Integrin laminin receptor profile of pulmonary squamous cell and adenocarcinomas

Patriarca, Carlo; Alfano, Rosa Maria; Sonnenberg, Arnoud; Graziani, Daniela; Cassani, Barbara; Melker, Annemieke De; Colombo, Piergiuseppe; Languino, Lucia R.; Fornaro, Mara; Warren, William H.; Coggi, Guido; Gould, Victor E.

doi:10.1016/s0046-8177(98)90247-7

Cited by 29 publications

(21 citation statements)

References 27 publications

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“…Thus, it is clear that certain signaling pathways that regulate MMP-9 expression are activated or altered during cellular immortalization or malignant progression. Many invasive tumors show increased expression levels of α3β1 (Bartolazzi et al, 1994;Natali et al, 1993;Patriarca et al, 1998) and its ECM ligand laminin-5 (Pyke et al, 1995) and recent studies in immortalized keratinocytes and tumor-derived cell lines have demonstrated important roles for α3β1 in several cell functions that contribute to tumor growth and malignant progression, including migration, invasion, metastasis and survival (Choma et al, 2004;Manohar et al, 2004;Morini et al, 2000;Tsuji et al, 2002;Wang et al, 2004). As MMP-9 has been implicated in some of these cell functions, our current data suggest that part of the role of α3β1 may be to regulate the stability and degradation of MMP-9 mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Knockout studies in mice have revealed important roles for α3β1 in maintaining basement membrane integrity during embryonic development of the epidermis and other tissues (DiPersio et al, 1997;Kreidberg et al, 1996). α3β1 is also expressed at high levels in most primary and metastatic tumors (Bartolazzi et al, 1994;Natali et al, 1993;Patriarca et al, 1998) and several recent studies in immortalized epithelial cells or carcinoma-derived cell lines suggest that this integrin has important roles in regulating functions that promote malignant tumor growth and progression, including cell survival, migration, invasion and metastasis (Morini et al, 2000;Choma et al, 2004;Wang et al, 2004;Manohar et al, 2004). Some of these α3β1-mediated cell functions may involve MMP-9, as α3β1 regulates MMP-9 secretion in some immortalized and malignantly transformed epithelial cells (Morini et al, 2000;DiPersio et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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α3β1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression

Iyer

Pumiglia

DiPersio

2005

Journal of Cell Science

105

131

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Matrix metalloproteinases facilitate cell migration and tumor invasion through their ability to proteolyse the extracellular matrix. The laminin-binding integrin α3β1 is expressed at high levels in squamous cell carcinomas and in normal keratinocytes during cutaneous wound healing. We showed previously that α3β1 is required for MMP-9/gelatinase B secretion in immortalized mouse keratinocytes (MK cells) and that this regulation was acquired as part of the immortalized phenotype, suggesting a possible role for α3β1 during malignant conversion. In the current study, we identify a novel mechanism whereby α3β1 regulates the induction of MMP-9 expression that occurs in response to activation of a MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Inhibition of MEK/ERK signaling in wild-type MK cells with a pharmacological inhibitor, U0126, showed that ERK activation was necessary for high levels of endogenous MMP-9 gene expression and activity of a transfected MMP-9 promoter. Furthermore, activation of MEK/ERK signaling in these cells with an oncogenic mutant of Ras, RasV12, increased both endogenous MMP-9 gene expression and MMP-9 promoter activity. Experiments with α3β1-deficient MK cells revealed that α3β1 was required for both baseline levels and RasV12-induced levels of MMP-9 mRNA expression. However, α3β1 was not required for RasV12-mediated activation of ERK or for ERK-dependent MMP-9 promoter activity. Direct comparison of mRNA turnover in the wild type and α3-null MK cells identified a requirement for α3β1 in stabilization of MMP-9 mRNA transcripts. These results identify a novel function for integrins in promoting mRNA stability as a mechanism to potentiate MAPK-mediated gene expression. They also suggest a role for α3β1 in maintaining high levels of MMP-9 mRNA expression in response to oncogenic activation of MEK/ERK signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

α3β1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression

Iyer

Pumiglia

DiPersio

2005

Journal of Cell Science

105

131

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“…In addition to the epidermis, p51/ p63 expression occurs in the basal cells of epithelia of the mammary gland (58), oral tissues (59), uterocervix (60), and bladder (30), where the ␣ 3 -inducing role of p51/p63 may also function. Furthermore, the overexpression of p51/p63 in squamous cell carcinomas of head, neck, and lung (7, 9) might contribute to the high-level ␣ 3 expression that determines cellular capability of invasion and metastasis (61)(62)(63). It is interesting to envisage that p51/p63, a hypothetical ancestor gene to tumor suppressor p53 (64), had evolved as an inducer of the critical interaction between growing epithelial cells and their niche.…”

