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Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer. Extracellular vesicles (EV)-mediated microRNA (miRNA) delivery is critical in cancer metastasis. We aimed to identify the mechanism of HCC cell-derived EVs-mediated miR-3129 in HCC. After EVs isolation and identification, miR-3129 expression in plasma EVs was evaluated and its diagnostic efficiency was analyzed. miR-3129 inhibitor was transfected into HepG2 and SMMC7721 cells, and cell malignant episodes were assessed. HCC cells were incubated with EVs from MHCC-97H cells and transfected with miR-3129 inhibitor and/or TXNIP. The nude mice were injected with MHCC-97H cells-EV or MHCC-97H cells-EV/miR-3129 inhibitor, and HCC growth and metastasis were assessed. miR-3129 was highly expressed in plasma EVs from HCC patients, which was the essential diagnostic biomarker for HCC. miR-3129 downregulation inhibited the malignant episodes of HCC cells. MHCC-97H cell-EVs were absorbed by HCC cells and transferred miR-3129 to HCC cells. EVs-carried miR-3129 promoted malignant episodes of HCC cells, which were weakened by miR-3129 inhibition in EVs. miR-3129 targeted TXNIP. TXNIP overexpression averted the effect of EVs-carried miR-3129 in HCC. In vivo, MHCC-97H cell-EVs transferred miR-3129 to facilitate HCC growth and metastasis. MHCC-97H cell-EVs transferred miR-3129 to promote HCC metastasis by targeting TXNIP. [ABSTRACT FROM AUTHOR]

• Aristolochic acid I activates C3a/C3aR system in aristolochic acid nephropathy. • C3a/C3aR system functions as a promoter in Aristolochic acid I induced EMT. • Antagonist of C3aR reverses the process of fibrosis caused by Aristolochic acid I. Previous studies have reported that the complement system is unconventionally activated in many kinds of glomerulonephritis. Multiple complement components participate in the pathogenic process by triggering immune response or other intracellular signaling pathways. Here, we have investigated the role of C3a and its receptor C3aR in aristolochic acid nephropathy (AAN), which, is featured with progressive interstitial fibrosis. Over release of C3a and increased expression of C3aR parallels to the up-regulation of α-SMA and TGF-β1 in AAN, which appeared to promote epithelial-mesenchymal-transition (EMT). To identify the role of complement activation in AAN, we used an inhibitor of C3aR (C3aRA) to block the coupling of C3a to its receptor. Our results confirmed from decreased EMT, the protective effect of C3aRA in cell apoptosis and inflammatory response induced by aristolochic acid I. These results showed that C3a and its receptor C3aR played pathogenic roles in AAN, and renal tubular epithelial cells were potentially pivotal targets of complement activation that could cause pro-fibrotic effects. [ABSTRACT FROM AUTHOR]

Background A number of factors may be responsible for the differences in the biologic behaviors of oral and lower lip squamous cell carcinomas (SCCs). Immunohistochemical invasion profiles have been used to detect invasion patterns like epithelial-mesenchymal-transition (EMT) and collective-cell-invasion (CCI), which have not been investigated in lower lip neoplasms. The aim of the present study was to compare the invasive phenotypes of SCCs of the lower lip and oral cavity. Method A total of 44 OSCCs and 37 lower lip SCCs were immunostained with E-Cadherin, N-Cadherin, and podoplanin. Based on their expression patterns, tumors were allocated to EMT, CCI or non-EMT/non-CCI categories. Results None of the oral SCCs showed EMT; while 5 lower lip SCCs demonstrated this phenotype. CCI was observed in 12 oral SCCs and 4 lower lip SCCs. The third group included 32 and 28 cases of oral and lower lip tumors, respectively. A significant difference in invasive phenotype was found between the two locations (P = 0.009). Conclusion Oral cavity and lip tumors differ in various aspects and according to our results; the pattern of invasion may be added to these features. Between the two major invasion patterns, EMT was more prevalent in lip tumors while CCI was observed more commonly in oral neoplasms. The significance of the different expression patterns of the non-EMT/non-CCI category requires further investigation. [ABSTRACT FROM AUTHOR]

