Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma

Wang, Zhuo; Yan, Ming; Li, Jiaan; Long, Jiafu; Li, Yan; Zhang, Hongmin

doi:10.1016/j.bbamcr.2018.11.016

Cited by 14 publications

(12 citation statements)

References 42 publications

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“…LPS has also been found to be related to the up-regulation of matrix metalloproteinases (MMPs) expression and activation by other pro-inflammatory signals, and zebrafish is a very suitable in vivo model for studying the regulation and activation of MMPs [ 61 , 62 , 63 ]. The upregulation of vascular endothelial growth factor ( VEGF ) expression by LPS has also been shown to induce angiogenesis in HCC cells through a STAT3-dependent pathway both in vitro and in vivo [ 25 ]. Another previous study found that LPS induced hepatic stellate cells to secrete a variety of pro-angiogenic factors, including VEGF , platelet-derived growth factor ( PDGF ), and angiopoietin-1 ( Ang-1 ) [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lipopolysaccharides (LPS), which are large molecules composed of lipids and polysaccharides that exist in the outer membrane of gram-negative bacteria, function by binding to toll-like receptor 4 (TLR4). In HCC, the cooperation of TLR4 and toll-like receptor 9 (TLR9) may activate the signal transducer and activator of transcription 3 (STAT3) [ 23 , 24 , 25 , 26 ]. Exposure to LPS leads to tumor growth and angiogenesis in HCC via the TLR4 receptor in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Exposure to LPS leads to tumor growth and angiogenesis in HCC via the TLR4 receptor in vivo. The signaling which occurs following induction by LPS also promotes EMT in HCC [ 25 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/krasV12 Double Transgenic Zebrafish

Lin

Sun

et al. 2022

Biomedicines

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The poor prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is directly associated with the multi-step process of tumor metastasis. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, is the most important epithelial-mesenchymal transition (EMT) gene involved in embryonic development, tumor progression, and metastasis. However, the role that TWIST1 gene plays in the process of liver tumor metastasis in vivo is still not well understood. Zebrafish can serve as a powerful model for cancer research. Thus, in this study, we crossed twist1a+ and kras+ transgenic zebrafish, which, respectively, express hepatocyte-specific mCherry and enhanced green fluorescent protein (EGFP); they also drive overexpression of their respective transcription factors. This was found to exacerbate the development of metastatic HCC. Fluorescence of mCherry and EGFP-labeled hepatocytes revealed that approximately 37.5% to 45.5% of the twist1a+/kras+ double transgenic zebrafish exhibited spontaneous tumor metastasis from the liver to the abdomen and tail areas, respectively. We also investigated the inflammatory effects of lipopolysaccharides (LPS) on the hepatocyte-specific co-expression of twist1a+ and kras+ in double transgenic zebrafish. Following LPS exposure, co-expression of twist1a+ and kras+ was found to increase tumor metastasis by 57.8%, likely due to crosstalk with the EMT pathway. Our results confirm that twist1a and kras are important mediators in the development of metastatic HCC. Taken together, our in-vivo model demonstrated that co-expression of twist1a+/kras+ in conjunction with exposure to LPS enhanced metastatic HCC offers a useful platform for the study of tumor initiation and metastasis in liver cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/krasV12 Double Transgenic Zebrafish

Lin

Sun

et al. 2022

Biomedicines

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“…Abnormalities of HIF-1α and angiogenic factors were associated with rat hepatocarcinogenesis [29,30] . HIF-1α binds to an evolutionary conserved HRE located in the rst introns of Ang-2.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α promotes hepatocellular carcinoma metastasis by regulating angiogenesis and epithelial-mesenchymal transition

