Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation

Impola, Ulla; Toriseva, Mervi; Suomela, Sari; Jeskanen, Leila; Hieta, Niina; Jahkola, Tiina; Grénman, Reidar; Kähäri, Veli‐Matti; Saarialho–Kere, Ulpu

doi:10.1002/ijc.10902

Cited by 65 publications

(79 citation statements)

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“…42 MMP-19 was widely expressed by keratinocytes at the basal epidermal layer of keratoacanthomas and sporadically in 40% of the SCCs. We and others have previously reported that MMP-19 is absent from invasive cancer cell nests of well-differentiated SCC, 14,34 and our new findings support these results. Thus, the loss of MMP-19 from basal epithelial cells of keratoacanthomas might serve as a warning sign of cancer development.…”

Section: Discussionsupporting

confidence: 91%

“…Particularly MMP-1, -2, -7, -9, -13, -14, and -26 have been shown to be present in well-differentiated cutaneous SCC. [10][11][12] Paradoxically, recent data show that some novel MMPs are in fact instrumental for normal keratinocyte proliferation (MMP-19 and -28) and disappear in cancer, 13,14 whereas MMP-3, -7, -9, and -12 effectively cleave plasminogen to angiostatin and type XVIII collagen to endostatin, leading to inhibition of angiogenesis and eventually retardation of tumor growth. 15,16 Our recent results suggest that epithelial expression of MMP-7, -12, and -13, but not that of MMP-1, -3, -8, -9, and -10, in chronic wounds provides a diagnostic clue for distinguishing welldifferentiated SCCs from nonmalignant wounds.…”

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confidence: 99%

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Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5c2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5c2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas. We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformationspecific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

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Section: Discussionsupporting

confidence: 91%

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Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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“…12 On the other hand, MMP19 is down-regulated or lost during neoplastic progression in breast, skin, and colon cancers. [14][15][16] The MMP19-deficiency mouse model showed MMP19 exhibited decreased tumor angiogenesis and invasion. 17 In NPC, Lu et al (2003) screened the expression of a set of MMPs in NPC tissues; MMP19 is down-regulated in NPC tissues as compared to normal controls.…”

Section: Discussionmentioning

confidence: 99%

“…13 In contrast to most MMPs, MMP19 is expressed in many types of normal tissues such as lung, pancreas, placenta, ovary, spleen, intestine, breast, and skin, but is down-regulated or lost during neoplastic progression in breast, skin, and colon carcinomas. 6,[14][15][16] In MMP19-deficient mice, increased tumor angiogenesis and invasion were observed. 17 These findings suggest MMP19 may play a possible role during malignant transformation.…”

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Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Chan

Lung

et al. 2011

Intl Journal of Cancer

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The association of Matrix metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelial cells of the nasopharynx. This cancer has a unique racial and geographic distribution with a high incidence in Southern China and Southeast Asia among the Southern Chinese population. 1 The etiology of NPC is believed to be multifactorial including dietary and

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“…In resting adult skin, most MMPs are not constitutively expressed in keratinocytes, with the exception of MMP-7 (matrilysin) in eccrine sweat gland epithelium, MMP-2 (gelatinase A) in occasional basal keratinocytes, MMP-19, tolloid, and tolloid-like 1. However, several MMPs are induced or up-regulated in keratinocytes in the context of inflammation, embryogenesis, and tissue repair/ remodeling, including MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, and MMP-19 (Kahari and Saarialho-Kere, 1997;Rattenholl et al, 2002;Impola et al, 2003;Kerkela and Saarialho-Kere, 2003;Sadowski et al, 2003;Veitch et al, 2003). Unstimulated NHKs in culture produce modest amounts of MMP-1, MMP-2, and MMP-9, but little MMP-10 or MMP19 (Varani et al, 1995a;Kahari and Saarialho-Kere, 1997;Impola et al, 2003;Kerkela and Saarialho-Kere, 2003;Sadowski et al, 2003).…”

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Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Kansra

Stoll

Johnson

et al. 2004

MBoC

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ErbB signaling through extracellular signal-regulated kinase (ERK) has been implicated in regulating the expression of ErbB ligands in hyperproliferative skin disorders and wound healing. Here, we characterize the process of autocrine ERK activation in cultured normal human keratinocytes (NHKs) subjected to growth factor (GF) deprivation. Basal ERK phosphorylation was lower after 48 h than after 24 h of GF deprivation, and lowest at 30 -60 min after an additional medium change. ERK phosphorylation was markedly increased by low concentrations of epidermal growth factor (EGF) (0.2-1 ng/ml) that provoked only a limited increase in ErbB1 tyrosine phosphorylation and internalization. Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing monoclonal antibody 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR). In contrast, these responses were unaffected by neutralizing antibodies against other ErbB1 ligands or the ErbB2 inhibitors geldanamycin and AG825. The time course of autocrine ERK phosphorylation correlated with the appearance of soluble AR, and two different metalloproteinase inhibitors blocked AR release. These results define an amphiregulin-and ErbB1-dependent mechanism by which autocrine ERK activation is maintained in NHKs, even when ErbB1 autophosphorylation and internalization are limited. INTRODUCTIONThe mammalian c-ErbB family is comprised of four closely related receptor tyrosine kinases (RTKs) that interact hierarchically in response to multiple ErbB receptor ligands (Klapper et al., 2000;Olayioye et al., 2000). Ligand binding to the extracellular domain promotes receptor homo-and heterodimerization, resulting in phosphorylation of specific tyrosine residues on the cytoplasmic domain. These events lead to activation of multiple signal transduction pathways via Src homology 2 (SH2)-and phosphotyrosine binding (PTB)-domain containing cytoplasmic proteins, ultimately affecting many cellular functions, including cell migration, proliferation, and differentiation (Hubbard et al., 1998;Hackel et al., 1999). We and others have demonstrated that human skin expresses ErbB1, ErbB2, and ErbB3, but little or no ErbB4 (Press et al., 1990;Prigent et al., 1992;De Potter et al., 2001;Stoll et al., 2001).ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al., 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al., 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al., 1998), and epiregulin (Draper et al., 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al., 2001). Organ cultures of skin display many features of early wounds, including rapid keratinocyte cytoskeletal alterations, an early ...

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Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation

Abstract: MMP-19 (also designated RASI) is a recently discovered

Cited by 65 publications

References 38 publications

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

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