Epithelium-specific ETS transcription factor 1 (ESE1) has been implicated in epithelial homeostasis, inflammation, as well as tumorigenesis, and cancer progression. However, numerous studies have reported contradictory roles-as an oncogene or a tumor suppressor of ESE1 in different cancers, and its function in the development and progression of pancreatic ductal adenocarcinoma (PDAC) has remained largely unexplored. Herein, we report that ESE1 was found upregulated in primary PDAC compared to normal pancreatic tissue, but high expression of ESE1 correlated to better relapse-free survival in patients with PDAC. Interestingly, ESE1 was found to exhibit dual roles in regulation of malignant properties of PDAC cells in that its overexpression promoted cell proliferation, whereas its downregulation enhanced epithelial-mesenchymal transition (EMT) phenotype. In the context of TGF-β-induced EMT, ESE1 is markedly downregulated at post-transcriptional level, and reconstituted ESE1 expression partially reversed TGF-β-induced EMT marker expression. Furthermore, we identify AGR2 as a novel transcriptional target of ESE1 that participates in TGF-β-induced EMT in PDAC. Collectively, our findings reveal an ESE1/AGR2 axis that interacts with TGF-β signaling to modulate EMT phenotype in PDAC.

Abstract Background Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms. Methods For drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3). Results FGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis. Conclusions Altogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

YAP1, a key mediator of the Hippo pathway, plays an important role in tumorigenesis. Alternative splicing of human YAP1 mRNA results in two major isoforms: YAP1-1, which contains a single WW domain, and YAP1-2, which contains two WW domains, respectively. We here investigated the functions and the underlying regulatory mechanisms of the two YAP1 isoforms in the context of EGF-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Human NSCLC cell lines express both YAP1-1 and YAP1-2 isoforms-although when compared to YAP1-1, YAP1-2 mRNA levels are higher while its protein expression levels are lower. EGF treatment significantly promoted YAP1 expression as well as EMT process in NSCLCs, whereas EGF-induced EMT phenotype was significantly alleviated upon YAP1 knockdown. Under normal culture condition, YAP1-1 stable expression cells exhibited a stronger migration ability than YAP1-2 expressing cells. However, upon EGF treatment, YAP1-2 stable cells showed more robust migration than YAP1-1 expressing cells. The protein stability and nuclear localization of YAP1-2 were preferentially enhanced with EGF treatment. Moreover, EGF-induced EMT and YAP1-2 activity were suppressed by inhibitor of AKT. Our results suggest that YAP1-2 is the main isoform that is functionally relevant in promoting EGF-induced EMT and ultimately NSCLC progression.