated necroptosis. Animal experiments found that the nude mice, intraperitoneally injected with HPSE high expressing HCC cells, had obvious necroptosis of MVECs and high intrahepatic metastasis rate, which could be relieved by inhibitor of necroptosis. Morever, HPSE elevated the expression levels of p38 mitogen-activated protein kinase (p38 MAPK) rather than nuclear factor kappa B in vitro. Our data suggest that HPSE induces necroptosis of MVECs to promote the metastasis of HCC by activating HPSE/SDC-1/TNF-? axis and p38 MAPK pathway.

SUBMITTER: Chen X

PROVIDER: S-EPMC7889896 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma.

Chen Xiaopeng X Cheng Bin B Dai Dafei D Wu Yuhai Y Feng Zhiwen Z Tong Chaogang C Wang Xiangming X Zhao Jun J

Cell death discovery 20210217 1

Heparanase (HPSE) is a kind of multifunctional extracellular hydrolase, and related to metastasis of hepatocellular carcinoma (HCC). Endothelial necroptosis promotes the metastasis of cancer cells. It is not clear whether HPSE could mediate necroptosis of microvascular endothelial cells (MVECs) to promote HCC metastasis. Here we found HPSE expression was up-regulated in HCC tissues and its over-expression was correlated with multiple tumor foci, microvascular invasion, and poor outcome of HCC pa ...[more]

PMID: 33597510

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Project description:Spinal metastasis occurs in 50?75% of bone metastases caused by hepatocellular carcinoma (HCC), and HCC?derived spinal metastasis can lead to a less favorable prognosis. Recently, several studies have demonstrated that C?X3?C motif chemokine ligand 1 (CX3CL1) is closely associated with cancer metastasis, and its secretion is modulated by a disintegrin and metalloproteinase 17 (ADAM17). Bone marrow endothelial cells (BMECs) are an essential component of bone marrow. However, little is known about the roles in and effects of BMECs on HCC spinal metastasis. The present study demonstrated that CX3CL1 and C?X?C motif chemokine receptor 3 (CXCR3) expression was upregulated in HCC spinal metastases, and that CX3CL1 promoted the migration and invasion of HCC cells to the spine. Western blot analysis revealed that the Src/protein tyrosine kinase 2 (PTK2) axis participated in CX3CL1?induced HCC cell invasion and migration. CX3CL1 also increased the expression of M2 macrophage markers in THP?1 monocytes. BMECs promoted the migration and invasion of Hep3B and MHCC97H cells by secreting soluble CX3CL1, whereas the neutralization of CX3CL1 inhibited this enhancement. CX3CL1 enhanced the activation of the phosphatidylinositol?4,5?bisphosphate 3?kinase catalytic subunit alpha (PIK3CA)/AKT serine/threonine kinase 1 (AKT1) and Ras homolog family member A (RHOA)/Rho associated coiled?coil containing protein kinase 2 (ROCK2) signaling pathways through the Src/PTK2 signaling pathway. Furthermore, ADAM17 was activated by mitogen?activated protein kinase (MAPK)z14 in BMECs and significantly promoted the secretion of CX3CL1. HCC cells enhanced the recruitment and proliferation of BMECs. The overexpression of CX3CR1 facilitated the spinal metastasis of HCC in a mouse model in vivo. In addition, in vivo experiments revealed that BMECs promoted the growth of HCC in the spine. The present study demonstrated that CX3CL1 participates in HCC spinal metastasis, and that BMECs play an important role in the regulation of CX3CL1 in the spinal metastatic environment.

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Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma.

Publications

Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma.

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