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1.  Aberrant Expression of TIMP-2 and PBEF Genes in the Placentae of Cloned Mice Due to Epigenetic Reprogramming Error 
PLoS ONE  2016;11(11):e0166241.
Cloned mice derived from somatic or ES cells show placental overgrowth (placentomegaly) at term. We had previously analyzed cloned and normal mouse placentae by using two-dimensional gel electrophoresis and mass spectrometry to identify differential protein expression patterns. Cloned placentae showed upregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2), which is involved in extracellular matrix degradation and tissue remodeling, and downregulation of pre-B cell colony enhancing factor 1 (PBEF), which inhibits apoptosis and induces spontaneous labor. Here, we used Western blotting to further analyze the protein expression levels of TIMP-2 and PBEF in cloned placentae derived from cumulus cells, TSA-treated cumulus cells, intracytoplasmic sperm injection (ICSI), and natural mating (NM control). Cloned and TSA-treated cloned placentae had higher expression levels of TIMP-2 compared with NM control and ICSI-derived placentae, and there was a positive association between TIMP-2 expression and the placental weight of cloned mouse concepti. Conversely, PBEF protein expression was significantly lower in cloned and ICSI placentae compared to NM controls. To examine whether the observed differences were due to abnormal gene expression caused by faulty epigenetic reprogramming in clones, we investigated DNA methylation and histone modification in the promoter regions of the genes encoding TIMP-2 and PBEF. Sodium bisulfite sequencing did not reveal any difference in DNA methylation between cloned and NM control placentae. However, ChIP assays revealed that the level of H3-K9/K14 acetylation at the TIMP-2 locus was higher in cloned placentae than in NM controls, whereas acetylation of the PBEF promoter was lower in cloned and ICSI placenta versus NM controls. These results suggest that cloned placentae appear to suffer from failure of histone modification-based reprogramming in these (and potentially other) developmentally important genes, leading to aberrant expression of their protein products. These changes are likely to be involved in generating the abnormalities seen in cloned mouse placentae, including enlargement and/or a lack of proper placental function.
PMCID: PMC5113924  PMID: 27855185
2.  Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling 
Scientific Reports  2016;6:37085.
Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.
PMCID: PMC5111066  PMID: 27848972
4.  A Functional Polymorphism (rs10817938) in the XPA Promoter Region Is Associated with Poor Prognosis of Oral Squamous Cell Carcinoma in a Chinese Han Population 
PLoS ONE  2016;11(9):e0160801.
Single nucleotide polymorphisms of XPA gene have been studied in several cancers such as rs10817938, rs2808668. However, the role of XPA polymorphisms in patients with oral squamous cell carcinoma (OSCC) remains unclear. Thus, we analyzed the association of XPA polymorphisms with OSCC risk, clinicopathological characteristics and prognosis in the present study. TaqMan genotyping was used to evaluate the frequency of rs10817938, rs2808668 polymorphisms in OSCC patients. The prognostic significance of these polymorphisms was evaluated using Kaplan-Meier curves, Log-Rank analyses, and the Cox proportional hazard model. Luciferase reporter assay, RT-PCR and western blot were used to determine whether rs10817938 could influence transcription activity and XPA expression. The results showed that individuals carrying TC and CC genotypes had significantly greater risk of developing OSCC (OR = 1.42, 95% CI 1.04–1.93; OR = 2.75, 95% CI 1.32–5.71, respectively) when compared with wild-type TT genotype at rs10817938. OSCC patients with C allele at rs10817938 were more susceptible to lymph metastases, poor pathological differentiation and late TNM stage (OR = 1.67, 95% CI 1.17–2.37; OR = 1.64, 95% CI 1.18–2.28; OR = 1.54, 95% CI 1.11–2.14; respectively). A significant gene-environment interaction between smoking and CC genotype at rs10817938 was observed (COR = 3.60, 95% CI 1.20–10.9) and data also showed that OSCC patients with CC genotype and C allele had worse survival (p<0.001 for both). The T to C substitution at rs10817938 significantly decreased transcription activity of XPA gene, XPA mRNA and protein were also decreased in individuals with C allele at rs10817938. In addition, no significant association of rs2808668 polymorphism with OSCC risk, prognosis could be observed. In conclusion, the present study showed that XPA rs10817938 polymorphism is a functional SNP in vitro and in vivo and a biomarker for poor prognosis in OSCC patients.
