Role of TGFβ in skin inflammation and carcinogenesis

Department of Otolaryngology, Cell & Developmental Biology, and Dermatology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 06/2006; 45(6):389-96. DOI: 10.1002/mc.20229
Source: PubMed


The functions of transforming growth factor beta-1(TGFbeta1) are cell-context specific. We have found that TGFbeta1 expression in human skin squamous cell carcinoma (SCC) samples has two distinct distribution patterns: (1) either predominantly in suprabasal layers or (2) throughout tumor epithelia including basal proliferative cells. To understand whether the spatial TGFbeta1 expression patterns affect its functions, we have generated several keratinocyte-specific transgenic mouse models in which TGFbeta1 overexpression can be induced either predominantly in the suprabasal epidermis or in the basal layer of the epidermis and hair follicles. Suprabasal TGFbeta1 overexpression inhibits keratinocyte proliferation, suppresses skin carcinogenesis at early stages, but promotes tumor invasion at later stages. In contrast, TGFbeta1 overexpression in the basal layer of the epidermis and hair follicles causes a severe inflammatory skin disorder and epidermal hyperproliferation. Given the importance of inflammation in cancer development, our data suggest that TGFbeta1-induced skin inflammation may override its tumor suppressive effect at early stages during skin carcinogenesis. This hypothesis is further suggested by our recent study that Smad3 knockout mice are resistant to skin chemical carcinogenesis at least in part via abrogation of endogenous TGFbeta1-induced inflammation. This review intends to summarize current insights into the role of TGFbeta1 in skin inflammation and carcinogenesis.

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    • "None of the mice lacking any components of NF-kB share epidermal phenotypes with Ikk-a -/ -mice. On the other hand, K5.IKK-a and Lori.IKK-a transgenic mice develop normally (Liu and others 2006, 2011). We detected slightly decreased p100 and elevated p52 levels but no increased classical NF-kB and IKK kinase activity in the skin of K5.IKK-a mice compared with wild-type skin, suggesting that slight variations in p100/p52 levels are not sufficient to cause skin lesions. "
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    ABSTRACT: IκB kinase alpha (Ikk-α) gene mutations and IKK-α downregulation have been detected in various human squamous cell carcinomas (SCCs), which are malignancies derived from squamous epithelial cells. These squamous epithelial cells distribute to many organs in the body; however, the epidermis is the only organ mainly composed of stratified squamous epithelial cells, called keratinocytes. SCC is the second most common type of skin cancer. Reducing IKK-α expression promotes tumor initiation, and its loss greatly enhances tumor progression from benign papillomas to malignant carcinomas during chemical skin carcinogenesis in mice. Thus, IKK-α has emerged as a tumor suppressor for SCCs. Furthermore, inducible deletion of IKK-α in the keratinocytes of adult mice causes spontaneous skin papillomas and carcinomas, indicating that IKK-α deletion functions as a tumor initiator as well as a tumor promoter. This article discusses IKK-α biological activities and associated molecular events in skin tumor development, which may provide insight into the diagnosis, treatment, and prevention of human squamous cell carcinomas (SCCs) in the future.
    Full-text · Article · Dec 2011 · Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research
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    • "The TGF-β superfamily comprises more than 40 structurally related polypeptides [31], including TGF-βs, activins and BMPs. Its members play multifunctional and diverse roles in the maintenance of tissue homeostasis by regulating biological processes, including cell growth/differentiation, apoptosis, migration, extracellular matrix formation, inflammatory/immune response, and angiogenesis through heteromeric signaling complexes [6-8,32]. Three TGF-β isoforms, TGF-β1, TGF-β2 and TGF-β3, are expressed ubiquitously in mammalian tissue with TGF-β1 being the predominant one. "
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    ABSTRACT: Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.
    Full-text · Article · Dec 2011 · Cancers
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    • "We demonstrate that UVB upregulates IL-6, IL-8 and TGF-b in HPV-immortalized cells to a significantly higher extent than in control keratinocytes. Since these cytokines display heterogeneous functions during the inflammatory process, including promotion of angiogenesis, neutrophil chemotaxis , keratinocyte proliferation and matrix metalloproteinase (MMP) production (Apte et al., 2006; Gabay 2006; Kishimoto 2006; Li et al., 2006), they may play a key role in micro-environmental promotion of skin cancer development via the paracrine pathway. They may synergistically promote keratinocyte proliferation and inflammation by recruiting mast cells, neutrophils and monocytes/ macrophages. "
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    ABSTRACT: Keratinocytes can be induced to produce cytokines by exogenous stimuli, such as UVB, and dysregulation of this production has been described in various skin diseases, including cancer. In this study, we compared the effect of UVB on the secretion of several cytokines involved in inflammation by human keratinocytes immortalized or not with human papillomavirus (HPV)16 or HPV38 at the mRNA and protein levels. We show that expression of the HPV E6/E7 oncoproteins influences not only the basal cytokine secretion profile of keratinocytes, but also its modulation upon UVB irradiation. In particular, UVB upregulates interleukin (IL)-6, IL-8 and transforming growth factor (TGF)-beta in HPV-immortalized cells to a higher extent than in control keratinocytes. Moreover, expression of other pro-inflammatory molecules such as S100A8/9 and interferon (IFN)-kappa was downregulated in HPV-immortalized cells. These data support the functional similarity between HPV16 and 38, and suggest an active role of these viruses in modulation of the inflammatory process.
    Preview · Article · Nov 2008 · Journal of General Virology
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