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Cited by 181Cellular Mechanics and InteractionsAngiogenesis and VEGF in CancerCaveolin-1 and cellular processes

Activation of Piezo1 contributes to matrix stiffness‐induced angiogenesis in hepatocellular carcinoma

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Li, Miao, Zhang, Xi, Wang, Mimi, Wang, Yaohui, Qian, Jiali, Xing, Xiaoxia, Wang, Zhiming, You, Yang +8 more·2022·Cancer Communications
DOI 10.1002/cac2.12364PMC PMC9648387
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Abstract

Background: Despite 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. Methods: The 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 Ca 2+ 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. Results: Increased 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. Conclusions: This study unravels a new mechanism by which the integrin β1/Piezo1 activation/Ca 2+ 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.

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  • As a Ca2+ influx channel that responds to mechanical stress, Piezo1 mediates a series of fibroblast movements upon activation, thereby forming a positive feedback loop that contributes to progression of liver fibrosis and cirrhosis.

    “In summary, as a Ca2+ influx channel that responds to mechanical stress, Piezo1 mediates a series of fibroblast movements upon activation, thereby forming a positive feedback loop that contributes to the progression of liver fibrosis and cirrhosis.91”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [91]

    The Results section ('Piezo1 activation and Ca2+ influx in HCC cells'; page unavailable) reports mechanically stimulated Piezo1-mediated Ca2+ influx. Another Results section ('A positive feedback loop worked in matrix stiffness-mediated Piezo1 upregulation'; page unavailable) proposes a Piezo1–collagen–stiffness feedback loop in hepatocellular carcinoma. These passages do not establish fibroblast movements or progression of liver fibrosis and cirrhosis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In a high-stiffness Sprague Dawley rat orthotopic liver cancer model, a positive feedback loop involving stiff matrix/integrin β1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates upregulation of Piezo1 expression by matrix stiffness.

    “Furthermore, in a high-stiffness Sprague Dawley (SD) rat orthotopic liver cancer model, a positive feedback regulatory loop involving stiff matrix/integrin β1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates the upregulation of Piezo1 expression by matrix stiffness.91”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [91]

    The Results section, “A positive feedback loop worked in matrix stiffness-mediated Piezo1 upregulation” (page unavailable), proposes the stated integrin β1/miR-625-5p/Piezo1/COL1 loop based on HCC-cell and substrate-gel experiments. The paper also reports a high-stiffness orthotopic liver cancer SD rat model in “Piezo1 participated in matrix stiffness-induced angiogenesis and metastasis” (page unavailable), but does not establish the full feedback loop in that rat model. The claim therefore overstates the setting in which the loop was shown. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Matrix stiffness enhances Piezo1 activation and Ca2+ influx, which inhibits HIF-1α ubiquitination, facilitating expression of pro-angiogenic factors VEGF, CXCL16, IGFBP2, accelerating liver cancer angiogenesis.

    “Li et al. demonstrated that the initial factor of matrix stiffness enhances the activation of Piezo1 and the influx of Ca2+, which in turn inhibits the ubiquitination of HIF-1α, thereby facilitating the expression of pro-angiogenic factors VEGF, CXCL16, and IGFBP2, ultimately accelerating liver cancer angiogenesis.91”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [91]

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Cited by

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Authors
Li, M., Zhang, X., Wang, M., Wang, Y., Qian, J., Xing, X., Wang, Z., You, Y., Guo, K., Chen, J., Gao, D., Zhao, Y., Zhang, L., Chen, R., Cui, J., & Ren, Z.
Affiliations
  • Fudan University (CN)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Cui, Jiefeng
  • Ren, Zhenggang
ORCID
Venue
Cancer Communications
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-10-01
Volume
42
Issue
11
Pages
1162-1184
ISSN
  • 1000-467X (ISSN-L)
  • 2523-3548
DOI
10.1002/cac2.12364
PMC
PMC9648387
OpenAlex
W4298326482
Cited by
181
References
4
Citations by year
2026: 56 · 2025: 74 · 2024: 30 · 2023: 19 · 2022: 2
FWCI
16.71
Type
journal article
Language
en
Open access
Licence
Locations
  • 癌症：英文版 (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81972910)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
Piezo1, extracellular matrix stiffness, angiogenesis, hepatocellular carcinoma, beta1 integrin, mechanosensing, miR-625-5p, type I collagen, vascular endothelial growth factor, CXCL16, IGFBP-2, tumor hypoxia, lung metastasis, liver stiffness, vascular endothelial cells
MeSH terms
Animals, Carcinoma, Hepatocellular, Humans, Ion Channels, Liver Neoplasms, Neovascularization, Pathologic, Rats, Sprague-Dawley, Integrin beta1, MicroRNAs, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Rats

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