PMCID: PMC5021261  PMID: 27622501
5.  Effects of early feeding on the host rumen transcriptome and bacterial diversity in lambs 
Scientific Reports  2016;6:32479.
Early consumption of starter feed promotes rumen development in lambs. We examined rumen development in lambs fed starter feed for 5 weeks using histological and biochemical analyses and by performing high-throughput sequencing in rumen tissues. Additionally, rumen contents of starter feed-fed lambs were compared to those of breast milk-fed controls. Our physiological and biochemical findings revealed that early starter consumption facilitated rumen development, changed the pattern of ruminal fermentation, and increased the amylase and carboxymethylcellulase activities of rumen micro-organisms. RNA-seq analysis revealed 225 differentially expressed genes between the rumens of breast milk- and starter feed-fed lambs. These DEGs were involved in many metabolic pathways, particularly lipid and carbohydrate metabolism, and included HMGCL and HMGCS2. Sequencing analysis of 16S rRNA genes revealed that ruminal bacterial communities were more diverse in breast milk-than in starter feed-fed lambs, and each group had a distinct microbiota. We conclude that early starter feeding is beneficial to rumen development and physiological function in lambs. The underlying mechanism may involve the stimulation of ruminal ketogenesis and butanoate metabolism via HMGCL and HMGCS2 combined with changes in the fermentation type induced by ruminal microbiota. Overall, this study provides insights into the molecular mechanisms of rumen development in sheep.
PMCID: PMC5006043  PMID: 27576848
6.  Robust succinic acid production from crude glycerol using engineered Yarrowia lipolytica 
Biotechnology for Biofuels  2016;9(1):179.
Integrating waste management with fuels and chemical production is considered to address the food waste problem and oil crisis. Approximately, 600 million tonnes crude glycerol is produced from the biodiesel industry annually, which is a top renewable feedstock for succinic acid production. To meet the increasing demand for succinic acid production, the development of more efficient and cost-effective production methods is urgently needed. Herein, we have proposed a new strategy for integration of both biodiesel and SA production in a biorefinery unit by construction of an aerobic yeast Yarrowia lipolytica with a deletion in the gene coding succinate dehydrogenase subunit 5.
Robust succinic acid production by an engineered yeast Y. lipolytica from crude glycerol without pre-treatment was demonstrated. Diversion of metabolic flow from tricarboxylic acid cycle led to the success in generating a succinic acid producer Y. lipolytica PGC01003. The fermentation media and conditions were optimized, which resulted in 43 g L−1 succinic acid production from crude glycerol. Using the fed-batch strategy in 2.5 L fermenter, up to 160 g L−1 SA was yielded, indicating the great industrial potential.
Inactivation of SDH5 in Y. lipolytica Po1f led to succinic acid accumulation and secretion significantly. To our best knowledge, this is the highest titer obtained in fermentation on succinic acid production. In addition, the performance of batch and fed-batch fermentation showed high tolerance and yield on biodiesel by-product crude glycerol. All these results indicated that PGC01003 is a promising microbial factorial cell for the highly efficient strategy solving the environmental problem in connection with the production of value-added product.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-016-0597-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5004273  PMID: 27579143
Yarrowia lipolytica; Metabolic engineering; Succinic acid; Crude glycerol; Fed-batch fermentation
7.  Proteins, Platelets, and Blood Coagulation at Biomaterial Interfaces 
Blood coagulation and platelet adhesion remain major impediments to the use of biomaterials in implantable medical devices. There is still significant controversy and question in the field regarding the role that surfaces play in this process. This manuscript addresses this topic area and reports on state of the art in the field. Particular emphasis is placed on the subject of surface engineering and surface measurements that allow for control and observation of surface-mediated biological responses in blood and test solutions. Appropriate use of surface texturing and chemical patterning methodologies allow for reduction of both blood coagulation and platelet adhesion, and new methods of surface interrogation at high resolution allow for measurement of the relevant biological factors.
PMCID: PMC5001692  PMID: 25448722
8.  Parity-time-symmetry enhanced optomechanically-induced-transparency 
Scientific Reports  2016;6:31095.
