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.
"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. "
[Show abstract][Hide abstract] 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.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 12/2011; 32(4):152-8. DOI:10.1089/jir.2011.0107 · 2.00 Impact Factor
"The TGF-β superfamily comprises more than 40 structurally related polypeptides , 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. "
[Show abstract][Hide abstract] 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.
"Smad3 has been shown to play an important role in mediating TGF-β signals in T cells, neutrophils and monocytes, and has a role in mediating antiproliferative effects of TGF-β as well as immunomodulatory effects such as the regulation of cytokine production.19–21 The loss of Smad3 makes mice resistant to chemically induced skin cancer, which is both stimulated and inhibited by inflammation.22 In humans, Smad3 mRNA expression is significantly higher in healthy skin of controls as compared with lesional skin of patients with atopic dermatitis.23 "
[Show abstract][Hide abstract] ABSTRACT: Background Transforming growth factor (TGF)-β is an important modulator of immune functions and cellular responses, such as differentiation, proliferation, migration and apoptosis. The Smad proteins, which are intracellular TGF-β signal transducers, mediate most actions of TGF-β.
Objectives This study examines the role of Smad3 in a murine model of contact hypersensitivity (CHS).
Methods The CHS response to oxazolone was studied in Smad3-deficient mice. The ear swelling response was measured and skin biopsies from oxazolone-sensitized skin areas were obtained for RNA isolation, immunohistochemical analyses and histology. Ear draining lymph nodes were collected for RNA isolation and proliferation tests. Quantitative real-time polymerase chain reaction was used to quantify mRNA expression of cytokines, chemokines and transcription factors.
Results The expression of proinflammatory [interleukin (IL)-1β, tumour necrosis factor-α, IL-6], Th2 (IL-4) and Th17 type cytokines (IL-17), as well as regulatory components (TGF-β, Foxp3) increased significantly at the mRNA level in the skin of oxazolone-treated Smad3−/− mice when compared with wild-type controls. The expression of the Th1 type cytokine IFN-γ and the chemokines CXCL9 and CXCL10 was, however, unaffected by the lack of Smad3. The number of neutrophils and expression of the chemokines CCL3 and CXCL5, which are both involved in neutrophil recruitment, were increased in mice lacking Smad3. Also Th2 type chemokines CCL24, CCL3 and CXCL5 were increased in the skin of Smad3−/− mice compared with wild-type mice. In the lymph nodes, mRNA of IL-1β and IL-17, but not IL-4, TGF-β or Foxp3, was increased in Smad3−/− mice during the CHS response.
Conclusions The lack of intact TGF-β signalling via Smad3 results in an increased proinflammatory, Th2 and Th17 type response in the skin, as well as increased expression of regulatory elements such as TGF-β and Foxp3. Understanding the role of Smad3 in the CHS response may offer treatment and prevention strategies in this often disabling disease.
British Journal of Dermatology 07/2008; 159(3):546-54. DOI:10.1111/j.1365-2133.2008.08696.x · 4.28 Impact Factor
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