Objective Tumor metastasis is still a great challenge for the prognosis of colorectal cancer (CRC). Although secreted phosphoprotein 1 (SPP1) over-expression is confirmed to associate with invasion, metastasis of CRC, the underlying mechanism by which modulates the CRC metastasis is still not fully explained. Method GDS4382 was obtained from GEO database and differentially expressed genes (DEGs) were analyzed by bioinformatics methods 55 paired samples of CRC and adjacent non-cancerous tissues were collected to detect the expression of SPP1 by q-PCR and western blot. Functional analysis of siRNA-SPP1, including proliferation, apoptosis, colony formation, cell cycle, migration, was investigated in CRC cell lines and tumor xenografts were conducted in nude mice. Protein expression of E-cadherin and vimentin was detected by western blot. Results 1887 DEGs were analyzed and selected from GDS4382, of which, SPP1 and epithelial-mesenchymal-transition (EMT) showed a close association by bioinformatics analysis. The mRNA and protein expression of SPP1 were significantly higher in CRC tissues than that in adjacent non-cancerous tissues (P < 0.05). Overexpression of SPP1 closely associated with tumor invasion, metastasis and low survival in CRC. Moreover, siRNA-SPP1 repressed proliferation, cell cycle, colony formation, migration and tumor growth in vivo and promoted cell apoptosis in CRC cell lines. In addition, Protein expression of E-cadherin was obviously up-regulated and Vimentin was down-regulated in CRC cells after siRNA-SPP1 (P < 0.05). Conclusion SPP1 expression was significantly up-regulated in CRC. And SPP1 promoted the metastasis of CRC by activating EMT, which could be a potentially therapeutic target for patients with CRC. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that long noncoding RNAs (lncRNAs) are crucial regulators of the Epithelial-Mesenchymal-Transition (EMT). TGF-β signaling is a major inducer of EMT and can facilitate lung cancer metastasis. However, the role of lncRNAs in this process remains largely unknown. Here, we have identified 291 lncRNAs which were differentially expressed in lung cancer tissues compared with adjacent normal tissues. Of these, the gene body or vicinity of 19 transcripts were also bound by SMAD3. The expression of LINC01186 was significantly decreased in A549 cells treated with TGF-β1. Furthermore, LINC01186 was stably down-regulated in lung cancer tissues compared with normal tissues in TCGA data sets and another published lung cancer data sets. The bioinformatics analysis suggested that LINC01186 was associated with TGF-β and might participate in EMT process. Moreover, knocking-down LINC01186 promoted cell migration and invasion, whereas, LINC01186 overexpression prevented cell metastasis. Importantly, LINC01186 expression was regulated by SMAD3. And LINC01186 affected several EMT markers expression. These findings suggest that LINC01186, a mediator of TGF-β signaling, can play a significant role in the regulation of EMT and lung cancer cell migration and invasion. [ABSTRACT FROM AUTHOR]

The process by which prostate cancer cells non-randomly disseminate to the bone to form lethal metastases remains unknown. Metastasis is the ultimate consequence of the long-range dispersal of a cancer cell from the primary tumor to a distant secondary site. In order to metastasize, the actively emigrating cell must move. Movement ecology describes an individual's migration between habitats without the requirement of conscious decision-making. Specifically, this paradigm describes four interacting components that influence the dynamic process of metastasis: (1) the microenvironmental pressures exerted on the cancer cell, (2) how the individual cell reacts to these external pressures, (3) the phenotypic switch of a cell to gain the physical traits required for movement, and (4) the ability of the cancer cell to navigate to a specific site. A deeper understanding of each of these components will lead to the development of novel therapeutics targeted to interrupt previously unidentified steps of metastasis. [ABSTRACT FROM AUTHOR]

Exposure to the toxic herbicide paraquat (PQ) can lead to the active absorption and enrichment of alveolar epithelial cells, resulting in pulmonary fibrosis and respiratory failure. At present, no effective clinical treatment is available. Notably, however, patients infected with human acquired immunodeficiency virus (HIV) (with T lymphocyte deficiency) do not show pulmonary fibrosis after PQ poisoning, suggesting that T lymphocytes may be involved in the occurrence and pathological development of lung fibers following PQ exposure, although relevant studies remain limited. Here, we found that the degree of pulmonary fibrosis induced by intragastric administration of PQ in congenital immunodeficiency BALB/C (nu/nu) nude (T lymphocyte loss) mice was lower than that in normal mice. However, pulmonary fibrosis was aggravated after transplantation of BALB/C (nu/nu) T lymphocytes into congenital immunodeficiency mice. This study is the first to report on the involvement of T lymphocytes in the occurrence and pathological development of lung fibers induced by PQ exposure. Thus, T cells may be an important cellular target for the clinical treatment of pulmonary fibrosis caused by PQ. • We report on the involvement of T lymphocytes in the occurrence and pathological development of PQ-induced lung fibrosis. • PQ-induced pulmonary fibrosis was lower in T lymphocyte-deficient nude mice than in normal mice. • Pulmonary fibrosis was aggravated after transplantation of BALB/C (nu/nu) T lymphocytes into congenital immunodeficient mice. • T cells may be an important cellular target for the clinical treatment of pulmonary fibrosis caused by PQ poisoning. [ABSTRACT FROM AUTHOR]