We propose and analyze a scheme to enhance optomechanically-induced-transparency (OMIT) based on parity-time-symmetric optomechanical system. Our results predict that an OMIT window which does not exist originally can appear in weak optomechanical coupling and driving system via coupling an auxiliary active cavity with optical gain. This phenomenon is quite different from these reported in previous works in which the gain is considered just to damage OMIT phenomenon even leads to electromagnetically induced absorption or inverted-OMIT. Such enhanced OMIT effects are ascribed to the additional gain which can increase photon number in cavity without reducing effective decay. We also discuss the scheme feasibility by analyzing recent experiment parameters. Our work provide a promising platform for the coherent manipulation and slow light operation, which has potential applications for quantum information processing and quantum optical device.
PMCID: PMC4973279  PMID: 27489193
9.  A novel hedgehog inhibitor iG2 suppresses tumorigenesis by impairing self‐renewal in human bladder cancer 
Cancer Medicine  2016;5(9):2579-2586.
Tumor recurrence is still a major challenge for clinical treatment of bladder cancer. Cumulative evidences indicate cancer stem cells (CSCs) contribute to drug resistance and leave a putative source for disease relapse. Identifying novel agents targeting CSCs may represent a new paradigm in the therapy of bladder cancer. Here, we separated a novel hedgehog (Hh) inhibitor, iG2, from streptomyces roseofulvus, which dramatically blocked the activation of Gli2 in bladder cancer cells. The iG2 strongly repressed the growth of cancer cells rather than the peri‐tumor stroma cells. Attenuated proliferation and enhanced apoptosis of tumor cells were observed upon iG2 stimulation. Furthermore, iG2 reduced the self‐renewal ability of bladder CSCs as well as the tumor formation. Collectively, iG2 is potentially used as a novel therapeutic agent for bladder cancer by targeting self‐renewal through inhibiting Hh pathway.
PMCID: PMC5055183  PMID: 27465044
Bladder cancer; Gli2; hedgehog; iG2
10.  Self-enhanced targeted delivery of a cell wall– and membrane-active antibiotics, daptomycin, against staphylococcal pneumonia 
Acta Pharmaceutica Sinica. B  2016;6(4):319-328.
Considering that some antibacterial agents can identify the outer structure of pathogens like cell wall and/or cell membrane, we explored a self-enhanced targeted delivery strategy by which a small amount of the antibiotic molecules were modified on the surface of carriers as targeting ligands of certain bacteria while more antibiotic molecules were loaded inside the carriers, and thus has the potential to improve the drug concentration at the infection site, enhance efficacy and reduce potential toxicity. In this study, a novel targeted delivery system against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was constructed with daptomycin, a lipopeptide antibiotic, which can bind to the cell wall of S. aureus via its hydrophobic tail. Daptomycin was conjugated with N-hydroxysuccinimidyl–polyethylene glycol–1,2-distearoyl-sn-glycero-3-phosphoethanolamine to synthesize a targeting compound (Dapt–PEG–DSPE) which could be anchored on the surface of liposomes, while additional daptomycin molecules were encapsulated inside the liposomes. These daptomycin-modified, daptomycin-loaded liposomes (DPD-L[D]) showed specific binding to MRSA as detected by flow cytometry and good targeting capabilities in vivo to MRSA-infected lungs in a pneumonia model. DPD-L[D] exhibited more favorable antibacterial efficacy against MRSA than conventional PEGylated liposomal daptomycin both in vitro and in vivo. Our study demonstrates that daptomycin-modified liposomes can enhance MRSA-targeted delivery of encapsulated antibiotic, suggesting a novel drug delivery approach for existing antimicrobial agents.
Graphical abstract
Daptomycin, as targeting molecules conjugated with NHS–PEG3400–DSPE, were modified on the surface of liposomes with more daptomycin molecules encapsulated. The specific targeting effect and promising therapeutic efficacy of the Dapt–PEG–DSPE-modified liposome against methicillin-resistant Staphylococcus aureus has been investigated, both in vitro and in vivo. This study may provide a novel drug delivery approach for treatment of staphylococcal infections.
PMCID: PMC4951592  PMID: 27471672
Daptomycin; Liposome; Targeted drug delivery; Lung infection; Staphylococcus aureus
11.  High-responsivity vertical-illumination Si/Ge uni-traveling-carrier photodiodes based on silicon-on-insulator substrate 
Scientific Reports  2016;6:27743.
