ABSTRACT
The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a ß-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFß-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFß-dependent regulatory loops conferring cellular plasticity and invasive behavior.
Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Breast Neoplasms/physiopathology , Endocytosis , Adaptor Proteins, Vesicular Transport/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cadherins/genetics , Cadherins/metabolism , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Signal Transduction , Transcription Factor 4/genetics , Transcription Factor 4/metabolism , Transforming Growth Factor beta/metabolism , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
BACKGROUND: Microneedling and soft-tissue filler injections have been used independently to improve acne scarring. The effectiveness of a combined approach using microneedling followed by polymethylmethacrylate (PMMA)-collagen gel has not been carefully studied. OBJECTIVE: The goal of this study was to assess the effectiveness and safety of microneedling alone versus microneedling followed by injection of PMMA-collagen gel filler for correction of atrophic facial acne scars. METHODS: We conducted a multicenter, open-label, randomized, prospective study on subjects with distensible atrophic acne scars in the face to determine whether microneedling with PMMA-collagen gel is a superior acne scar treatment over microneedling alone. Forty-four subjects received 3 microneedling treatments over a 12-week period followed by randomization to treatments with PMMA-collagen gel (treatment group) or no further treatment (control group). RESULTS: At 24 weeks, the treatment group achieved a statistically significant improvement in acne scores over microneedling alone. The improvement continued at 36 weeks. At 24 weeks, the treatment group showed a strong trend in improvement on the Physician Global Aesthetic Improvement Scale compared with microneedling alone.
Subject(s)
Cicatrix/therapy , Collagen/administration & dosage , Dermal Fillers/administration & dosage , Needles , Polymethyl Methacrylate/administration & dosage , Acne Vulgaris/complications , Adult , Aged , Atrophy/diagnosis , Atrophy/etiology , Atrophy/therapy , Cicatrix/diagnosis , Cicatrix/etiology , Collagen/adverse effects , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Dermal Fillers/adverse effects , Face , Female , Humans , Injections, Intralesional , Male , Middle Aged , Pilot Projects , Polymethyl Methacrylate/adverse effects , Prospective Studies , Severity of Illness Index , Treatment Outcome , Young AdultABSTRACT
Following injury, keratinocytes switch gene expression programs from the one that promotes differentiation to the one that supports migration. A common feature of human wounds and ulcerations of any form is the expression of matrix metalloproteinase 1 (MMP-1; collagenase-1) by leading-edge basal keratinocytes migrating across the dermal or provisional matrix. Induction of MMP-1 occurs by signaling from the α2ß1 integrin in contact with dermal fibrillar type I collagen, and the activity of MMP-1 is required for human keratinocytes to migrate on collagen. Thus, MMP-1 serves a critical role in the repair of damaged human skin. Here, we evaluated the mechanisms controlling MMP-1 expression in primary human keratinocytes from neonatal foreskin and adult female skin. Our results demonstrate that shortly following contact with type I collagen extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase were markedly activated, whereas c-Jun N-terminal kinase (JNK) phosphorylation remained at basal levels. ERK inhibition markedly blocked collagen-stimulated MMP-1 expression in keratinocytes. In contrast, inhibiting p38 or JNK pathways had no effect on MMP-1 production. Moreover, investigating the role of Rho GTPases revealed that Cdc42 attenuates MMP-1 expression by suppressing ERK activity. Thus, our data indicate that injured keratinocytes induce MMP-1 expression through ERK activation, and this process is negatively regulated by Cdc42 activity.
