Graphical Abstract Highlights d Tumorigenesis depends on functional OXPHOS d OXPHOS-derived ATP is not required for tumor formation d DHODH-driven pyrimidine biosynthesis requires CoQ redoxcycling d CoQ redox-cycling via OXPHOS drives tumorigenesis through pyrimidine biosynthesis

Galectin-1 is implicated in making tumor cells immune privileged, in part by regulating the survival of infiltrating T cells. Galectin-1 is strongly expressed in activated pancreatic stellate cells (PSCs); however, whether this is linked to tumor cell immune escape in pancreatic cancer is unknown. Galectin-1 was knocked down in PSCs isolated from pancreatic tissues using small interfering RNA (siRNA), or overexpressed using recombinant lentiviruses, and the PSCs were cocultured with T cells. CD31 , CD4 1 and CD8 1 T cell apoptosis was detected by flow cytometry; T cell IL-2, IL-4, IL-5 and INF-c production levels were quantified using ELISA. Immunohistochemical analysis showed increased numbers of PSCs expressed Galectin-1 (p < 0.01) and pancreatic cancers had increased CD3 1 T cell densities (p < 0.01) compared to normal pancreas or chronic pancreatitis samples. In coculture experiments, PSCs that overexpressed Galectin-1 induced apoptosis of CD4 1 T cells (p < 0.01) and 05). Supernatants from T cells cocultured with PSCs that overexpressedGalectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-c, p < 0.01). However, the knockdown of PSC Galectin-1 had the opposite effect on Th1 and Th2 cytokine secretion. Our study suggests that the overexpression of Galectin-1 in PSCs induced T cell apoptosis and Th2 cytokine secretion, which may regulate PSC-dependent immunoprivilege in the pancreatic cancer microenvironment. Galectin-1 may provide a novel candidate target for pancreatic cancer immunotherapy.Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, which is resistant to currently available systemic therapies. PDAC has one of the worst prognoses of all human cancers with incidence rates nearly equal to mortality rates. 1 There is evidence that excessive desmoplasia play a crucial role in the aggressive behavior of pancreatic cancer, 2 which impedes effective systemic treatments on a molecular level. Pancreatic stellate cells (PSCs) are stellate-shaped mesenchymal pancreatic cells, which have been identified as important regulators of desmoplasia in PDAC. 3In their quiescent state, PSCs can be identified by the presence of vitamin A-containing lipid droplets in the cytoplasm and the expression of desmin and glial-fibrillary-acidic protein (GFAP). 4 In response to pancreatic damage or stress, PSC are transformed into an activated myofibroblast-like phenotype. Activated PSCs express a-smooth muscle actin (a-SMA), and synthesize excessive amounts of ECM proteins, including Collagen I and III, fibronectin and matrix-degrading enzymes such as MMPs.5-7 Activated PSCs have a variety of cell functions and can promote the proliferation, migration, invasion and metastasis of pancreatic cancer cells; 1,8,9 however, the factors that PSCs secrete to advance pancreatic cancer progression remain largely unknown.Galectin-1, a member of the galectin family of b-galactosidebinding proteins, is a homodimer of 14-kDa subunits pos...