Si/Ge uni-traveling carrier photodiodes exhibit higher output current when space-charge effect is overcome and the thermal effects is suppressed. High current is beneficial for increasing the dynamic range of various microwave photonic systems and simplifying high-bit-rate digital receivers in many applications. From the point of view of packaging, detectors with vertical-illumination configuration can be easily handled by pick-and-place tools and are a popular choice for making photo-receiver modules. However, vertical-illumination Si/Ge uni-traveling carrier (UTC) devices suffer from inter-constraint between high speed and high responsivity. Here, we report a high responsivity vertical-illumination Si/Ge UTC photodiode based on a silicon-on-insulator substrate. When the transmission of the monolayer anti-reflection coating was maximum, the maximum absorption efficiency of the devices was 1.45 times greater than the silicon substrate owing to constructive interference. The Si/Ge UTC photodiode had a dominant responsivity at 1550 nm of 0.18 A/W, a 50% improvement even with a 25% thinner Ge absorption layer.
PMCID: PMC4899750  PMID: 27279426
12.  Effects of Nutrients in Substrates of Different Grains on Aflatoxin B1 Production by Aspergillus flavus 
BioMed Research International  2016;2016:7232858.
The current study was to better understand the potential factors affecting aflatoxin B1 (AFB1) accumulation varies between different grains. The nutrient composition and contents of defatted substrates were determined; additionally, according to the nutrient content of the substrates, the effects of starch, soluble sugars, amino acids, and trace elements on AFB1 production and mycelial growth in Czapek-Dox medium were examined. These results verified that removal of lipids from ground substrates significantly reduced the substrate's potential for AFB1 production by Aspergillus flavus. Maltose, glucose, sucrose, arginine, glutamic acid, aspartic acid, and zinc significantly induced AFB1 production up to 1.7- to 26.6-fold. And stachyose more significantly promoted A. flavus growth than the other nutrients. Thus, this study demonstrated that, combined with the nutrients content of grains, in addition to lipids, sucrose, stachyose, glutamic acid, and zinc might play key roles in various grains that are differentially infected by A. flavus. Particularly, two new nutrients (arginine and stachyose) of the grains we found significantly stimulate AFB1 production and A. flavus growth, respectively. The results provide new concepts for antifungal methods to protect food and animal feed from AFB1 contamination.
PMCID: PMC4886045  PMID: 27294129
13.  Gold@silver bimetal nanoparticles/pyramidal silicon 3D substrate with high reproducibility for high-performance SERS 
Scientific Reports  2016;6:25243.
A novel and efficient surface enhanced Raman scattering (SERS) substrate has been presented based on Gold@silver/pyramidal silicon 3D substrate (Au@Ag/3D-Si). By combining the SERS activity of Ag, the chemical stability of Au and the large field enhancement of 3D-Si, the Au@Ag/3D-Si substrate possesses perfect sensitivity, homogeneity, reproducibility and chemical stability. Using R6G as probe molecule, the SERS results imply that the Au@Ag/3D-Si substrate is superior to the 3D-Si, Ag/3D-Si and Au/3D-Si substrate. We also confirmed these excellent behaviors in theory via a commercial COMSOL software. The corresponding experimental and theoretical results indicate that our proposed Au@Ag/3D-Si substrate is expected to develop new opportunities for label-free SERS detections in biological sensors, biomedical diagnostics and food safety.
PMCID: PMC4855179  PMID: 27143507
14.  Reduced cytosolic carboxypeptidase 6 (CCP6) level leads to accumulation of serum polyglutamylated DNAJC7 protein: A potential biomarker for renal cell carcinoma early detection 
Oncotarget  2016;7(16):22385-22396.
Renal cell carcinoma (RCC) is frequently diagnosed at advanced stages of disease, although early diagnosis has much favorable prognosis. This study assessed aberrant expression of cytosolic carboxypeptidase 6 (CCP6) leading to accumulation of serum polyglutamylated DNAJC7 as a biomarker for early RCC detection. A total of 835 RCCs, 143 chronic nephritis, 170 kidney stones and 415 health controls were collected for qRT-PCR, immunohistochemistry and Western blot analysis of CCP6 expression and mass spectrometry of DNAJC7 and polyglutamylated DNAJC7. The data showed that CCP6 expression was significantly decreased in 30 RCC tissues and that mass spectrometric and pull-down analysis identified DNAJC7 as a substrate of CCP6 and showed upregulated polyglutamylated-DNAJC7 (polyE-DNAJC7) in sera of RCC patients. The electrochemiluminescence immunoassay of large-scale serum samples from multi-institutes further confirmed the remarkable increase of polyE-DNAJC7 in 805 RCCs compared to that of 385 healthy controls (p < 0.001), 128 patients with chronic nephritis (p < 0.001), and 153 with kidney stone (p < 0.001). Serum level of DNAJC7-polyE protein was also associated with advanced RCC stage and grade in 805 patients. The data from the current study for the first time demonstrated increased serum polyglutamylated DNAJC7 as a potential biomarker for RCC early detection and association with advanced tumor stages and grade, which provides support of further polyglutamylation research in RCC.
