Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models. We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT. Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-β1-induced EMT. Inhibition of HSP27 with OGX-427 efficiently blocks EMT and fibrosis development. Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment.

All-transretinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-β1/Smad3 signaling pathway in rats

“…Consistent with its activation of E-cadherin expression, ATRA inhibited BLM-induced Snail and Twist expression, further supporting that ATRA ameliorated lung fibrosis via inhibiting EMT. Recent studies 40,43,[45][46][47] support our findings. For example, Snail and Twist are upregulated by the majority of EMT inducers and they play a crucial role in this transforming event.…”

“…To further study the effect of ATRA on EMT, we examined the expression of Snail and Twist, two most thoroughly studied transcription factors involved in EMT. 40,41 It is believed that Snail directly inhibits E-cadherin, whereas Twist suppresses the expression of E-cadherin indirectly. 42 Gene overexpression studies have shown that Snail is sufficient to induce EMT, and snail deficiency attenuates TGF-b1-induced EMT in alveolar epithelial type II (ATII) cells.…”

“…qRT-PCR was performed using a SYBR green-based PCR master mix kit from Takara Bio (Shiga, Japan) on a Rotor Gene3000 real-time PCR system from Corbett Research (Sydney, Australia). The PCR conditions were as follows: initial denaturation at 951 C for 5 min followed by 40 Table 1.…”

HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis

“…HSPB1 has been reported to mediate the EMT by promoting the stabilization of SNAIL in idiopathic pulmonary fibrosis and enhancing the EMT in lung cancer, leading to tumor invasion and metastasis (32,48). These findings, which contradict our results, may be explained by the different roles of the protein in normal and pathologic cells or cell-/tissue-specific patterns of expression (33).…”

Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

“…Targeting IL-8 may provide a novel strategy for the treatment of cancer. Previous studies have also revealed close associations between EMT and SNAIL in tumor metastasis (42)(43)(44). ZEB1, TWIST and SNAIL have also been implicated in carcinoma via the phosphatidyl inositol 3-kinase (PI3K) (45,46) and glycogen synthase kinase 3β signaling pathways (42).…”