Epithelial to mesenchymal transition-related proteins ZEB1, β-catenin, and β-tubulin-III in idiopathic pulmonary fibrosis

Abstract

Epithelial to mesenchymal transition has been suggested as a relevant contributor to pulmonary fibrosis, but how and where this complex process is triggered in idiopathic pulmonary fibrosis is not fully understood. Beta-tubulin-III (Tubβ3), ZEB1, and β-catenin are partially under the negative control of miR-200, a family of micro-RNAs playing a major role in epithelial to mesenchymal transition, that are reduced in experimental lung fibrosis and idiopathic pulmonary fibrosis. We wonder whether in situ expression of these proteins is increased in idiopathic pulmonary fibrosis, to better understand the significance of miR-200 feedback loop and epithelial to mesenchymal transition. We investigated the immunohistochemical and immunofluorescent expression and precise location of ZEB1, Tubβ3, and β-catenin in tissue samples from 34 idiopathic pulmonary fibrosis cases and 21 controls (5 normal lungs and 16 other interstitial lung diseases). In 100% idiopathic pulmonary fibrosis samples, the three proteins were concurrently expressed in fibroblastic foci, as well in damaged epithelial cells overlying these lesions and in pericytes within neo-angiogenesis areas. These results were also confirmed by immunofluorescence assay. In controls the abnormal expression of the three proteins was absent or limited. This is the first study that relates concurrent expression of Tubβ3, ZEB1, and β-catenin to abnormal epithelial and myofibroblast differentiation in idiopathic pulmonary fibrosis, providing indirect but robust evidence of miR-200 deregulation and epithelial to mesenchymal transition activation in idiopathic pulmonary fibrosis. The abnormal expression and localization of these proteins in bronchiolar fibro-proliferative lesions are unique for idiopathic pulmonary fibrosis, and might represent a disease-specific marker in challenging lung biopsies.

Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

“…Treatment options for patients are limited 35 and the underlying mechanisms for fibrosis are still debated 36 . EMT has been suggested to have a direct role in IPF, with studies showing co-localisation of epithelial and mesenchymal markers [37][38][39][40][41] , and laser capture micro-dissection isolated RNA from epithelial cells in IPF lungs confirmed expression of mesenchymal markers 42 . However, lineage tracing studies found the number of fibroblasts derived from epithelial cells to be small 43,44 , and these cells were not found to colocalise with α-SMA suggesting they did not transition to myofibroblasts 45,46 .…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…The two ZEB family members, ZEB1 and ZEB2, are transcriptional inhibitors that are involved in cell proliferation, migration, invasion, and apoptosis. Extensive studies have confirmed that ZEB1 is upregulated in the EMT and plays a key role in the development of tumors and fibrosis . It was reported that the Np63‐miR‐205 axis increased epithelial marker gene expression and decreased mesenchymal marker gene expression in oral squamous cell carcinoma by downregulating ZEB1 and ZEB2 .…”

“…Extensive studies have confirmed that ZEB1 is upregulated in the EMT and plays a key role in the development of tumors and fibrosis. 99,100 It was reported that the Np63-miR-205 axis increased epithelial marker gene expression and decreased mesenchymal marker gene expression in oral squamous cell carcinoma by downregulating ZEB1 and ZEB2. 101 Moreover, the heterogeneous expression of ZEB1 induced by EMT played an important role in metastasis through the regulation of miR-200c.…”

Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β‐catenin signaling and sensitizes cancer cells to FH535 therapy

“…One important role for β ‐catenin is induction of a morphogenic change in epithelial cells . During this process, epithelial cells cease to express E‐cadherin, Zonula occludens 1 (ZO1) protein, and cytokeratin and begin to synthesize vimentin, alpha smooth muscle actin (ACTA2), and fibroblast‐specific protein 1 (FSP1) . β ‐catenin expression is disturbed in many types of cancer.…”