• Piperlongumine (PL) ameliorates bile duct ligation (BDL) induced oxidative stress and inflammation. • Piperlongumine inhibited the hepatic stellate cell activation and ECM deposition in BDL-induced LF mice model. • Piperlongumine downregulated TGF-β/Smad and Epithelial mesenchymal transition in BDL-induced LF. Liver fibrosis (LF) is a progressive liver injury that may result in excessive accumulation of extracellular matrix (ECM). However, transforming growth factor-beta (TGF-β) and epithelial to mesenchymal transition (EMT) play a central role in the progression of LF through the activation of matrix producing hepatic stellate cells (HSCs). Piperlongumine (PL), an alkaloid extracted from Piper longum , has been reported to possess anti-inflammatory and antioxidant activities in various diseases but its hepatoprotective and antifibrotic effects have not been reported yet. Therefore, in the present study, we investigated the protective effect of PL in bile duct ligation (BDL)-induced LF model and explored the molecular mechanisms underlying its antifibrotic effect. BDL group displayed a significant degree of liver damage, oxidative-nitrosative stress, hepatic inflammation and collagen deposition in the liver while these pathological changes were effectively attenuated by treatment with PL. Furthermore, we found that PL treatment greatly inhibited HSCs activation and ECM deposition via downregulation of fibronectin, α-SMA, collagen1a, and collagen3a expression in the fibrotic livers. We further demonstrated that PL administration significantly inhibited TGF-β1/Smad and EMT signaling pathways. Our study demonstrated that PL exerted strong hepatoprotective and antifibrotic activities against BDL-induced LF and might be an effective therapeutic agent for the treatment of LF. [ABSTRACT FROM AUTHOR]

• MiRNA-451a attenuates inflammatory infiltration in asthmatic mouse pups. • MiRNA-451a suppresses asthmatic airway remodeling in vivo. • Cadherin 11 is identified as a novel target for miRNA-451a. • MiRNA-451a inhibits EMT by decreasing Cadherin 11 expression. Airway remodeling happens in childhood asthma, in parallel with, but not necessarily subsequent to, airway inflammation. The differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal-transition (EMT) is one of the mechanisms underlying airway remodeling. This study aimed at identifying novel molecules involved in pediatric asthma-associated airway remodeling. Asthma model was established by challenging C57BL/6 mouse pups with ovalbumin (OVA). We found that the expression of Cadherin 11 (CDH11), a type II cadherin, was increased by OVA treatments in the airway epithelium. Our earlier microarray data suggested miRNA-451a-5p (miRNA-451a) as a potential regulator of CDH11. In contrast to CDH11, miRNA-451a expression decreased in the asthmatic lung. MiRNA-451a was then packaged into a lentivirus vector and systematically given to the asthmatic pups. Our data indicated that OVA-induced infiltration of inflammatory cells, including eosnophils, neutrophils, macrophages and lymphocytes, was reduced by miRNA-451a over-expression. EMT was initiated in asthmatic mice as demonstrated by increased alpha-smooth muscle actin (α-SMA) positive cells present in airway epithelium, which was inhibited by miRNA-451a. CDH11 elevation in vivo was also inhibited by miRNA-451a. Dual-Luciferase analysis further showed CDH11 as a novel valid target of miRNA-451a. Additionally, in vitro, EMT was triggered in human 16HBE airway epithelial cells by pro-fibrotic transforming growth factor β (TGF-β). Corresponding to the anti-EMT effects observed in vivo , miRNA-451a also inhibited TGF-β-induced collagen deposition in cultured airway epithelial cells by targeting in CDH11. In summary, our study demonstrates that the deregulated miRNA-451a-CDH11 axis contributes to airway remodeling in childhood asthma. [ABSTRACT FROM AUTHOR]