Antrodia camphorata-Derived Antrodin C Inhibits Liver Fibrosis by Blocking TGF-Beta and PDGF Signaling Pathways.

Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis. Antrodia camphorata (A. camphorata) is a medicinal fungus with hepatoprotective effect. This study investigated whether Antrodin C, an A. camphorata-fermented metabolite, could exert a protective role on liver fibrosis both in vitro and in vivo. The anti-fibrotic effect of Antrodin C was investigated in CFSC-8B cell (hepatic stellate cell) stimulated by transforming growth factor-ß1 (TGF-ß1) or platelet-derived growth factor-BB (PDGF-BB) in vitro and in CCl4 induced liver fibrosis in mice. Antrodin C (50 µM) inhibited TGF-ß1 or PDGF-BB stimulated CFSC-8B cell activation, migration and extracellular matrix (ECM) accumulation (all p < 0.05). Antrodin C (3, 6 mg/kg/d) oral administration reduced the degree of liver fibrosis induced by CCl4 in mice. Antrodin C down-regulated the expression of α-smooth muscle actin (α-SMA) and collagen I in fibrotic livers. Furthermore, Antrodin C ameliorated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation in serum (all p < 0.05). Mechanistically, Antrodin C executes its anti-fibrotic activity through negatively modulate TGF-ß1 downstream SMAD Family Member 2 (Smad2), AKT Serine/Threonine Kinase 1 (AKT), extracellular signal-regulated kinase (ERK), and P38 MAP Kinase (P38), as well as PDGF-BB downstream AKT and ERK signaling pathways. Antrodin C ameliorates the activation, migration, ECM production in HSCs and CCl4-induced liver fibrosis in mice, suggesting that Antrodin C could serve as a protective molecule against liver fibrosis.

Comprehensive molecular and clinical characterization of SLC1A5 in human cancers.

Although SLC1A5 has been reported to be closely associated with some cancer types, a comprehensive and systematic assessment of SLC1A5 across human cancers is lacking. Thus, Pan-cancer analysis of SLC1A5 was performed across 30 types of human cancers in this study. We examined mRNA expression, protein expression, copy number variation (CNV), DNA methylation, clinical relevance, cell functions, drug response and total immune infiltrates of SLC1A5 in more than 9000 patients across 30 human cancer types from The Cancer Genome Atlas (TCGA) dataset. Additionally, nine independent Gene Expression Omnibus datasets, more than 800 cancer cell lines from the Cancer Cell Line Encyclopedia dataset and the Project Achilles dataset were used to validate our findings in the TCGA dataset. Landscapes of SLC1A5 were established across multiple cancers. We showed that SLC1A5 is upregulated in multiple cancers, particularly in digestive and respiratory system cancers. SLC1A5 upregulation may be driven by CNV gain and DNA hypomethylation in human cancers. Furthermore, SLC1A5 overexpression is associated with tumor progression and poor survival in multiple cancers. Moreover, we systematically explored the potential effects of SLC1A5 expression on cell functions and drug response in human cancers. SLC1A5 knockdown showed significant proliferation-inhibiting effects in most human cancer types, especially in the digestive system and KRAS-mutant cancers. SLC1A5 expression is associated with proliferation activities of KRAS-mutant cancer cell lines and drug response of many anti-cancer drugs. Finally, we demonstrated that SLC1A5-realted tumor immune microenvironment characteristics showed strong heterogeneity in human cancers. Taken together, our findings highlight the important roles of SLC1A5 in tumorigenesis, progression, prognosis and therapy.

Comprehensive ceRNA network analysis and experimental studies identify an IGF2-AS/miR-150/IGF2 regulatory axis in colorectal cancer.

Recently, a growing body of studies has demonstrated that long non-coding RNA (lncRNA) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression and play essential roles in tumor initiation and progression. In the present study, we constructed a competitive endogenous RNA (ceRNA) network and identified potential regulatory axes in colorectal cancer (CRC) through both bioinformation and experimental validation. Firstly, we obtained differentially expressed (DE) lncRNAs, miRNAs, and mRNAs by analyzing the RNA expression profiles of CRC retrieved from The Cancer Genome Atlas (TCGA) database and CRC patients' data from affiliated Hospital of Jiangnan University, respectively. Then, we established a ceRNA regulatory network of CRC that includes 23 lncRNAs, 7 miRNAs and 244 mRNAs. To further identify these lncRNA-miRNA-mRNA regulatory axes which might play vital roles in CRC tumorigenesis and prognosis, we performed additional analyses using comprehensive bioinformatic methods. Several ceRNA regulatory axes, which consist of 2 lncRNAs, 2 miRNAs and 5 mRNAs, were obtained from the network. Finally, the interactions and correlations among these ceRNA networks were validated by experiments on CRC cell lines and clinical tumor tissues, and a potential IGF2-AS/miR-150/IGF2 axis that perfectly conform to the ceRNA theory was determined. According to the qRT-PCR results, miR-150 overexpression remarkably decreased IGF2-AS and IGF2 expression. Meanwhile, IGF2-AS expression was positively correlated with IGF2 expression in tumor tissue of CRC patients. Besides, dual luciferase reporter assays indicated that miR-150 could bound to IGF2-AS and the 3'UTR of and IGF2. In general, the constructed novel IGF2-AS/miR-150/IGF2 network might provide potential mechanisms of CRC development, and could act as a promising target for CRC treatment.