Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

Malaponte,

doi:10.3892/or_00000831

Cited by 28 publications

(29 citation statements)

References 30 publications

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“…Malaponte et al (6) found that plasma levels of MMP-2 and TGF-β in patients with primary melanoma were significantly higher than those of healthy controls and those significantly higher levels were found in patients with metastatic melanoma. Extracellular factors, such as the inflammatory cytokine IL-1β has been implicated in facilitating inflammation and melanoma tumor growth (10).…”

Section: Discussionmentioning

confidence: 99%

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Modulation of MMP-2 and −9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells

et al. 2017

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Abstract. Melanoma, an extremely aggressive cancer, causes the most skin cancer-related deaths, due to metastasis to other areas of the body, such as lymph nodes, lungs, liver, brain or bone. It is characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in regulation of MMP-2 and -9 in human melanoma A-2058 cells. Human A-2058 cells were grown in DMEM supplemented with 15% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with PBS and incubated in serum-free media with phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; TNF-α and IL-1β at 0.1, 1, 10 and 25 ng/ml; LPS at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Melanoma A-2058 demonstrated strong expression of MMP-2 and slight expression of MMP-9. PMA at 100 ng/ml showed no effect on MMP-2 secretion but potently upregulated MMP-9 secretion to 400% that of control. TNF-α showed no significant overall effect on expression of MMP-2 but potent dose-dependent increased MMP-9 secretion with 200% of control at 25 ng/ml. IL-1β showed no significant effect on MMP-2 or MMP-9 secretion by A-2058 cells, except at 25 ng/ml where MMP-2 level was reduced by ~40% and MMP-9 secretion ~50%. LPS treatment showed no significant effect on MMP-2 secretion and enhanced MMP-9 secretion up to 25 µg/ml followed by decreased level. EGCG, NM and doxycycline, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide and retinoic acid had inhibitory effects on MMP-2, while dexamethasone showed slight stimulatory effect on MMP-2 secretion. Our results showed that select cytokines, mitogens and inhibitors modulated A-2058 MMP-2 and MMP-9 expression. They suggest the clinical potential of MMP inhibitors, especially the non-toxic ones, such as the nutrient mixture and its component EGCG in management of melanoma.

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Section: Discussionmentioning

confidence: 99%

“…Clinical and experimental studies have demonstrated that elevated levels of matrix metalloproteinases are associated with rapid progression of metastatic melanoma (5,6). MMP activity is regulated by and dependent upon environmental influences from surrounding stroma cells, ECM proteins, systemic hormones and other factors.…”

Section: Introductionmentioning

confidence: 99%

Modulation of MMP-2 and −9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells

et al. 2017

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“…MMPs are a family of proteinases with various substrates and functions, including angiogenesis, tissue invasion, inflammation, and tumor metastasis (HadlerOlsen et al, 2010;Kessenbrock et al, 2010). In melanoma, both MMP-2 and MMP-9 were involved in cell invasion (van den Oord et al, 1997;Simonetti et al, 2002); however, only overexpression of MMP-2 is correlated with progression and survival (Vaisanen et al, 1998(Vaisanen et al, , 2008Orimoto et al, 2008;Malaponte et al, 2010). To our best knowledge, regulation of MMP-2 by Nox1 has not been reported in cancer cells including melanoma.…”

Section: Introductionmentioning

confidence: 98%

NADPH Oxidase 1 Overexpression Enhances Invasion via Matrix Metalloproteinase-2 and Epithelial–Mesenchymal Transition in Melanoma Cells

Liu

Garcia

Meyskens

2012

Journal of Investigative Dermatology

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NADPH oxidase 1 (Nox1) is a member of the NADPH oxidase family that has not been well characterized in the melanocytic cell lineage. Here we demonstrated that Nox1 and Nox4 were detected in melanocytic lineage, with only Nox1 detected in normal human melanocytes and Nox4 in a subset of metastatic melanoma cell lines. The protein level and enzymatic activity of Nox1 was elevated in all melanoma cells as compared with normal melanocytes. Overexpression of GFP-Nox1 protein in Wm3211 primary melanoma cells increased invasion rate by 4- to 6-fold as measured by Matrigel invasion assay, whereas knocking down or inhibiting Nox1 decreased invasion by approximately 40-60% in Wm3211 and SK-Mel-28 cells. Matrix metalloproteinase-2 (MMP-2) was increased by Nox1 overexpression at the mRNA, protein, and activity levels, and decreased by Nox1 knockdown. MMP-2 promoter activity was also regulated by Nox1 knockdown. In addition, stable clones overexpressing Nox1 exhibited an epithelial-mesenchymal transition (EMT) as examined by cell morphology and EMT markers; knockdown or inhibiting Nox1 led to a reversal of EMT. Supplementing MMP-2 to culture media did not induce EMT, suggesting that EMT induction by Nox1 was not through MMP-2 upregulation. In summary, Nox1 was overexpressed in all melanoma cell lines examined, and enhanced cell invasion by MMP-2 upregulation and EMT induction.

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“…Since GLI2 is a critical substrate that is necessary for response of the hedgehog (HH) pathway, cross-talk between the TGF-beta and HH pathways may induce a positive feedback loop, promoting tumor progression and metastasis [46]. TGF-beta leads to MMP-2 upregulation in several cancers and expression of the two proteins has been found to be correlated in plasma from advanced melanoma patients [47]. Intravital imaging and microarray analysis of B16 melanoma tumors demonstrated that TGF-beta signaling can reverse features that are characteristics of differentiated melanocytes and increase cell motility [48].…”

Section: Tgf-betamentioning

confidence: 99%

Cell metastasis in Melanoma

Ott¹,

Hodi²

2012

Open J. Hematol.

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Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-β in melanoma development and progression

Cited by 28 publications

References 30 publications

Modulation of MMP-2 and −9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells

Modulation of MMP-2 and −9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells

NADPH Oxidase 1 Overexpression Enhances Invasion via Matrix Metalloproteinase-2 and Epithelial–Mesenchymal Transition in Melanoma Cells

Cell metastasis in Melanoma

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