Transforming growth factor-β (TGFβ) is crucial for liver fibrogenesis and the blunting of TGFβ signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFβ signalling and liver fibrogenesis. However, the regulation of TGFβ receptor I (TβRI) production by miRNA remains poorly understood. Here we demonstrate that the miR-101 family members act as suppressors of TGFβ signalling by targeting TβRI and its transcriptional activator Kruppel-like factor 6 (KLF6) during liver fibrogenesis. Using a mouse model of carbon tetrachloride (CCl4 )-induced liver fibrosis, we conducted a time-course experiment and observed significant down-regulation of miR-101 in the fibrotic liver as well as in the activated HSCs and injured hepatocytes in the process of liver fibrosis. Meanwhile, up-regulation of TβRI/KLF6 was observed in the fibrotic liver. Subsequent investigations validated that TβRI and KLF6 were direct targets of miR-101. Lentivirus-mediated ectopic expression of miR-101 in liver greatly reduced CCl4 -induced liver fibrosis, whereas intravenous administration of antisense miR-101 oligonucleotides aggravated hepatic fibrogenesis. Mechanistic studies revealed that miR-101 inhibited profibrogenic TGFβ signalling by suppressing TβRI expression in both HSCs and hepatocytes. Additionally, miR-101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC-specific markers. In hepatocytes, miR-101 attenuated profibrogenic TGFβ signalling and suppressed the consequent up-regulation of profibrogenic cytokines, as well as TGFβ-induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR-101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis.
The present study aimed to investigate the protective role of limonene in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and limonene (25, 50, and 75 mg/kg) was injected intraperitoneally 1 h prior to LPS administration. After 12 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Limonene pretreatment at doses of 25, 50, and 75 mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, pretreatment with limonene inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. Furthermore, we demonstrated that limonene blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in LPS-induced ALI. The results presented here suggest that the protective mechanism of limonene may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of NF-κB and MAPK activation.
BackgroundThe Forkhead box M1 (FOXM1), an important regulator of cell differentiation and proliferation, is overexpressed in a number of aggressive human carcinomas. The purpose of this study was to examine the expression levels of FOXM1 in epithelial ovarian cancer (EOC), to identify the relationship between FOXM1 expression and patient survival, and to investigate the role of FOXM1 in human ovarian cancer development.MethodsImmunohistochemical analysis for FOXM1 was performed in a total of 158 ovarian tissue specimens, all with linked clinical outcome data. Kaplan–Meier method and Cox proportional hazards analysis were used to relate FOXM1 expression to clinicopathological variables and to progression-free survival (PFS) and overall survival (OS). In vitro studies were performed to determine the function of FOXM1 in cell proliferation, migration and invasion in EOC cells using pcDNA3.1-FOXM1 and FOXM1 shRNA.ResultsElevated FOXM1 levels were associated with lymph node metastasis (P = 0.009), but not with age, FIGO stage, histological grade and histological type. Patients with high expression of FOXM1 had poorer PFS (P = 0.0001) and OS (P < 0.0001) than patients with low expression of FOXM1. Furthermore, multivariate analyses indicated that FOXM1 positivity was an independent prognostic factor for PFS (P = 0.046) and OS (P = 0.022), respectively. Overexpression of FOXM1 increased expression and activity of matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor-A (VEGF-A), and cancer cell proliferation, migration and invasion of HO-8910 cells, whereas knockdown of FOXM1 reduced expression and activity of MMP-2, MMP-9 and VEGF-A, and cancer cell proliferation, migration and invasion of HO-8910 PM cells.ConclusionsOur results suggest that FOXM1 expression is likely to play important roles in EOC development and progression. FOXM1 expression is a potential prognostic factor for PFS and OS, and it could be a novel treatment target in EOC patients.
CD44 and EpCAM play crucial roles in intraperitoneal ovarian cancer development. In this study, we developed an RNA-based bispecific CD44-EpCAM aptamer that is capable of blocking CD44 and EpCAM simultaneously by fusing single CD44 and EpCAM aptamers with a double stranded RNA adaptor. With the aid of a panel of ovarian cancer cell lines, we found that bispecific CD44-EpCAM aptamer was much more effective than either single CD44 or EpCAM aptamer in the ability to inhibit cell growth and to induce apoptosis. When these aptamers were tested in intraperitoneal ovarian cancer xenograft model, bispecific CD44-EpCAM aptamer suppressed intraperitoneal tumor outgrowth much more significantly than single CD44 and EpCAM aptamer either alone or in combination. The enhanced efficacy of bispecific CD44-EpCAM aptamer is most likely to be attributed to its increased circulation time over the single aptamers. Moreover, we showed that bispecific CD44-EpCAM aptamer exhibited no toxicity to the host and was unable to trigger innate immunogenicity. Our study suggests that bispecific CD44-EpCAM aptamer may represent a promising therapeutic agent against advanced ovarian cancer.
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