PMCID: PMC5008367  PMID: 26993597
renal cell carcinoma; polyglutamylation; CCP6; polyE-DNAJC7; diagnosis biomarker
15.  Meeting report: Second Hydrogen Molecule Biomedical Symposium in Beijing, China 
Medical Gas Research  2016;6(1):57-58.
PMCID: PMC5075685  PMID: 27826424
16.  3D Spheroid Culture Enhances the Expression of Antifibrotic Factors in Human Adipose-Derived MSCs and Improves Their Therapeutic Effects on Hepatic Fibrosis 
Stem Cells International  2016;2016:4626073.
Three-dimensional (3D) cell culture has been reported to increase the therapeutic potentials of mesenchymal stem cells (MSCs). However, the action mechanisms of 3D MSCs vary greatly and are far from being thoroughly investigated. In this study, we aimed to investigate the therapeutic effects of 3D spheroids of human adipose-derived MSCs for hepatic fibrosis. Our results showed that 3D culture enhanced the expression of antifibrotic factors by MSCs, including insulin growth factor 1 (IGF-1), interleukin-6 (IL-6), and hepatocyte growth factor (HGF). In vitro studies indicated conditioned medium of 3D cultured MSCs protected hepatocytes from cell injury and apoptosis more effectively compared with 2D cultured cells. More importantly, when transplanted into model mice with hepatic fibrosis, 3D spheroids of MSCs were more beneficial in ameliorating hepatic fibrosis and improving liver function than 2D cultured cells. Therefore, the 3D culture strategy improved the therapeutic effects of MSCs and might be promising for treatment of hepatic fibrosis.
PMCID: PMC4789048  PMID: 27022400
17.  PS341 inhibits hepatocellular and colorectal cancer cells through the FOXO3/CTNNB1 signaling pathway 
Scientific Reports  2016;6:22090.
Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future.
PMCID: PMC4768146  PMID: 26915315
18.  Demethylation of c-MYB binding site mediates upregulation of Bdnf IV in cocaine-conditioned place preference 
Scientific Reports  2016;6:22087.
Abnormal BDNF signaling contributes to the structural and behavioral plasticity induced by drugs of abuse. However, the mechanisms regulating expression of Bdnf in drug addiction remain elusive. In the present study, using the conditioned place preference (CPP) model, we showed that expression of Bdnf IV is upregulated in the nucleus accumbens (NAc) of conditioned animals while Bdnf I is upregulated in cocaine-treated mice irrespective of conditioning. The methylation level of a putative c-MYB binding site in the promoter region of Bdnf IV was significantly decreased in the NAc under cocaine CPP conditioning but remained unchanged without conditioning, concurrently with increased binding of c-MYB to this site. Exon IV promoter/luciferase reporter assays revealed that transactivation of Bdnf by c-MYB was blocked by methylation of this c-MYB binding site. Administration of methionine, a precursor of SAM, inhibited cocaine CPP, reversed demethylation of c-MYB binding site and induction of Bdnf IV expression by cocaine CPP. Our results imply that Bdnf IV demethylation at c-MYB binding site is involved in cocaine-triggered seeking behavior, whereas Bdnf I responds to the immediate pharmacological effects of cocaine.
PMCID: PMC4766519  PMID: 26912258
19.  Dilute Magnetic Semiconductor and Half-Metal Behaviors in 3d Transition-Metal Doped Black and Blue Phosphorenes: A First-Principles Study 
We present first-principles density-functional calculations for the structural, electronic, and magnetic properties of substitutional 3d transition metal (TM) impurities in two-dimensional black and blue phosphorenes. We find that the magnetic properties of such substitutional impurities can be understood in terms of a simple model based on the Hund’s rule. The TM-doped black phosphorenes with Ti, V, Cr, Mn, Fe, and Ni impurities show dilute magnetic semiconductor (DMS) properties while those with Sc and Co impurities show nonmagnetic properties. On the other hand, the TM-doped blue phosphorenes with V, Cr, Mn, and Fe impurities show DMS properties, with Ni impurity showing half-metal properties, whereas Sc- and Co-doped systems show nonmagnetic properties. We identify two different regimes depending on the occupation of the hybridized electronic states of TM and phosphorous atoms: (i) bonding states are completely empty or filled for Sc- and Co-doped black and blue phosphorenes, leading to nonmagnetic; (ii) non-bonding d states are partially occupied for Ti-, V-, Cr-, Mn-, Fe- and Ni-doped black and blue phosphorenes, giving rise to large and localized spin moments. These results provide a new route for the potential applications of dilute magnetic semiconductor and half-metal in spintronic devices by employing black and blue phosphorenes.
