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Objective: To investigate the anti-liver cancer effects and aspartic acid (Asp)-related action mechanism of Euphorbia fischeriana Steud. (Lang Du, LD). Methods: The mice model of liver cancer was established by injection of H22 cells. After 5 days, mice were randomly divided into model group, sorafenib group (20 mg/kg), LD high-dose (LDH, 1.36 g/kg) group, LD medium-dose (LDM, 0.68 g/kg) group, and LD low-dose (LDL, 0.34 g/kg) group, 10 mice each group. Drugs were intragastrically administered to the mice once daily for 10 days, respectively. Body weight, tumor size and tumor weight were recorded. Hepatic index was calculated. Pathological changes of liver cancer tissues were evaluated by hematoxylin and eosin staining and TUNEL staining. Liquid chromatography-mass spectrometer was used to analyze different metabolites between the model and LDH groups. Results: After LD treatment, tumor weight, tumor size and hepatic index were reduced compared with the model group. Necrocytosis and karyorrhexis of tumor cells were found. Moreover, 61 differential metabolites (18 up-regulated, 43 down-regulated) were affirmed and 20 pathways of KEGG (P<0.05) were gotten. In addition, Bel-7402, HepG2 and H22 cell viabilities were significantly increased after adding Asp into the medium. And then, the cell proliferation effect induced by Asp was ameliorated by LD. Conclusion: The anti-liver cancer efficacy of LD extract was validated in H22 mice model, and inhibition of Asp level might be the underlying mechanism. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is highly malignant. The migration, invasion, and chemoresistance contribute to poor prognosis of osteosarcoma. Research reported that endogenous bornavirus-like nucleoprotein 3 pseudogene (EBLN3P) promotes the progression of osteosarcoma. Methods: In this study, the expression of EBLN3P in osteosarcoma tissue with different methotrexate (MTX) treatment responses was measured. Osteosarcoma cell lines with MTX resistance were constructed, and bioinformatic analysis was performed to explore the potential involved targets and pathways. Results: Higher EBLN3P was associated with MTX resistance. Downregulation of LncEBLN3P decreased the MTX resistance of osteosarcoma cells by sponging miR-200a-3p, an important microRNA that affects epithelial-mesenchymal transition (EMT). The decreased miR-200a-3p resulted in the upregulation of its target gene O-GlcNAc transferase (OGT), which in turn promoted the EMT process of osteosarcoma cells. Further analysis confirmed that the loss of OGT and over-expression of miR-200a-3p could partly abolish the MTX resistance induced by LncEBLN3P. Conclusion: LncEBLN3P is upregulated in osteosarcoma and increases the MTX resistance in osteosarcoma cells through downregulating miR-200a-3p, which in turn promoted the EMT process of osteosarcoma cells by increasing the OGT. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma (LAC) is a common malignancy worldwide. Emerging findings indicated that circular RNAs possess complex capacities of gene modulation in tumorigenesis and metastasis. Nevertheless, the role of circular RNA in LAC is still largely unknown. Materials and Methods: The level of circular RNA cMras (circ_cMras), alpha-beta hydrolase domain 5 (ABHD5), and adipose triglyceride lipase (ATGL) was determined by quantitative real-time polymerase chain reaction assay. Protein levels of ABHD5, ATGL, p53, p65, and phospho-p65 (p-p65) were examined by Western blot. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to detect cell proliferation in vitro. Cell apoptosis was estimated using flow cytometry. Transwell assay was used to measure cell migration and invasion in A549 and HCC827 cells. Finally, the role of circ_cMras was explored using xenograft tumor model. Results: Low levels of circ_cMras, ABHD5, and ATGL were observed in LAC tissues and cells. Upregulation of circ_cMras could hamper tumor aggression in vitro and in vivo, exhibiting as the inhibition of cell proliferation, migration, invasion, and promotion of cell apoptosis, as well as the inhibition on tumor growth in vivo. Moreover, ABHD5 deletion could overturn the effects of circ_cMras overexpression on cell behaviors in LAC cells. Furthermore, the inhibiting effects of ABHD5 on cell aggression were reversed by ATGL deficiency in vitro. Mechanically, circ_cMras/ABHD5/ATGL axis exerted its role through NF-κB signaling pathway in LAC cells. Conclusion: Circ_cMras exerted its function through ABHD5/ATGL axis using NF-κB signaling pathway in LAC, which might provide a novel insight for the diagnosis and prognosis of LAC. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear.Methods: BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate.Results: tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown.Conclusions: The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been developed as a promising treatment modality for laryngeal cancer. 