Abstract
Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT, it is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFβ1 and TNFα were used to induce EMT in human lung carcinoma A549 cells, we found an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFα and not the TGFβ1 that induced the fibroblast-like morphology changes. TNFα also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFα-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFα-induced molecular functional networks related to inflammation and cell movement. Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration and fibroblast-like morphology. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFα-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies.
Highlights
Inflammatory mediators are important constituents of local environment for tumors, and evidences suggest that they are closely linked to cancer and inflammation [1]
Western blotting revealed that tumor necrosis factor alpha (TNFa) and transforming-growth factor b1 (TGFb1) together decreased expressions of ECadherin and Occludin, typical epithelial adherens and tight junction (TJ) marker proteins, and increased expressions of Vimentin, a typical mesenchymal marker (Figure 1D)
We found that TNFa and TGFb1 may have different roles in these human lung cancer cells
Summary
Inflammatory mediators are important constituents of local environment for tumors, and evidences suggest that they are closely linked to cancer and inflammation [1]. One of the key mediators implicated in inflammationassociated cancer is tumor necrosis factor alpha (TNFa) [3]. TNFa was first identified for its ability to induce rapid hemorrhagic necrosis of experimental cancers, TNFa is known to be produced in cancer cells as an endogenous tumor promoter [2,3]. TNFa2/2 and TNFR12/2 mice are resistant to chemically induced carcinogenesis in the skin [6]. TNFR12/2 mice are resistant to chemical carcinogenesis in the liver [7], and in the development of liver metastasis in experimental colon cancer [8]. TNFa has been suggested as a target for renal-cell carcinoma treatment [10]
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