Paracrine effect of TAK1 in fibroblasts on the oncogenic potential of adjacent epithelia.

• Main Author: Yeo, Ronne Wee Yeh.
• Other Authors: Tan Nguan Soon
• Format: Final Year Project
• Language: English
• Published: 2009
• Subjects: DRNTU::Science::Biological sciences::Molecular biology
• Online Access: http://hdl.handle.net/10356/15455
• Institution: Nanyang Technological University

Among the different cell types of the stroma, fibroblasts are the key contributors of paracrine signals which govern epithelial homeostasis. Transforming growth factor-beta (TGFβ) is one such signal which exhibits autocrine and paracrine effects. Recent findings have shown that TGFβ signaling in fibroblasts exerts tumor suppressive effects on the adjacent epithelia. However, the molecular mechanisms behind this process, as well as contributions of the downstream signal mediator TGF-activated kinase 1 (TAK1), remain unclear. An organotypic coculture of human keratinocytes with fibroblasts deficient in TGFβ receptor II (TβRII) and TAK1 resulted in increased proliferation of the resultant epidermis. Expression profiling of the epidermis revealed a pattern of gene expression which reflects an oncogenic potential. Levels of various growth-promoting factors in the conditioned media were also elevated. These observations suggest that TβRII- and TAK1-deficiency in stromal fibroblasts primes the overlying epidermis for uncontrolled growth. The overlapping phenotypes also highlight the importance of TAK1 in mediating the growth inhibitory effects of fibroblast TGFβ signaling, suggesting that this pathway could be attenuated in cancer. Further characterizations of the TGFβ-TAK1 pathway are necessary to identify potential amenable sites in anti-cancer therapy.