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Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma.

ABSTRACT: We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4⁺ endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/M?) to be selectively enriched in the perivascular areas of CXCR4⁺ vessels in HCC samples. The depletion of Mo/M? with gadolinium chloride (GdCl₃) or zoledronic acid (ZA) treatment significantly reduced vascular CXCR4 expression in HCC tumors. This phenomenon was also confirmed in CCR2-KO mice, which exhibited reduced infiltration of inflammatory Mo/M? in tumor tissues. Mechanistic studies revealed that inflammatory cytokines derived from tumor conditioned Mo/M?, especially TNF-?, could up-regulate CXCR4 expression on ECs. TNF-?-induced activation of the Raf-ERK pathway, but not Notch signaling, was responsible for the expression of CXCR4. Moreover, the combination treatment of sorafenib with ZA was associated with improved anti-tumor efficacy by significantly reducing vascular CXCR4 expression. These findings revealed that Mo/M? could regulate CXCR4 expression in the tumor vasculature. Thus, the inhibition of Mo/M? inflammation might enhance the treatment efficacy of sorafenib in HCC.

SUBMITTER: Meng YM

PROVIDER: S-EPMC5790393 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma.

Meng Ya-Ming YM Liang Jing J Wu Chong C Xu Jing J Zeng Dan-Ni DN Yu Xing-Juan XJ Ning Huiheng H Xu Li L Zheng Limin L

Oncoimmunology 20171213 3

We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4<sup>+</sup> endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/Mϕ) to be selectively enriched in the perivascular areas of CXCR4<sup>+</sup> vess ...[more]

PMID: 29399411

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Project description:Rational: Increasing evidence indicates that the physical environment is a critical mediator of tumor behavior. Hepatocellular carcinoma (HCC) develops in an altered biomechanical environment, and increased matrix stiffness is a strong predictor of HCC development. C-X-C chemokine receptor type 4 (CXCR4) is known to trigger HCC progression. However, CXCR4 as a mediator of mechanical cues in HCC is not well characterized. Methods: qRT-PCR, Western blot and IHC were used to detect the CXCR4 expression in different matrix stiffness gels. MTT was used to measure the cell proliferation of HCC cells. Immunoblotting was used for detection of epithelial-to-mesenchymal transition (EMT) and stemness on the matrix stiffness. Immunofluorescence (IF) was used to detect the nuclear location in HCC cells. IP was used to show the interaction between YAP, UbcH5c and β-TrCP. Results: We identified CXCR4 as a critical intracellular signal transducer that relays matrix stiffness signals to control mechano-sensitive cellular activities through ubiquitin domain-containing protein 1 (UBTD1)-mediated YAP signaling pathway. We found that CXCR4 expression was remarkably up-regulated in HCC cells with increasing matrix stiffness and mediated proliferation, epithelial to mesenchymal transition, and stemness. Mechanistically, matrix stiffness acts through CXCR4 to decrease the levels of UBTD1, which is involved in the proteasome-dependent degradation of YAP, a major cell mechano-transducer. UBTD1 interacted with components of the YAP degradation complex and promoted the interaction between YAP and its E3 ubiquitin ligase β-TrCP. UBTD1 knockdown decreased YAP ubiquitylation and resulted in the activation of YAP-targeted genes and YAP downstream signaling. Downregulation of UBTD1 in HCC tissues correlated with malignant prognostic features and overall survival. Finally, luteolin, a natural product, suppressed matrix stiffness-induced biological effects and CXCR4-mediated YAP signaling pathway in HCC cells. Conclusion: Our findings reveal CXCR4 as a molecular switch in mechano-transduction, thereby defining a mechano-signaling pathway from matrix stiffness to the nucleus.

Dataset Information

Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma.

Publications

Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma.

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