Hepatocellular carcinoma (HCC) ranks third in cancer-related mortality due to late diagnosis and poor treatment options. Autophagy is a lysosome-mediated protein and organelle degradation process which is characterized by the formation of double-membrane vesicles, known as autophagosomes. Increasing evidence reveals that autophagy functions as a survival mechanism in liver cancer cells against drug-induced apoptosis. In this study, we found that autophagy was suppressed by miR-101 in the HCC cell line HepG2. miR-101 inhibited autophagy via targets including RAB5A, STMN1 and ATG4D. Moreover, miR-101 enhanced apoptosis induced by cisplatin in the HepG2 cell line. The possible mechanism of this effect may be through inhibition of autophagy. Our results indicate a novel and critical role for miR-101 and autophagy in the chemoresistance of cisplatin in HCC. We propose that gene therapy targeting miR-101/autophagy should be investigated further as a potential alternative therapeutic strategy for HCC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal malignant tumors in humans with very poor prognosis, due to a variety of causes including the insidious onset, absence of efficient screening methods for early detection, low rate of surgical resection at the time of clinical presentation and chemoradiation resistance. 1 Although scholars have been committed during the last three decades to studying genetic and/or epigenetic molecular changes of PDAC cells and chemotherapy with a combination of cytotoxic drugs have been implemented, the survival of patients with PDAC has not yet significantly improved.2,3 Until recently, an encouraging FOLFIRINOX scheme was reported to provide a statistically and clinically significant benefit over single-agent gemcitabine in patients with advanced PDAC but Key words: pancreatic ductal adenocarcinoma, pancreatic stellate cells, tumor microenvironment Abbreviations: ADMR: adrenomedullin receptor; AM: adrenomedullin; ATRA: all-trans retinoic acid; CTGF: connective tissue growth factor; DCs: dendritic cells; ECM: extracellular matrix; EGF: epidermal growth factor; EMMPRIN: extracellular matrix metalloproteinase inducer; EMT: epithelial-mesenchymal transition; ET-1: endothelin-1; FGF: fibroblast-growth-factor; GFAP: glial-fibrillary-acidic protein; HGF: hepatocyte growth factor; HPDE: human pancreatic duct epithelial; HSCs: hepatic stellate cells; HUVEC: endothelial cells; IGF-1: insulin-like growth factor-1; IL: interleukin; MMPs: matrix metalloproteinases; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; PAEE: palmitic acid ethyl ester; PCLMs: pancreatic cancer liver metastases; PDAC: pancreatic ductal adenocarcinoma; PDGF: platelet-derived growth factor; PEDF: pigment epithelium-derived factor; PK: prokineticin; PKR: prokineticin receptor; PSCs: pancreatic stellate cells; ROS: oxygen species; Runx-2: Runt-related transcription factor-2; SDF-1: stromal cell-derived factor-1; sFRP4: secreted frizzled-related protein 4; SMO: smoothened; a-SMA: a-smooth muscle actin; SPARC: secreted protein acidic and rich in cysteine; TFF1: trefoil factor 1; TGF-b: transforming gr...

Background:Expression of ABCG2 is normally absent or low in the pancreas, but high in human pancreatic cancer cells. The mechanism by which ABCG2 is altered in human cancers remains unknown.Methods:We investigated ABCG2 expression in four pancreatic cancer cell lines, and used three microRNA (miRNA) target prediction programmes, and information from the existing literature to predict and identify hsa-miR-520h as an miRNA that targets ABCG2. The function of this miRNA was investigated by transient transfection of the pancreatic cancer cell line PANC-1 with oligonucleotides that mimic hsa-miR-520h.Results:Results showed that both mRNA and protein levels of ABCG2 were reduced, indicating that it was a target of hsa-miR-520h. Introduction of hsa-miR-520h mimics into PANC-1 cells also resulted in inhibition of cell migration and invasion, and reduction of side population cells. Cell proliferation, cell cycle progression and apoptosis were not affected.Conclusions:We propose that the effects of hsa-miR-520h may be, at least in part, caused by its regulation of ABCG2. Thus, our findings provide a new insight into the function of miRNA in the regulation of ABCG2 expression in pancreatic cancer. Gene therapy using miRNA mimics may therefore be useful as a pancreatic cancer therapy.

Background: Accumulating literatures have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Urothelial cancer associated 1 (UCA1) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the molecular mechanism of UCA1 in renal cancer is still needed to further explore. Methods: The relative expression level of UCA1 was determined by Real-Time qPCR in a total of 88 patients with urothelial renal cancer and in different renal cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of UCA1 and miR-182-5p on renal cancer cell proliferation, migration, apoptosis and tumorigenicity. Comprehensive transcriptional analysis, dual-luciferase reporter assay and western blot etc. were performed to explore the molecular mechanisms underlying the functions of UCA1. Results: In this study, we found that UCA1 was significantly up-regulated in renal cancer. Moreover, increased UCA1 expression was positively correlated with differentiation and advanced TNM stage. Further experiments demonstrated that knockdown of UCA1 inhibited malignant phenotypes and Notch signal path of renal cancer cells, and miR-182-5p was reverse function as UCA1. UCA1 functioned as a miRNA sponge to positively regulate the expression of Delta-like ligand 4(DLL4) through sponging miR-182-5p and subsequently promoted malignant phenotypes of renal cancer cells, thus UCA1 playing an oncogenic role and miR-182-5p as an antioncogenic one in renal cancer pathogenesis. Conclusion: UCA1-miR-182-5p-DLL4 axis is involved in proliferation and progression of renal cancer. Thus, this study demonstrated that UCA1 plays a critical regulatory role in renal cancer cell and UCA1 may serve as a potential diagnostic biomarker and therapeutic target of renal cancer.