PACS numbers: 73.22.-f, 75.50.Pp, 75.75. + a
PMCID: PMC4747940  PMID: 26858159
Dilute magnetic semiconductor; Half-metal; Transition metal doping; Phosphorene
20.  Novel variants in MLL confer to bladder cancer recurrence identified by whole-exome sequencing 
Oncotarget  2015;7(3):2629-2645.
Bladder cancer (BC) is distinguished by high rate of recurrence after surgery, but the underlying mechanisms remain poorly understood. Here we performed the whole-exome sequencing of 37 BC individuals including 20 primary and 17 recurrent samples in which the primary and recurrent samples were not from the same patient. We uncovered that MLL, EP400, PRDM2, ANK3 and CHD5 exclusively altered in recurrent BCs. Specifically, the recurrent BCs and bladder cancer cells with MLL mutation displayed increased histone H3 tri-methyl K4 (H3K4me3) modification in tissue and cell levels and showed enhanced expression of GATA4 and ETS1 downstream. What's more, MLL mutated bladder cancer cells obtained with CRISPR/Cas9 showed increased ability of drug-resistance to epirubicin (a chemotherapy drug for bladder cancer) than wild type cells. Additionally, the BC patients with high expression of GATA4 and ETS1 significantly displayed shorter lifespan than patients with low expression. Our study provided an overview of the genetic basis of recrudescent bladder cancer and discovered that genetic alterations of MLL were involved in BC relapse. The increased modification of H3K4me3 and expression of GATA4 and ETS1 would be the promising targets for the diagnosis and therapy of relapsed bladder cancer.
PMCID: PMC4823060  PMID: 26625313
bladder cancer; tumor recurrence; MLL; drug-resistance; whole-exome sequencing
21.  MicroRNA-497 inhibits tumor growth and increases chemosensitivity to 5-fluorouracil treatment by targeting KSR1 
Oncotarget  2015;7(3):2660-2671.
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-497 (miR-497) has been observed in CRC tissues. In this study, we found that miR-497 expression levels were downregulated in human CRC specimens compared to the adjacent normal tissues. MiR-497 expression levels were strongly correlated with clinical stages and lymph node metastases. Furthermore, kinase suppressor of ras 1 (KSR1), a known oncogene, was a direct target of miR-497, and KSR1 expression levels were inversely correlated with miR-497 expression levels in human CRC specimens. Overexpression of miR-497 inhibited cell proliferation, migration, invasion and increased chemosensitivity to 5-fluorouracil treatment, whereas forced expression of KSR1 had the opposite effect. Taken together, these results revealed that lower miR-497 levels in human CRC tissues induce KSR1 expression which is associated with CRC cancer occurrence, advanced stages, metastasis and chemoresistance. Lower miR-497 levels may be a potential biomarker for CRC advanced stages and treatment response.
PMCID: PMC4823062  PMID: 26673620
miR-497; colorectal cancer; KSR1; tumorigenesis; chemosensitivity
22.  An epigenetic biomarker combination of PCDH17 and POU4F2 detects bladder cancer accurately by methylation analyses of urine sediment DNA in Han Chinese 
Oncotarget  2015;7(3):2754-2764.
