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

ABSTRACT: 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 ?-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 ?-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.

SUBMITTER: Yang N

PROVIDER: S-EPMC7255012 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yang Nan N Chen Tianxiang T Wang Liang L Liu Runkun R Niu Yongshen Y Sun Liankang L Yao Bowen B Wang Yufeng Y Yang Wei W Liu Qingguang Q Tu Kangsheng K Liu Zhikui Z

Theranostics 20200427 13

<b>Rational</b>: 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. <b>Methods</b>: qRT-PCR, Western blot and IHC were used to detect th ...[more]

PMID: 32483419

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Project description:BackgroundDespite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis, other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma (HCC) remain obscure. Here, we explored the interplay between Piezo1 and integrin β1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis.MethodsThe role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background, and its clinical significance was evaluated in human HCC tissues. Matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin (FN)-coated cell culture system with different stiffness, Western blotting and Ca2+ probe. The effects of shPiezo1-conditioned medium (CM) on angiogenesis were examined by tube formation assay, wound healing assay and angiogenesis array. The underlying mechanism by which Piezo1 participated in matrix stiffness-induced angiogenesis was analyzed by microRNA quantitative real-time polymerase chain reaction (qRT-PCR), matrix stiffness measurement, dual-luciferase reporter assay, ubiquitination assay and co-immunoprecipitation.ResultsIncreased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels, and high expression of Piezo1 indicated an unfavorable prognosis. High matrix stiffness also noticeably enhanced the activation level of Piezo1, similar to its expression level. Piezo1 knockdown significantly suppressed tumor growth, angiogenesis, and lung metastasis of HCC rat models with high liver stiffness background. shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably, and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor (VEGF), CXC chemokine ligand 16 (CXCL16) and insulin-like growth factor binding protein 2 (IGFBP2). Matrix stiffness-caused Piezo1 upregulation/activation restrained hypoxia inducible factor-1α (HIF-1α) ubiquitination, subsequently enhanced the expression of downstream pro-angiogenic factors to accelerate HCC angiogenesis. Besides, collagen 1 (COL1)-reinforced tissue stiffening resulted in more expression of Piezo1 via miR-625-5p.ConclusionsThis study unravels a new mechanism by which the integrin β1/Piezo1 activation/Ca2+ influx/HIF-1α ubiquitination/VEGF, CXCL16 and IGFBP2 pathway participates in matrix stiffness-driven HCC angiogenesis. Simultaneously, a positive feedback regulation loop as stiff matrix/integrin β1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates matrix stiffness-caused Piezo1 upregulation.

Dataset Information

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

Publications

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

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