9-Hydroxypheophorbide α (9-HPbD), a novel chlorophyll-derived photosensitizer, has a longer absorption wavelength, which increases the penetration of light to malignant tissues. Carboplatin (CBDCA), a second-generation platinum derivative, also has gained more popularity for the treatment of laryngeal cancer. Our previous studies have elucidated that 9-HPbD-PDT could inhibit the migration and invasion of HEp-2 cells. The objective of this study is to investigate the change of migration and invasion of HEp-2 cells induced by a combined modality of CBDCA and 9-HPbD-PDT in vitro. A wound healing assay, cell migration assay and Matrigel invasion assay were used to evaluate the cellular migration and invasion. Reactive oxygen species (ROS) and Western blots for epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin), MMPs (MMP-2 and MMP-9) and MEK/ERK signalling pathway were performed to investigate the possible mechanisms that may be involved. We observed that CBDCA and 9-HPbD-PDT administration synergistically inhibited the migration and invasion of HEp-2 cells. Moreover, the combined modality cooperatively repressed the EMT process and down-regulated expressions of MMP-2 and MMP-9 via ROS-mediated inhibition of phosphorylation in the MEK/ERK signalling pathway. Our results suggested that the combination of CBDCA and 9-HPbD-PDT might be a promising therapeutic strategy for laryngeal cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment.Methods: Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines.Results: Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP-dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab.Conclusions: Several studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression. [ABSTRACT FROM AUTHOR]

Introduction: To explore muscarinic receptor signaling in 4 bladder cancer cell lines, bladder urothelial cells (BUC) have been shown to release and respond to various putative neurotransmitters. Methods: Reverse transcription-polymerase chain reaction was used to detect the presence of m1-m5 transcripts in the J82, RT4, T24, and 5637 lines of cancer BUC. Immunofluorescence was used to detect expression of m3 protein. Cancer and normal BUC were stimulated with carbachol (100 μM), a muscarinic agonist. Carbachol-evoked changes in intracellular calcium ([Ca2+]i) levels were measured using fura-2 ratiometric microfluorimetry. Transfection of J82 cells with m3 plasmid was performed, and changes in carbachol-evoked [Ca2+]i were re-examined. Results: None of the cancer cell lines expressed m3 transcripts, unlike normal BUC, which expressed m3. None of the 4 bladder cancer cell lines responded to carbachol. However, 47% of normal BUC responded to carbachol. The m3-transfected J82 cells expressed both m3 transcript and protein. Thirteen percent of m3-transfected J82 cells responded to carbachol. Conclusions: This is the first description of altered muscarinic signaling in cancer BUC. Unlike normal BUC, bladder urothelial cancer cells neither expressed m3 transcript nor responded to carbachol, as measured by changes in [Ca2+]i. We could partially reverse this defect in one of the cancer cell lines, J82, by transfecting these cells with the m3 plasmid. Although the effects of muscarinic receptor signaling on urothelial cell are unknown, this signaling pathway may play a role in urothelial cell adhesion similar to that in keratinocytes. [Copyright &y& Elsevier]

Maimendong and Qianjinweijing Tang (Jin formula), a classic Chinese formula, can enhance therapeutic efficacy and reduce adverse effects in patients with lung cancer. To evaluate the anti-lung cancer effect of Jin formula in vivo and in vitro, and to explore the role of microRNA (miRNA) in the anti-lung cancer mechanism of Jin formula. Cell survival was determined via a colorimetric method, and apoptotic condition was revealed by flow cytometric analysis. Cell migration and invasion were detected by scratch and transwell assays. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay was applied to measure the changes of miRNA expression. Pathological histology of lung tissues were assessed by hematoxylin-eosin (HE) staining. Immunohistochemistry and immunoblotting were used to detect the expression of marker proteins of Wnt/β-catenin pathway. The relationship between miR-149-3p and MYC associated zinc finger protein (MAZ) was verified using a dual-luciferase reporter assay system. Our findings demonstrated the anti-cancer effect of Jin formula in vitro, and revealed that Jin formula could suppress the proliferation, migration and invasion of human lung cancer A549 and H1299 cells. We also confirmed the capability of Jin formula to reduce tumor growth through the up-regulation of miR-149-3p and down-regulation of Wnt/β-catenin signaling in animal models. qRT-PCR analysis in vitro further confirmed a dose-dependent increase of miR-149-3p by treatment with Jin formula. Functional studies identified MAZ as a downstream target of miR-149-3p. Overexpression of miR-149-3p inhibited cell proliferation, migration, invasion and induced apoptosis in A549 and H1299 cells, similar to our findings on the effects of Jin formula treatment. In contrast, inhibiting the expression of miR-149-3p reversed the anti-cancer effects of Jin formula. Additionally, we revealed that miR-149-3p was involved in the anti-cancer effects of Jin formula, at least in part, by inhibiting MAZ expression and the Wnt/β-catenin signaling cascade. Our study illustrated that Jin formula suppressed the development of lung cancer and the mechanism may be associated with the miR-149-3p/MAZ/Wnt/β-catenin axis. Image 1 • Jin formula suppresses tumor growth in the mouse model of orthotopic Lewis lung cancer. • Jin formula could suppress lung cancer cell proliferation, migration, and invasion in vitro. • Jin formula suppresses lung cancer by up-regulation of miR-149-3p and down-regulation of Wnt/β-catenin signaling. • MYC associated zinc finger protein (MAZ) is identified as a direct target of miR-149-3p. [ABSTRACT FROM AUTHOR]