To develop a routine and effectual procedure of detecting bladder cancer (BlCa), an optimized combination of epigenetic biomarkers that work synergistically with high sensitivity and specificity is necessary. In this study, methylation levels of seven biomarkers (EOMES, GDF15, NID2, PCDH17, POU4F2, TCF21, and ZNF154) in 148 individuals—which including 58 urothelial cell carcinoma (UCC) patients, 20 infected urinary calculi (IUC) patients, 20 kidney cancer (KC) patients,20 prostate cancer (PC) patients, and 30 healthy volunteers (HV)—were quantified by qMSP using the urine sediment DNA. Receiver operating characteristic (ROC) curves were generated for each biomarker. The combining predictors of possible combinations were calculated through logistic regression model. Subsequently, ROC curves of the three best performing combinations were constructed. Then, we validated the three best performing combinations and POU4F2 in another 72 UCC, 21 IUC, 26 KC and 22 PC, and 23 HV urine samples. The combination of POU4F2/PCDH17 has yielded the highest sensitivity and specificity of 90.00% and 93.96% in all the 312 individuals, showing the capability of detecting BlCa effectively among pathologically varied sample groups.
PMCID: PMC4823069  PMID: 26700620
bladder cancer; epigenetics; methylation; biomarkers; qMSP
23.  Dynamics of the Transcriptome during Human Spermatogenesis: Predicting the Potential Key Genes Regulating Male Gametes Generation 
Scientific Reports  2016;6:19069.
Many infertile men are the victims of spermatogenesis disorder. However, conventional clinical test could not provide efficient information on the causes of spermatogenesis disorder and guide the doctor how to treat it. More effective diagnosis and treating methods could be developed if the key genes that regulate spermatogenesis were determined. Many works have been done on animal models, while there are few works on human beings due to the limited sample resources. In current work, testis tissues were obtained from 27 patients with obstructive azoospermia via surgery. The combination of Fluorescence Activated Cell Sorting and Magnetic Activated Cell Sorting was chosen as the efficient method to sort typical germ cells during spermatogenesis. RNA Sequencing was carried out to screen the change of transcriptomic profile of the germ cells during spermatogenesis. Differential expressed genes were clustered according to their expression patterns. Gene Ontology annotation, pathway analysis, and Gene Set Enrichment Analysis were carried out on genes with specific expression patterns and the potential key genes such as HOXs, JUN, SP1, and TCF3 which were involved in the regulation of spermatogenesis, with the potential value serve as molecular tools for clinical purpose, were predicted.
PMCID: PMC4750114  PMID: 26753906
24.  Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals 
Oncotarget  2015;7(2):1341-1353.
Early studies indicated that mast cells in prostate tumor microenvironment might influence prostate cancer (PCa) progression. Their impacts to PCa therapy, however, remained unclear. Here we found PCa could recruit more mast cells than normal prostate epithelial cells then alter PCa chemotherapy and radiotherapy sensitivity, leading to PCa more resistant to these therapies. Mechanism dissection revealed that infiltrated mast cells could increase p21 expression via modulation of p38/p53 signals, and interrupting p38-p53 signals via siRNAs of p53 or p21 could reverse mast cell-induced docetaxel chemotherapy resistance of PCa. Furthermore, recruited mast cells could also increase the phosphorylation of ATM at ser-1981 site, and inhibition of ATM activity could reverse mast cell-induced radiotherapy resistance. The in vivo mouse model with xenografted PCa C4-2 cells co-cultured with mast cells also confirmed that mast cells could increase PCa chemotherapy resistance via activating p38/p53/p21 signaling. Together, our results provide a new mechanism showing infiltrated mast cells could alter PCa chemotherapy and radiotherapy sensitivity via modulating the p38/p53/p21 signaling and phosphorylation of ATM. Targeting this newly identified signaling may help us better suppress PCa chemotherapy and radiotherapy resistance.
PMCID: PMC4811464  PMID: 26625310
prostate cancer; docetaxel; radiotherapy; p38; ATM
25.  Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia 
Cancer Cell  2016;29(1):32-48.
Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia.
Graphical Abstract
•PRMT1 recruitment is necessary but not sufficient for transformation by AML fusions•MLL fusions and MOZ-TIF2 recruit KDM4C to remove H3K9me3 repressive marks•KDM4C and PRMT1 regulate aberrant epigenetic and transcriptional networks in AML•Molecular or pharmacology inhibition of KDM4C or PRMT1 suppresses AML
Cheung et al. show that PRMT1 is necessary but insufficient for acute myeloid leukemia induction by chimeric transcription factors, which also recruit KDM4C for epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation abilities of the MOZ-TIF2 and MLL fusions.
PMCID: PMC4712026  PMID: 26766589
histone methyltransferase; histone demethylase; leukemia epigenetics; KMT; PMT; KDM; PRMT1; KDM4C; MLL fusions; MOZ-TIF2; acute myeloid leukemia; AML

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