Matrix Metalloproteinase 8 (Collagenase 2) Induces the Expression of Interleukins 6 and 8 in Breast Cancer Cells

Thirkettle, Sally; Decock, Julie; Arnold, Hugh; Pennington, Caroline J.; Jaworski, Diane M.; Edwards, Dylan R.

doi:10.1074/jbc.m113.464230

Cited by 59 publications

(42 citation statements)

References 49 publications

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“…To dissect the involvement of proteolytic activity of MMP-8 in its biological role, cells were transfected with an enzymatically inactive form of MMP-8 (MMP-8 EA), generated by a point mutation in the catalytic domain in which an essential glutamic acid residue is changed to alanine [39]. In order to compare protein expression levels, conditioned media (CM) were collected from cells transfected with MMP-8 WT, MMP-8 EA or empty pcDNA4 vector, then concentrated 20×, and immunoprecipitated for MMP-8.…”

Section: Resultsmentioning

confidence: 99%

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Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function

et al. 2017

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BackgroundNormal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS.MethodsPrimary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (β6-1089) cell lines, were used to assess MMP-8 expression and function. β6-1089 lacking MMP-8 were transfected with MMP-8 WT and catalytically inactive MMP-8 EA, and MMP-8 in N-1089 MEC was knocked down with siRNA. The effect on adhesion and migration to extracellular matrix (ECM), localisation of α6β4 integrin to hemidesmosomes (HD), TGF-β signalling and gelatinase activity was measured. The effect of altering MEC MMP-8 expression on tumour cell invasion was investigated in 2D and 3D organotypic models.ResultsAssessment of primary cells and MEC lines confirmed expression of MMP-8 in normal MEC and its loss in DCIS-MEC. Over-expression of MMP-8 WT but not MMP-8 EA in β6-1089 cells increased adhesion to ECM proteins and reduced migration. Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration. Expression of MMP-8 WT in β6-1089 led to greater localisation of α6β4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089. Over-expression of MMP-8 WT reduced TGF-β signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-β signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor. MMP-8 WT but not MMP-8 EA over-expression in β6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion. Staining of breast cancer cases for MMP-8 revealed a statistically significant loss of MMP-8 expression in DCIS with invasion versus pure DCIS (p = 0.001).ConclusionsThese data indicate MMP-8 is a vital component of the myoepithelial tumour-suppressor function. It restores MEC interaction with the matrix, opposes TGF-β signalling and MMP-9 proteolysis, which contributes to inhibition of tumour cell invasion. Assessment of MMP-8 expression may help to determine risk of DCIS progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0822-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…The wild-type MMP-8 (WT) and inactive mutant MMP-8 (EA) coding inserts cloned into pcDNA4 (EcoRI and XhoI restriction sites, Invitrogen, K103002) have been described previously [39]. Empty pcDNA4 vector was used as a control.…”

Section: Methodsmentioning

confidence: 99%

Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function

et al. 2017

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“…, Thirkettle et al. ) contributing to osteoclast activation. BMP3 suppresses osteoblast proliferation (Daluiski et al.…”

Section: Discussionmentioning

confidence: 99%

“…Typically, matrix metalloprotease expression is low in healthy periodontal tissues, and their secretion is regulated by various proinflammatory cytokines such as IL1b and TNFa, which stimulate gingival fibroblasts to secrete MMP3, MMP8 and MMP9 thereby enhancing ECM and basement membrane breakdown. MMP8 (neutrophil collagenase) also plays a role in fracture healing, hematopoietic stem cell mobilization and immune cell recruitment (Gamer et al 2009, Steinl et al 2013, Thirkettle et al 2013 contributing to osteoclast acti-vation. BMP3 suppresses osteoblast proliferation (Daluiski et al 2001, Kokabu et al 2012 and is elevated in ageing tissues causing imbalance in bone remodelling.…”

Section: Discussionmentioning

confidence: 99%

Bone biology‐related gingival transcriptome in ageing and periodontitis in non‐human primates

Pandruvada

González

Kirakodu

et al. 2016

J Clinic Periodontology

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Aim Cellular and molecular immunoinflammatory changes in gingival tissues drive alveolar bone loss in periodontitis. Since aging is a risk factor for periodontitis, we sought to identify age-related gingival transcriptome changes associated with bone metabolism in both healthy and in naturally-occurring periodontitis. Materials and Methods Adult (12–16 years) and aged (18–23 years) non-human primates (M. mulatta) (n=24) were grouped into healthy and periodontitis. Gingival tissue samples were obtained and subjected to microarray analysis using the Gene Chip Macaque Genome Array. Gene expression profiles involved in osteoclast/osteoblast proliferation, adhesion, and function were evaluated and compared across and between the age groups. QPCR was also performed on selected genes to validate microarray data. Results Healthy aged tissues showed a gene profile expression that suggest enhancement of osteoclastic adhesion, proliferation/survival and function (SPP1, TLR4, MMP8, and TFEC) and impaired osteoblastic activity (SMEK3P and SMAD5). The gingival transcriptome in both adult and aged animals with naturally-occurring periodontitis (FOS, IL6, TLR4, MMP9, MMP10 and SPP1 genes) was consistent with a local inflammatory response driving towards bone/connective tissue destruction. Conclusion A pro-osteoclastogenic gingival transcriptome is associated with periodontitis irrespective of age; however; a greater bone-destructive molecular environment is associated with aging in healthy tissues.

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“…Genes that are up-regulated in stroma associated with tumor includes various ECM-related molecules, such as MMP-1 collagenase, which are expressed at high levels in invasive tumors [145]. Matrix Metalloproteinase 8 [Collagenase 2] expression by breast cancer cells is deleterious to long-term growth, but it induces the expression of Interleukins 6 and 8, factors that conventionally promote malignancy [146]. Activation of proMMP-1 is initiated by serine proteinase secreted by either fibroblast or tumor cells.…”

Section: Collagenase As Markers Of Tumor Progressionmentioning

confidence: 99%

An overview on therapeutic potential and various applications of microbial collagenases

Azmi

Chauhan

Gautam

2017

J Microbiol Biotech Res

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Matrix Metalloproteinase 8 (Collagenase 2) Induces the Expression of Interleukins 6 and 8 in Breast Cancer Cells

Cited by 59 publications

References 49 publications

Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function

Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function

Bone biology‐related gingival transcriptome in ageing and periodontitis in non‐human primates

An overview on therapeutic potential and various applications of microbial collagenases

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