4.7 Article

C1r Upregulates Production of Matrix Metalloproteinase-13 and Promotes Invasion of Cutaneous Cell Carcinoma

Journal

JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 142, Issue 5, Pages 1478-+

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2021.10.008

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Funding

  1. University of Turku
  2. Abo Akademi University
  3. Biocenter Finland
  4. Finnish Cancer Research Foundation
  5. Jane and Aatos Erkko Foundation
  6. Sigrid Juse lius Foundation
  7. Turku University Hospital [13336, 11027]
  8. Cancer Society of Southwest Finland
  9. Finnish Cultural Foundation
  10. Ida Montin Foundation
  11. Maud Kuistila Memorial Foundation
  12. Cancer Foundation of Finland
  13. Finnish Dermatological Society
  14. Turku University Foundation

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This study investigates the mechanistic role of serine proteinase C1r in cutaneous squamous cell carcinoma (cSCC). Knockout of C1r in cSCC cells leads to a decrease in proliferation, migration, and invasion. Additionally, knockout of C1r inhibits tumor growth and vascularization, promotes apoptosis of tumor cells, and reduces MMP production and collagen degradation. These findings highlight the importance of C1r in promoting the invasion of cSCC cells and provide potential therapeutic targets.
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, with increasing incidence worldwide. Previous studies have shown the role of the complement system in cSCC progression. In this study, we have investigated the mechanistic role of serine proteinase C1r, a component of the classical pathway of the complement system, in cSCC. Knockout of C1r in cSCC cells using CRISPR/Cas9 resulted in a significant decrease in their proliferation, migration, and invasion through collagen type I compared with that of wild-type cSCC cells. Knockout of C1r suppressed the growth and vascularization of cSCC xenograft tumors and promoted apoptosis of tumor cells in vivo. mRNA-sequencing analysis after C1r knockdown revealed significantly regulated Gene Ontology terms cell-matrix adhesion, extracellular matrix component, basement membrane, and metalloendopeptidase activity and Kyoto Encyclopedia of Genes and Genomes pathway extracellular matrix-receptor interaction. Among the significantly regulated genes were invasion-associated matrix metalloproteinases (MMPs) MMP1, MMP13, MMP10, and MMP12. Knockout of C1r resulted in decreased production of MMP-1, MMP-13, MMP-10, and MMP-12 by cSCC cells in culture. Knockout of C1r inhibited the expression of MMP-13 by tumor cells, suppressed invasion, and reduced the amount of degraded collagen in vivo in xenografts. These results provide evidence for the role of C1r in promoting the invasion of cSCC cells by increasing MMP production.

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