The Journal of pathology
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The Journal of pathology · Sep 2014
Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12.
The X-linked transcription factor FOXP3 is expressed by epithelial cells of organs including the breast, where it is considered a tumour suppressor. The chemokine receptor CXCR4 also regulates the development of breast cancer by stimulating cell migration towards CXCL12-expressing sites of metastatic spread. During activation, human T cells show reciprocal regulation of FOXP3 and CXCR4. ⋯ These cells also showed a significantly increased chemotactic response towards CXCL12, consistent with a role for FOXP3 in the regulation of cell migration. Results from this study are consistent with FOXP3 functioning as an important tumour suppressor in breast cancer. Indeed, the potential functions of FOXP3 in breast epithelium can now be extended to include regulation of CXCR4 expression and response to the pro-metastatic chemokine CXCL12.
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The Journal of pathology · Sep 2014
MicroRNA-101 suppresses liver fibrosis by targeting the TGFβ signalling pathway.
Transforming growth factor-β (TGFβ) is crucial for liver fibrogenesis and the blunting of TGFβ signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFβ signalling and liver fibrogenesis. However, the regulation of TGFβ receptor I (TβRI) production by miRNA remains poorly understood. Here we demonstrate that the miR-101 family members act as suppressors of TGFβ signalling by targeting TβRI and its transcriptional activator Kruppel-like factor 6 (KLF6) during liver fibrogenesis. ⋯ Additionally, miR-101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC-specific markers. In hepatocytes, miR-101 attenuated profibrogenic TGFβ signalling and suppressed the consequent up-regulation of profibrogenic cytokines, as well as TGFβ-induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR-101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis.