Complement factor I upregulates expression of matrix metalloproteinase‐13 and ‐2 and promotes invasion of cutaneous squamous carcinoma cells

Nezhad, Pegah Rahmati; Riihilä, Pilvi; Piipponen, Minna; Kallajoki, Markku; Meri, Seppo; Nissinen, Liisa; Kähäri, Veli‐Matti

doi:10.1111/exd.14349

Cited by 13 publications

(12 citation statements)

References 52 publications

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“…These results identify FD as a putative tumor cell-associated biomarker and therapeutic target of cSCC and, for the first time, introduce the small-molecule FD inhibitor danicopan as a highly sensitive and specific drug in precision cancer therapy ( Figure 6 ). Together with our previous studies showing the role of FB, C3, FI and FH in AP, and C1r and C1s in the classical pathway in cSCC progression [ 25 , 26 , 27 , 28 , 29 , 30 ], these results provide further evidence for the role of specific complement components as biomarkers and potential therapeutic targets in cSCC ( Figure 6 ).…”

Section: Discussionsupporting

confidence: 85%

“…Recent studies have revealed the importance of local or autocrine production and activation of complement components compared to systemic liver-derived complement synthesis [ 25 , 26 , 27 , 28 , 29 , 30 ]. However, only anaphylatoxin receptors C5aR1 and C3aR, as well as anaphylatoxin C5a, have been targeted in anti-cancer therapy [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…The cancer-promoting properties of tumor cell-derived complement components have been recently demonstrated, and they have been shown to promote cancer progression independently of local and systemic complement activation [ 11 , 20 , 21 , 22 , 23 , 24 ]. Our previous studies have revealed significant upregulation of four complement system activators (FB and C3 in AP; C1r and C1s in the classical pathway) plus two complement inhibitors, complement factor I (FI) and complement factor H (FH), in cSCC cell lines in vitro as well as in tumor cells in cSCC in vivo, when compared with normal human epidermal keratinocytes (NHEKs) and normal skin, respectively [ 25 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Nezhad

Riihilä

Knuutila

et al. 2022

Cancers

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Cutaneous squamous cell carcinoma (cSCC) is the most prevalent metastatic skin cancer. Previous studies have demonstrated the autocrine role of complement components in cSCC progression. We have investigated factor D (FD), the key enzyme of the alternative complement pathway, in the development of cSCC. RT-qPCR analysis of cSCC cell lines and normal human epidermal keratinocytes (NHEKs) demonstrated significant up-regulation of FD mRNA in cSCC cells compared to NHEKs. Western blot analysis also showed more abundant FD production by cSCC cell lines. Significantly higher FD mRNA levels were noted in cSCC tumors than in normal skin. Strong tumor cell-associated FD immunolabeling was detected in the invasive margin of human cSCC xenografts. More intense tumor cell-specific immunostaining for FD was seen in the tumor edge in primary and metastatic cSCCs, in metastases, and in recessive dystrophic epidermolysis bullosa-associated cSCCs, compared with cSCC in situ, actinic keratosis and normal skin. FD production by cSCC cells was dependent on p38 mitogen-activated protein kinase activity, and it was induced by interferon-γ and interleukin-1β. Blocking FD activity by Danicopan inhibited activation of extracellular signal-regulated kinase 1/2 and attenuated proliferation of cSCC cells. These results identify FD as a novel putative biomarker and therapeutic target for cSCC progression.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Nezhad

Riihilä

Knuutila

et al. 2022

Cancers

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“…MMP-13 is a matrix metalloproteinase that participates in the degradation of the extracellular matrix and is involved in tumor cell metastasis (16,17). Our previous studies found that EGFR and MMP-13 are highly expressed in CSCC (18,19). However, the potential functions of EGFR and MMP-13 in the proliferation and metastasis of CSCC remain largely unclear.…”

Section: Microrna-27b-3p Inhibits the Proliferation And Invasion Of Cutaneous Squamous Cell Carcinoma By Targeting Egfr And Mmp-13mentioning

confidence: 99%

MicroRNA‑27b‑3p inhibits the proliferation and invasion of cutaneous squamous cell carcinoma by targeting EGFR and MMP‑13

