CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway

Yang, Nan; Chen, Tianxiang; Wang, Liang; Liu, Runkun; Niu, Yongshen; Sun, Liankang; Yao, Bowen; Wang, Yufeng; Yang, Wei; Liu, Qingguang; Tu, Kangsheng; Liu, Zhikui

doi:10.7150/thno.44789

Cited by 61 publications

(47 citation statements)

References 41 publications

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“…Our previous studies show that increased matrix stiffness not only strengthens the malignant characteristics of HCC cells [19][20][21][22], but also promotes HCC metastasis by facilitating lung premetastatic niche formation [23]. Other studies also support that increased matrix stiffness enhances cell proliferation, chemotherapeutic resistance, and stem cell characteristics in HCC [16,45] and is positively correlated with poor prognosis [46]. Thereby, matrix stiffness around HCC cells as an important regulator influences or determines the pathological process of HCC invasion and metastasis.…”

Section: Discussionmentioning

confidence: 89%

Matrix stiffness‐mediated effects on macrophages polarization and their LOXL2 expression

et al. 2020

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Previously, we reported that the secreted lysyl oxidase like 2 (LOXL2) from hepatocellular carcinoma (HCC) cells under higher stiffness stimulation contributed to the formation of lung premetastatic niche. To further clarify whether matrix stiffness also alters LOXL2 expression in other cells within tumor microenvironment, we developed a gel‐based culture system combined with a model of macrophage polarization to evaluate the effects of matrix stiffness on the polarization of M2 macrophages and their LOXL2 expression. THP‐1 cells cultured on 6KPa, 10KPa, and 16KPa stiffness substrates were first incubated with 100nM phorbol 12‐myristate 13‐acetate (PMA) for 24 hours and subsequently treated with 20nM interleukin‐4 (IL‐4) and 20nM interleukin‐13 (IL‐13) for 48 hours. The polarization states of M2 macrophages under different stiffness stimulation were comparatively analyzed, and their LOXL2 expressions as well as the underlying molecular mechanism were further explored. Our results demonstrated that increased matrix stiffness remarkably strengthened M2 macrophage polarization and promoted their LOXL2 expression. Activation of integrin β5‐FAK‐MEK1/2‐ERK1/2 pathway participated in matrix stiffness‐mediated HIF‐1α upregulation, and HIF‐1α upregulation resulted in a significant improvement in LOXL2 expression. Additionally, M2 macrophage polarization state and LOXL2 expression in HCC tissues with COL1High/LOXHigh were consistent with the results in vitro, further confirming the regulation roles of matrix stiffness in macrophage polarization and LOXL2 expression. The findings about LOXL2 upregulation in the polarized macrophages under higher stiffness stimulation will be helpful to better understand the underlying mechanism of matrix stiffness‐induced premetastatic niche formation in HCC.

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Section: Discussionmentioning

confidence: 89%

Matrix stiffness‐mediated effects on macrophages polarization and their LOXL2 expression

et al. 2020

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“…Since both L1CAM and CXCR4 have been implicated in YAP activation in other cancers 19 , 20 and YAP is known to enforce CSC phenotype in CRC GEMM (genetically engineered mouse model) 21 , 22 we looked at the relationship between L1CAM and CXCR4 expression with regards to YAP activation in CRC cells. We first assessed YAP cellular localization in SW480 and SW620 L1CAM low vs L1CAM high and CXCR4 low vs CXCR4 high sorted cells upon treatment with recombinant Nodal.…”

Section: Resultsmentioning

confidence: 99%

Nodal-induced L1CAM/CXCR4 subpopulation sustains tumor growth and metastasis in colorectal cancer derived organoids