the volume expansion of electrodes, poor impact resistance, high potential for gas production, easy corrosion of aluminum foil and oxidation of copper foil. Liquid electrolytes show poor compatibility with electrodes in some potential high-energy batteries. Other drawbacks of liquid electrolytes derive from the unstable longterm life cycle and poor performance in restraining the growth of lithium dendrites in LIBs, especially when lithium metal is used as an anode. Some potential cathodes, including transition metals, polysulfides in sulfur electrodes, and organic electrodes, tend to dissolve in liquid electrolytes, hindering the development of next-generation batteries. [1][2][3][4] Solid polymer electrolytes (SPEs) are considered a prospective approach to solving the above problems. [4] An alkali metal salt and polymer host, which plays a role as a solid matrix, form SPEs without additional organic liquid solvents. [5] Several outstanding advantages have been produced by SPEs over conventional liquid electrolytes such as low flammability, low electrolytes leakage, safety, high flexibility, and high stability between the electrode and electrolytes, etc. [6] Furthermore, SPEs possess excellent advantages over inorganic solid electrolytes, such as flexibility, light weight, ease of processing, suitability for large-scale manufacturing, and strong adhesion to electrodes. More importantly, the flexibility of polymer structural design and the suitability of various lithium salts and functional fillers provide many options for SPE design. [6][7][8] Among SPEs, high molecular weight polyethylene oxide (PEO)-based SPEs are commonly considered to be the finest candidates for polymer matrices due to their solvation power and complexation ability. [9] Wright et al. discovered that PEO can be used as a conductive matrix for alkali metal ions. [10,11] In 1983, Armand et al. reported the first PEO/Li + dry SPE system for LIBs (≈10 −4 S cm −1 at 40-60 °C). [12] Their pioneering work constituted a major breakthrough in the research on solid-state lithium-ion batteries (SSLIBs). Since then, polymers have attracted widespread attention as electrolytes for rechargeable SSLIBs. [8,[12][13][14] In LIBs, the SPE acts as an ion-conducting medium operating between the anode and cathode, and it plays the role of an electronically insulating separator. SPEs that meet these criteria should have six characteristics. [5][6][7][8] i) High ionic conductivity (σ) and high Li + transference numbers (t Li+ ). The polymers of SPEs must be able to dissolve sufficient amounts of lithium Solid-state polymer electrolytes (SPEs) for high electrochemical performance lithium-ion batteries have received considerable attention due to their unique characteristics; they are not prone to leakage, and they exhibit low flammability, excellent processability, good flexibility, high safety levels, and superior thermal stability. However, current SPEs are far from commercialization, mainly due to the low ionic conductivity, low Li + transference number (t Li+ ), ...

Altered metabolism is a critical part of cancer cell properties, but real-time monitoring of metabolomic profiles has been hampered by the lack of a facile method. Here, we propose real-time metabolomic monitoring of live cancer cells using (13) C6 -glucose and heteronuclear two-dimensional (2D) NMR. The method allowed for metabolomic differentiation between cancer and normal cells on the basis of time-dependent changes in metabolite concentrations. Cancer cells were found to have large in- and out-flux of pyruvate as well as increased net production of alanine and acetate. The method also enabled evaluation of the metabolic effects of galloflavin whose anticancer effects have been attributed to its specific inhibition of lactate dehydrogenase. Our approach revealed previously unknown functional targets of galloflavin, which were further confirmed at the protein levels. Our method is readily applicable to the study of metabolic alterations in other cellular disease model systems.