Liang

Zhang

2021

Oncol Lett

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Cutaneous squamous cell carcinoma is a common malignant tumor. The aim of the present study was to examine the biological function of microRNA (miR)-27b-3p in cutaneous squamous cell carcinoma (CSCC) and its underlying mechanism. The relative expression levels of miR-27b-3p were determined in A-431, Colo-16 and NHEK/SVTERT3-5 cell lines. The regulatory effects of miR-27b-3p on the proliferation of CSCC cells were evaluated using MTT and colony formation assays. Transwell assays were conducted to examine the role of miR-27b-5p in the migratory and invasive abilities of CSCC cells. The levels of EGFR, MMP-13, Akt, phosphorylated (p)-Akt, cyclin D1, N-cadherin (CAD) and E-CAD were detected in CSCC cells using reverse transcription-quantitative PCR and western blot analysis. Binding between miR-27b-3p and the 3'-untranslated region (UTR) of EGFR or MMP-13 was assessed using a dual-luciferase reporter assay. miR-27b-3p was significantly downregulated in CSCC cell lines, compared with the skin keratinocyte cell line. Transfection with a miR-27b-3p mimic significantly reduced the proliferative, migratory and invasive abilities of CSCC cells in vitro. Moreover, miR-27b-3p mimic transfection downregulated the mRNA and protein levels of EGFR, MMP-13, cyclin D1, p-Akt and N-CAD, whilst upregulating E-CAD levels in CSCC cells. miR-27b-3p was found to target the EGFR and MMP-13 3'-UTRs, thus downregulating the expression of these molecules. The inhibition of CSCC proliferation by miR-27b-3p was effectively reversed by EGFR overexpression. Moreover, the inhibitory effect of miR-27b-3p on the migratory and invasive abilities of CSCC cells was abolished by MMP-13 overexpression. In conclusion, miR-27b-3p inhibits the proliferation, migration and invasion of CSCC cells by downregulating the expression of EGFR and MMP-13 and may represent a potential diagnostic marker and therapeutic option for CSCC.

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“…Evidence points to that the aggressiveness is in large caused by changes in the microenvironment ( Ng et al, 2012 ; Mittapalli et al, 2016 ; Guerra et al, 2017 ). It should be emphasized that all the discussed disease modifiers have been implicated in supporting the progression of SCC in the context of RDEB-associated SCCs and other SCCs ( Ng et al, 2012 ; Martins et al, 2016 ; Mittapalli et al, 2016 ; Föll et al, 2017 ; Rahmati Nezhad et al, 2021 ). Thus, therapies aiming at modulating the activity of these disease modifiers could create a microenvironment less supportive of malignant conversion of keratinocytes and high-risk tumor behavior.…”

Section: Disease Modifiersmentioning

confidence: 99%

Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers

2021

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The phenotypic presentation of monogenetic diseases is determined not only by the nature of the causative mutations but also is influenced by manifold cellular, microenvironmental, and external factors. Here, heritable extracellular matrix diseases, including dystrophic epidermolysis bullosa (DEB), are no exceptions. Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene encoding collagen VII. Deficiency of collagen VII leads to skin and mucosal fragility, which progresses from skin blistering to severe fibrosis and cancer. Clinical and pre-clinical studies suggest that targeting of secondary disease mechanisms or employment of natural disease modifiers can alleviate DEB severity and progression. However, since many of these mechanisms are needed for tissue homeostasis, informed, selective targeting is essential for safe and efficacious treatment. Here, we discuss a selection of key disease modifiers and modifying processes active in DEB, summarize the still scattered knowledge of them, and reflect on ways forward toward their utilization for symptom-relief or enhancement of curative therapies.

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Complement factor I upregulates expression of matrix metalloproteinase‐13 and ‐2 and promotes invasion of cutaneous squamous carcinoma cells

Cited by 13 publications

References 52 publications

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

MicroRNA‑27b‑3p inhibits the proliferation and invasion of cutaneous squamous cell carcinoma by targeting EGFR and MMP‑13

Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers

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