ABSTRACT
Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. KEY MESSAGES: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo.
ABSTRACT
IQ motif-containing guanosine triphosphatase (GTPase)-activating protein 1 (IQGAP1) is a cytosolic scaffolding protein involved in cell migration. Our previous studies suggest sphingosine 1-phosphate (S1P) triggers bone marrow (BM) mesenchymal stromal cells (BMSCs) to damaged liver, thereby promoting liver fibrosis. However, the role of IQGAP1 in S1P-induced BMSC migration and liver fibrogenesis remains unclear. Chimeric mice of BM cell labeled by EGFP were used to build methionine-choline-deficient and high-fat (MCDHF)-diet-induced mouse liver fibrosis. IQGAP1 small interfering RNA (siRNA) was utilized to silence IQGAP1 in vivo. IQGAP1 expression is significantly elevated in MCDHF-diet-induced mouse fibrotic livers. Positive correlations are presented between IQGAP1 and fibrosis hallmarks expressions in human and mouse fibrotic livers. In vitro, depressing IQGAP1 expression blocks S1P-induced motility and cytoskeleton remodeling of BMSCs. S1P facilitates IQGAP1 aggregating to plasma membrane via S1P receptor 3 (S1PR3) and Cdc42/Rac1. In addition, IQGAP1 binds to Cdc42/Rac1, regulating S1P-induced activation of Cdc42/Rac1 and mediating BMSC migration in concert. In vivo, silencing IQGAP1 reduces the recruitment of BMSCs to impaired liver and effectively alleviates liver fibrosis induced by MCDHF diet. Together, silencing IQGAP1 relieves liver fibrosis by blocking BMSC migration, providing an effective therapeutic strategy for liver fibrosis.
ABSTRACT
BACKGROUND: The long noncoding RNA VPS9D1 antisense RNA 1 (VPS9D1-AS1) has emerged as a critical regulator in non-small-cell lung, gastric, and prostate cancers. In this study, we measured the expression levels of VPS9D1-AS1 in colorectal cancer (CRC) and determined the role of VPS9D1-AS1 in regulating the biological activities of CRC cells. In addition, we thoroughly elucidated the molecular mechanism mediating the oncogenic activities of VPS9D1-AS1 in CRC. METHODS: The expression levels of VPS9D1-AS1 in CRC tissues and cell lines were detected via quantitative reverse transcription-polymerase chain reaction. Loss-of-function experiments were performed to detect the effects of VPS9D1-AS1 silencing on CRC cell proliferation, apoptosis, migration, and invasion as well as on tumor growth in vivo. Bioinformatics analysis predicted the potential microRNAs (miRNAs) interacting with VPS9D1-AS1, and this prediction was further confirmed via RNA immunoprecipitation and luciferase reporter assays. RESULTS: Our results demonstrated the upregulated expression of VPS9D1-AS1 in CRC tissues and cell lines. Functionally, VPS9D1-AS1 interference suppressed CRC cell proliferation, migration, and invasion and promoted cell apoptosis in vitro. In addition, the loss of VPS9D1-AS1 hindered tumor growth in vivo. Mechanistic studies identified VPS9D1-AS1 as a competing endogenous RNA in CRC cells, in which VPS9D1-AS1 acted as a molecular sponge of miR-525-5p and consequently increased the expression of high-mobility group AT-hook 1 (HMGA1). Moreover, rescue experiments revealed that the regulatory effects of VPS9D1-AS1 deficiency on CRC cells were abolished after miR-525-5p inhibition or HMGA1 restoration. CONCLUSION: The newly identified competing endogenous RNA pathway involving VPS9D1-AS1, miR-525-5p, and HMGA1 is implicated in the control of CRC progression and may provide an effective target for CRC diagnosis and therapy.
ABSTRACT
BACKGROUND AND OBJECTIVE: Metabolomics has recently been applied in the field of oncology. In this study, we aimed to use metabolomics to explore biomarkers in peritoneal metastasis of gastric cancer. METHODS: Peritoneal lavage fluid (PLF) of 65 gastric cancer patients and related clinical data were collected from the First Hospital of Jilin University. The metabolic components were identified by liquid chromatography-mass spectrometry (LC-MS). Total ion current (TIC) spectra, principal component analysis (PCA), and the Student's t-test were used to identify differential metabolites in PLF. A support vector machine (SVM) was used to screen the differential metabolites in PLF with a weight of 100%. Cluster analysis was used to evaluate the similarity between samples. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic ability of the metabolites. Univariate and multivariate logistic regression analyses were used to identify potential risk factors for peritoneal metastasis of gastric cancer. RESULTS: We found the differential levels of PLF metabolites by LC-MS, TIC spectra, PCA and the t-test. Cluster analysis showed the co-occurrence of metabolites in the peritoneal metastasis group (p<0.05). ROC analysis showed the diagnostic ability of metabolites (p<0.05). Univariate and multivariate logistic regression analyses showed the potential independent risk factors for peritoneal metastasis in gastric cancer patients (p<0.05). CONCLUSION: Through the statistical analysis of metabolomics, we found that TG (54:2), G3P, α-aminobutyric acid, α-CEHC, dodecanol, glutamyl alanine, 3-methylalanine, sulfite, CL (63:4), PE-NMe (40:5), TG (53:4), retinol, 3-hydroxysterol, tetradecanoic acid, MG (21:0/0:0/0:0), tridecanoic acid, myristate glycine and octacosanoic acid may be biomarkers for peritoneal metastasis of gastric cancer.
ABSTRACT
Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the role of sphingosine 1-phosphate receptors (S1PRs) in fatty liver injury and explored whether S1PR2/3 blockade could cure fatty liver injury. A methionine-choline-deficient and a high-fat (MCDHF) diet was used to induce fatty liver injury, and the number of macrophages was evaluated by flow cytometry. Gene expressions were detected using RT-qPCR and cytometric bead array. In MCDHF-diet-fed mice, pro-inflammatory factor expressions were upregulated by fatty liver injury. The S1P level and S1PR2/3 expressions were significantly elevated. Moreover, increased S1P level and S1PR2/3 mRNA expressions were positively correlated with pro-inflammatory factor expressions in the liver. Furthermore, the number of pro-inflammatory macrophages (iMφ) increased in injured liver, and they were mainly bone-marrow-derived macrophages. In vivo, S1PR2/3 blockade decreased the amount of iMφ and inflammation and attenuated liver injury and fibrosis, although liver fat accumulation was unchanged. These data strongly suggest that anti-inflammatory treatment by blocking the S1P/S1PR2/3 axis attenuates fatty liver injury, which might serve as a potential target for fatty liver injury.