Yao

Wang

Chen

et al. 2020

Preprint

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Background Invasion and metastasis of hepatocellular carcinoma (HCC) still remain to be hard in medical society. However, little knowledge is known regarding the hypoxia impact in HCC with angiogenesis and epithelial-mesenchymal transition (EMT). The aims of this study were to explore the regulating roles of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and EMT of HCC. Methods The levels of HIF-1α, angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) expression in a cohort of chronic liver diseases were detected by enzyme-linked immunosorbent assays, and their dynamic up-regulations were confirmed in model of rat hepatocyte malignant transformation. After HIF-1α gene transfected with specific miRNA, biological behaviors of HCC cells were analyzed by transwell or invasion assay; angiogenesis and EMT were analyzed at protein level by Western blot or at mRNA by quantitative real-time PCR. Results The levels of circulating HIF-1α, VEGF, and Ang-2 in the HCC group (145.6 ± 32.6 µg/L, 458.9 ± 125.3 µg/L, and 42.9 ± 5.1 µg/L) were significantly higher (P < 0.001) than those in the LC (79.5 ± 8.4 µg/L, 206.8 ± 56.8 µg/L, and 26.2 ± 6.1 µg/L) or the CH (60.1 ± 18.8 µg/L, 178.1 ± 85.4 µg/L, and 21.8 ± 6.9 µg/L) group, respectively. Dynamic up-regulations of HIF-1α and angiogenic factors have been confirmed by rat model with hepatocyte malignant transformation. There were closely positive correlations (P < 0.001) between them of HIF-1α and VEGF or Ang-2. After HCC cells transfected with specific HIF-1α-miRNA, the levels of HIF-1α, VEGF and Ang-2 expression were significantly down-regulated, with inhibiting infiltration or migration, blockading EMT with increasing E-cadherin and decreasing of snail, twist and vimentin. Conclusions These data have highlighted the HIF-1α over-expression could promote the metastasis or invasion of HCC via regulating neovascularization and EMT formation.

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“…Signal transducers and activators of transcription (STAT) proteins can transduce extracellular signals and regulate transcription of target genes (Shin et al, 2009). Among the STATs, STAT3 is most closely related with tumorigenesis (Aggarwal et al, 2006) and is constitutively activated and overexpressed in various tumor types such as breast carcinoma, prostate cancer, melanoma, multiple myeloma, and leukemia (Liu et al, 2017; Pathak et al, 2007; Wang Z. et al, 2018). STAT3 can be activated by many factors and promote inflammation (Vukelic et al, 2018; Zegeye et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cryptotanshinone Attenuates Airway Remodeling by Inhibiting Crosstalk Between Tumor Necrosis Factor-Like Weak Inducer of Apoptosis and Transforming Growth Factor Beta 1 Signaling Pathways in Asthma

et al. 2019

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The study is to investigate the effect of cryptotanshinone (CTS) on airway remodeling and the possible mechanism. Male BALB/c mice were pretreated with CTS or dexamethasone 30 min before nebulized inhalation of ovalbumin (OVA). CTS significantly inhibited OVA-induced increases of eosinophils and neutrophils infiltration of bronchoalveolar lavage fluids (BALFs), reduced airway resistance in asthmatic mice, decreased the accumulation of inflammatory cells, the hyperplasia of goblet cells and the deposition of collagen in asthmatic mice lung tissue, as well as markedly attenuated the leakage of inflammatory cells and the level of OVA-specific immunoglobulin E in BALFs. CTS also inhibited the expressions of alpha-smooth muscle actin, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), Fn14, transforming growth factor (TGF)-β1, Smad4, and phosphorylation of Smad2/3 and STAT3 (Tyr705). In comparison to TWEAK inhibitor or TWEAK small interfering RNA (siRNA), which were used to inhibit TWEAK/STAT3 signaling pathways, CTS caused a similar effect as them on airway remodeling. Additionally, CTS also played a similar role as the TGF-β1 inhibitor or TGF-β1 siRNA in TGF-β1/STAT3 signaling pathways in airway remodeling. The anti-inflammatory effects of CTS against OVA-induced airway remodeling may be through inhibiting STAT3, which further suppresses TWEAK and TGF-β1 signaling cross talk in asthma. CTS may be a promising therapeutic reagent for asthma treatment.

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Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma

Cited by 14 publications

References 42 publications

Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/krasV12 Double Transgenic Zebrafish

Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/krasV12 Double Transgenic Zebrafish

HIF-1α promotes hepatocellular carcinoma metastasis by regulating angiogenesis and epithelial-mesenchymal transition

Cryptotanshinone Attenuates Airway Remodeling by Inhibiting Crosstalk Between Tumor Necrosis Factor-Like Weak Inducer of Apoptosis and Transforming Growth Factor Beta 1 Signaling Pathways in Asthma

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