Section: Induction Of An Ecm-binding Phenotype and Integrin ␣mentioning

confidence: 99%

p51/p63 Controls Subunit α3 of the Major Epidermis Integrin Anchoring the Stem Cells to the Niche

Kurata

Okuyama

Osada

et al. 2004

Journal of Biological Chemistry

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p51/p63, a member of the tumor suppressor p53 gene family, is crucial for skin development. We describe here identification of ITGA3 encoding integrin ␣ 3 as a target of its trans-activating function, proposing that p51/p63 allows epidermal stem cells to express laminin receptor ␣ 3 ␤ 1 for anchorage to the basement membrane. When activated by genotoxic stress or overexpressed ectopically in non-adherent cells, p51/p63 transduced a phenotype to attach to extracellular matrices, which was accompanied by expression of ITGA3. Motifs matching the p53-binding consensus sequence were located in a scattered form in intron 1 of human ITGA3, and served as p51/p63-responsive elements in reporter assays. In addition to the trans-activating ability of the TA isoform, we detected a positive effect of the ⌬N isoform on ITGA3. The high level ␣ 3 production in human keratinocyte stem cells diminished upon elimination of p51/p63 by small interfering RNA or by Ca 2؉ -induced differentiation. Furthermore, a chromatin immunoprecipitation experiment indicated a physical interaction of p51/p63 with intron 1 of ITGA3. This study provides a molecular basis for the standing hypothesis that p51/p63 is essential for epidermal-mesenchymal interactions.

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“…Considering the pro-survival effects of LN-5 discussed above, it is possible that adhesion to newly deposited LN-5 also contributes to keratinocyte survival during migration into the provisional wound ECM. LN-5, α3β1 and α6β4 are also expressed at high levels in many invasive carcinomas, suggesting possible roles for these adhesion proteins in promoting tumor cell invasion and survival, as well (Dajee et al, 2003;Felding-Habermann, 2003;Bartolazzi et al, 1994;Natali et al, 1993;Patriarca et al, 1998;Lohi et al, 2000;Pyke et al, 1995). Indeed, previous studies have suggested that α6β4 promotes survival of normal or transformed epithelial cells (Dowling et al, 1996;Weaver et al, 2002;Bachelder et al, 1999), possibly through activation of PI3K (Shaw et al, 1997).…”

mentioning

confidence: 99%

α3β1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway

Manohar

Shome

Lamar

et al. 2004

Journal of Cell Science

112

106

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Inadequate or inappropriate adhesion of epithelial cells to extracellular matrix leads to a form of apoptosis known as anoikis. During various tissue remodelling events, such as wound healing or carcinoma invasion, changes in the physical properties, and/or composition of the extracellular matrix, can lead to anoikis of epithelial cells that lack appropriate receptor-matrix interactions. Laminin-5 is the major ligand for keratinocyte adhesion in the epidermis, and it also promotes keratinocyte survival in vivo and in vitro. Integrins α3β1 and α6β4 are the major receptors for laminin-5; however, specific roles for these integrins in keratinocyte survival have not been determined. In the current study, we exploited keratinocyte cell lines derived from wild-type or α3 integrin knockout mice to reveal a critical role for α3β1 in protecting keratinocytes from apoptosis upon serum withdrawal. We show that α3β1-mediated adhesion to laminin-5 extracellular matrix inhibits proteolytic activation of caspase-3 and TUNEL-staining, both hallmarks of apoptosis. We also show that α3β1-mediated adhesion activates focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), and that inhibition of either FAK or ERK signaling leads to apoptosis of keratinocytes attached to laminin-5. α6β4-mediated adhesion to laminin-5 only partially protects cells from apoptosis in the absence of α3β1, and α6β4 is not necessary for cell survival in the presence of α3β1. These results suggest that α3β1 is necessary and sufficient for maximal keratinocyte survival on laminin-5. We propose a model to address the potential importance of α3β1-mediated survival for migrating keratinocytes at the leading edge of a cutaneous wound.

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Integrin laminin receptor profile of pulmonary squamous cell and adenocarcinomas

Cited by 29 publications

References 27 publications

α3β1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression

α3β1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression

p51/p63 Controls Subunit α3 of the Major Epidermis Integrin Anchoring the Stem Cells to the Niche

α3β1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway

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