Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients

Fréchet, Mathilde; Warrick, Emilie; Vioux, Corinne; Chevallier, Odile; Spatz, Alan; Benhamou, Simone; Sarasin, Alain; Bernerd, Françoise; Magnaldo, Thierry

doi:10.1038/onc.2008.153

Cited by 25 publications

(22 citation statements)

References 52 publications

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“…Increased MMP1 levels were shown in dermal fibroblasts, dermal equivalents, and skin sections from XP patients mutated in the XPC gene, leading to the suggestion that MMP-1 overespression could be a worsening actor toward exacerbated premature skin aging and tumor susceptibility in these patients. Nevertheless, no evidence of ECM alterations was reported in the analyzed XP-C cells and tissues (39). Further studies are needed to ascertain whether the reduced levels of COL1 observed in the present study together with the previously reported lowered amount of COL6A1 secreted by TTD dermal fibroblasts (6) might create a microenvironment not conducive for cancer cells to survive and grow.…”

Section: Discussionmentioning

confidence: 52%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancerprone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.T he extracellular matrix (ECM) is a complex structural network that surrounds and supports cells within connective tissues. It generally includes three major types of macromolecules: fibrous proteins (collagens and elastic fibers), glycoproteins (such as fibronectins and laminins), and glycosaminoglycans/ proteoglycans. The type, amount and composition of the ECM give tissues their unique physical and biological properties (1). Notably, the ECM is not only a structural scaffold but also exhibits important functional roles in controlling key cellular events (e.g., adhesion, migration, proliferation, differentiation, and survival) involved in tissue homeostasis, development, inflammation, and tissue repair (2, 3). Thus, inherited or acquired structural alterations as well as metabolic disturbances of the ECM may cause cellular and tissue changes leading to the onset and progression of specific disorders, such as those affecting the connective tissues (osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan's syndrome) or demanding ECM degradation (tumor invasion and metastasis) (4, 5). Recently, a reduced synthesis of the ECM component collagen type VI (COL6) was shown in confluent fibroblast cultures from patients with trichothiodystrophy [TTD; Online Mendelian Inheritance in Man (OMIM) #601675] (6), an autosomal recessive disorder characterized by symptoms affecting several tissues and organs (7). The most relevant features of TTD are hair abnormalities, ichthyotic skin, physical and mental retardation, neurodegeneration, and sign...

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Section: Discussionmentioning

confidence: 52%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The mechanism by which persistent DSBs induces an oxidative stress is not known but may be related to an elevated cellular metabolism to achieve DNA repair. In agreement with this hypothesis, the existence of a link between defects in DNA damage repair pathways and increased ROS production is now becoming more and more clear [21]–[24]. Whatever the mechanism, the presence of persistent DSBs in the absence of p400 may contribute to the observed increase in ROS levels.…”

Section: Discussionmentioning

confidence: 85%

“…Strikingly more and more evidence suggests that persistent DNA damage (due for example to defective DNA repair pathways) induces an oxidative stress [21]–[24]. Since p400 depleted cells present an increase in DNA breaks (see Figure 2D and 2E), we tested whether this increase in DNA damage could participate in ROS production.…”

Section: Resultsmentioning

confidence: 99%

The E1A-Associated p400 Protein Modulates Cell Fate Decisions by the Regulation of ROS Homeostasis

et al. 2010

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The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM–dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400.

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“…Interestingly over-expression of these MMPs has been reported in CAF of sporadic BCCs [47], [48]. MMP1 over-expression was also observed in dermal fibroblasts from xeroderma pigmentosum group C patients and is thought to be involved in skin cancer development in these patients [49]. Epidermal over-expression of MMP1 in transgenic mice induces epidermal hyperplasia [50].…”

Section: Discussionmentioning

confidence: 98%

PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

et al. 2009

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Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

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Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients

Cited by 25 publications

References 52 publications

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

The E1A-Associated p400 Protein Modulates Cell Fate Decisions by the Regulation of ROS Homeostasis

PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

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