Krüpple-like-factor 4 Attenuates Lung Fibrosis via Inhibiting Epithelial-mesenchymal Transition

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Krüpple-like-factor 4 (KLF4), has been suggested to play an important role in the phenotype transition. However, its function in pulmonary fibrosis and EMT of human alveolar epithelial cells (AECs) remains unclear. This study aimed to examine the role of KLF4 in pulmonary fibrosis and EMT. Decreased expression of KLF4 was first observed in human IPF lung tissues and models of bleomycin-induced pulmonary fibrosis. Transgenic mice with overexpression of KLF4 were subjected to bleomycin-induced pulmonary fibrosis model and showed attenuated lung fibrosis and EMT compared to wild type group. Furthermore, the effects overexpression and knockdown of KLF4 on TGF-β1-induced EMT were examined in AECs. Adenovirus-mediated overexpression of KLF4 attenuated TGF-β1-induced EMT and activation of Smad2/3 and Dvl in AECs. Conversely, knockdown of KLF4 promoted the activation of pathways above mentioned and TGF-β1-induced EMT. Our results demonstrates that KLF4 plays an important role in bleomycin-induced lung fibrosis through suppressing TGFβ1-induced EMT. Thus, it may serve as a potential target for the treatment of pulmonary fibrosis.

How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

“…No significant differences were found in the expression of these genes between the two groups. On the other hand, KLF4, known as another master player in self-renew and differentiation of stem cells, was downregulated in IPF-MSCs; this result is in line with those by Lin [24] that reported decreased level of KLF4 in lung tissues of human IPF and mouse models of bleomycin-induced pulmonary fibrosis. Several studies have shown that MSCs are affected by the surrounding microenvironment, becoming themselves protagonists of the disease development [25]; for this reason, MSCs were further characterized by IIF/ICC and qRT-PCR through the expression of α-SMA, collagen type 1 (COL1A1), fibronectin, and TGF-β1.…”

Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC‐derived air‐liquid interface model

“…This is supported by the presence of known epithelial‐specific transcripts among the commonly deregulated genes, many of which have been associated with lung fibrosis. In accordance with previous reports, KLF4 , VEGFA , IL32, and SLC19A3 are among the commonly downregulated transcripts 7,72‐74 . BPIFB1 which was described to localize to the bronchiolized epithelium in the honeycomb cysts in usual interstitial pneumonia and MMP10 , are among the commonly upregulated transcripts 75,76 .…”

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

“…TGF-b1 triggers EMT in lung cancer via the JNK pathway (Khan et al, 2018). Our previous published data demonstrated that overexpression of KLF4 attenuated TGF-b1-induced EMT in A549 (Lin et al, 2017), which were consistent with other publications (Liu et al, 2016). Our data showed that the overexpression of KLF4 can cause a downregulation of p-JNK, which indicate that the overexpression of KLF4 contributed to the decreased ability of migration and invasion through JNK/EMT signaling pathway.…”

“…Our previous published data demonstrated that overexpression of KLF4 attenuated TGF-b1-induced EMT in A549 (Lin et al, 2017).…”

“…KLF4 also plays a vital role in pulmonary hypertension (Shatat et al, 2014;Ban et al, 2019) and pulmonary fibrosis. Our previous work showed that KLF4 attenuated lung fibrosis via an inhibition of epithelial-mesenchymal transition (EMT) (Lin et al, 2017), which also played an important role in cancer metastasis. Li et al found that KLF4 inhibited invasion and metastasis via suppressing MMP2 promoter activity .…”