Regulation of extracellular matrix remodeling following transforming growth factor-beta1/epidermal growth factor-stimulated epithelial-mesenchymal transition in human premalignant keratinocytes.

During tumor progression, malignant cells exploit critical developmental and tissue remodeling programs, often promoting a plastic phenotype referred to as an epithelial-mesenchymal transition (EMT). Autocrine/paracrine signaling due to tumor microenvironment cytokines, such as members of the transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) families, largely regulates the morphological and invasive phases of the EMT phenotype. Notably, epithelial cell initiation often coincides with a switch in the response of these cells to TGF-beta and is concomitant with EGF receptor amplification. Modeling these events, we have observed that premalignant human keratinocytes, HaCaTs, acquire a highly motile and scattered phenotype indicative of EMT following stimulation with TGF-beta1 and EGF. TGF-beta1 and EGF have been shown to upregulate a number of matrix metalloproteinases (MMP) in epithelial cells, which may in turn play a role in developing metastatic potential in these cells. We have established that an increase in MMP-10 expression occurs following treatment of HaCaT cells with a combination of TGF-beta1 and EGF. This increase in MMP-10 expression paralleled the development of a collagenolytic phenotype that was sensitive to components of the plasminogen activation system, including the plasminogen activator inhibitor type-1 (PAI-1). Significantly high levels of MMP-10 have been detected in squamous cell carcinomas of the head and neck, esophagus, oral cavity and skin. Importantly, TGF-beta1 in addition to upregulating MMP-10 has been shown to upregulate PAI-1 expression in HaCaT cells. Taken together, these observations suggest that TGF-beta1 and EGF play a complex role in modulating proteolytic and transitional events such as EMT that may facilitate the progression of human premalignant epithelial cells toward a more invasive phenotype.

Wilkins-Port CE ，Higgins PJ 《-》

Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells.

Uttamsingh S ，Bao X ，Nguyen KT ，Bhanot M ，Gong J ，Chan JL ，Liu F ，Chu TT ，Wang LH ... -  《-》

TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes.

Räsänen K ，Vaheri A 《-》

The role of gremlin, a BMP antagonist, and epithelial-to-mesenchymal transition in proliferative vitreoretinopathy.

Lee H ，O'Meara SJ ，O'Brien C ，Kane R ... -  《INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE》

Epidermal growth factor and transforming growth factor-beta1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway.

Tian YC ，Chen YC ，Chang CT ，Hung CC ，Wu MS ，Phillips A ，Yang CW ... -  《EXPERIMENTAL CELL RESEARCH》