Cave¹,

Hernando‐Momblona²,

Sevillano³

et al. 2021

Theranostics

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Background: Colorectal cancer (CRC) is currently the third leading cause for cancer-related mortality. Cancer stem cells have been implicated in colorectal tumor growth, but their specific role in tumor biology, including metastasis, is still uncertain. Methods: Increased expression of L1CAM, CXCR4 and NODAL was identified in tumor section of patients with CRC and in patients-derived-organoids (PDOs). The expression of L1CAM, CXCR4 and NODAL was evaluated using quantitative real-time PCR, western blotting, immunofluorescence, immunohistochemistry and flow cytometry. The effects of the L1CAM, CXCR4 and NODAL on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo . Results: We found that human colorectal cancer tissue contains cancer stem cells defined by L1CAM high /CXCR4 high expression that is activated by Nodal in hypoxic microenvironment. This L1CAM high /CXCR4 high population is tumorigenic, highly resistant to standard chemotherapy, and determines the metastatic phenotype of the individual tumor. Depletion of the L1CAM high /CXCR4 high population drastically reduces the tumorigenic potential and the metastatic phenotype of colorectal tumors. Conclusion: In conclusion, we demonstrated that a subpopulation of migrating L1CAM high /CXCR4 high is essential for tumor progression. Together, these findings suggest that strategies aimed at modulating the Nodal signaling could have important clinical applications to inhibit colorectal cancer-derived metastasis.

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“…Specifically, CXCR4-induced signaling pathways, including Gαi, Annexin A2 and Rac, activate actin polymerization to migrate HCC cells ( Li et al, 2019 ). Notably, CXCR4 serves as an important intracellular signal transducer, can relay matrix stiffness signals through ubiquitin domain-containing protein 1 (UBTD1)-mediated YAP signaling pathway to drive HCC progression ( Yang et al, 2020 ). Recent studies have shown that CXCL12 improves cell invasion potential of HCC cells and CXCR4 overexpression is associated with aggressive characteristics and poor prognosis of HCC, while inhibition of CXCR4 activity via CXCR4 knockdown, AMD3100 or neutralizing antibody administration suppresses tumorigenesis of hepatoma cells in vitro and in vivo ( Liu H. et al, 2015 ; Lu et al, 2015 ).…”

Section: Cxcr4 Signaling Pathway In Hccmentioning

confidence: 99%

Emerging Importance of Chemokine Receptor CXCR4 and Its Ligand in Liver Disease

Wang

Gao

et al. 2021

Front. Cell Dev. Biol.

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Chemokine receptors are members of the G protein-coupled receptor superfamily, which together with chemokine ligands form chemokine networks to regulate various cellular functions, immune and physiological processes. These receptors are closely related to cell movement and thus play a vital role in several physiological and pathological processes that require regulation of cell migration. CXCR4, one of the most intensively studied chemokine receptors, is involved in many functions in addition to immune cells recruitment and plays a pivotal role in the pathogenesis of liver disease. Aberrant CXCR4 expression pattern is related to the migration and movement of liver specific cells in liver disease through its cross-talk with a variety of significant cell signaling pathways. An in-depth understanding of CXCR4-mediated signaling pathway and its role in liver disease is critical to identifying potential therapeutic strategies. Current therapeutic strategies for liver disease mainly focus on regulating the key functions of specific cells in the liver, in which the CXCR4 pathway plays a crucial role. Multiple challenges remain to be overcome in order to more effectively target CXCR4 pathway and identify novel combination therapies with existing strategies. This review emphasizes the role of CXCR4 and its important cell signaling pathways in the pathogenesis of liver disease and summarizes the targeted therapeutic studies conducted to date.

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CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway

Cited by 61 publications

References 41 publications

Matrix stiffness‐mediated effects on macrophages polarization and their LOXL2 expression

Matrix stiffness‐mediated effects on macrophages polarization and their LOXL2 expression

Nodal-induced L1CAM/CXCR4 subpopulation sustains tumor growth and metastasis in colorectal cancer derived organoids

Emerging Importance of Chemokine Receptor CXCR4 and Its Ligand in Liver Disease

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