Role of TGFβ in skin inflammation and carcinogenesis
ABSTRACT 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.
- SourceAvailable from: Feng Zhu
- "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. "
Article: IκB kinase alpha and cancer.[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 · 3.90 Impact Factor
- "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. "