We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated ...proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.
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•Proteomic subgroups stratify patient survival and allocate specific treatments•Alterations of the liver-specific proteome and metabolism in HCC are identified•Multi-omics profile of key signaling and metabolic pathways in HCC is depicted•CTNNB1 mutation-associated ALDOA phosphorylation promotes HCC cell proliferation
Proteogenomic characterization of HBV-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues identifies three subgroups with distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact ...function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.
We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized ...genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.
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•Proteomic subgroups linked to iCCA patient survival, treatment, and molecular features•TP53, KRAS, FGFR2, IDH1/2, and BAP1 showed diverse pathways and therapeutic potential•Immunogenomics revealed the peptide immunogenicity derived from FGFR2 fusion•HKDC1 and SLC16A3 as significant prognostic indicators with biological functions
Dong et al. yield insights into cancer etiology and taxonomy of intrahepatic cholangiocarcinoma (iCCA) through large-scale proteogenomics. They identify four iCCA subgroups with distinct clinical and multi-omics features, as well as prognostic biomarkers and potential therapeutic targets
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Perfect mixed 26-facet and 18-facet polyhedra of Cu2O microcrystals were successfully synthesized by a hydrothermal process with use of stearic acid as a structure-directing agent. Cu2O octahedra and ...cubes were also prepared under hydrothermal conditions. The obtained microstructures were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), and UV−vis spectrum. The adsorption and photocatalytic activity of as-prepared 26-facet and 18-facet Cu2O polyhedra for decomposition of methyl orange were investigated and compared to that of octahedra and cubes. The results show that mixed 26-facet and 18-facet polyhedra with dominant {110} facets have a higher adsorption and photocatalytic activity than Cu2O octahedra with dominant {111} surfaces and cubes with {100} surfaces. A higher surface energy and a greater density of the “Cu” dangling bonds on {110} facets of 26-facet and 18-facet polyhedra may be ascribed to its higher catalytic activity. Moreover, as compared with octahedra and cubes, mixed 26-facet and 18-facet polyhedra have more edges and corners, which could improve photocatalytic activity. This simple one-pot synthetic route could provide a good starting point for the research of morphology construction and shape-dependent catalytic properties of other materials.
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IJS, KILJ, NUK, PNG, UL, UM
Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative ...correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein–binding protein–associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. Conclusion: These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515‐528).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs ...in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.
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This paper reports a surface functional monomer-directing strategy for the highly dense imprinting of 2,4,6-trinitrotoluene (TNT) molecules at the surface of silica nanoparticles. It has been ...demonstrated that the vinyl functional monomer layer of the silica surface can not only direct the selective occurrence of imprinting polymerization at the surface of silica through the copolymerization of vinyl end groups with functional monomers, but also drive TNT templates into the formed polymer shells through the charge-transfer complexing interactions between TNT and the functional monomer layer. The two basic processes lead to the formation of uniform core−shell TNT-imprinted nanoparticles with a controllable shell thickness and a high density of effective recognition sites. The high capacity and fast kinetics to uptake TNT molecules show that the density of effective imprinted sites in the nanoshells is nearly 5 times that of traditional imprinted particles. A critical value of shell thickness for the maximum rebinding capacity was determined by testing the evolution of rebinding capacity with shell thickness, which provides new insights into the effectiveness of molecular imprinting and the form of imprinted materials. These results reported here not only can find many applications in molecularly imprinting techniques but also can form the basis of a new strategy for preparing various polymer-coating layers on silica support.
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IJS, KILJ, NUK, PNG, UL, UM
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•β-subunits, acidic and basic subunits contribute to solid-like properties of layer.•The mixed monolayers with protein and monoglycerides are formed in all samples.•The presence of ...monoglycerides reduces the amount of adsorbed protein.•Monoglycerides displace most subunits from the fat droplets except β-subunit.
The effect of the adsorption behavior of soy proteins hydrolysates and monoglycerides on the properties of the film at oil-water interfaces in emulsions and emulsion stability was investigated. Surface tension, adsorbed protein composition and interfacial rheological properties were measured to gain insights into the relationships between molecular composition and properties. The interfacial film formed by 7S (β-conglycinin), 11S (Glycinin) and native soy protein isolate (NSPI) exhibited high elasticity due to a high concentration of adsorbed β-subunits, acidic and basic subunits. Soy protein isolate hydrolyzed by pepsin (SPHPe) and soy protein isolate hydrolyzed by papain (SPHPa) had a high percentage of small peptides, less β-subunits and acidic subunits, forming a fluid-like interfacial film at the beginning of the time sweep. Commercial soy protein isolate (CSPI) film without main soy protein subunits induced fluid-like properties. Monoglycerides displaced the small peptides, acidic and basic subunits from the interface and led to fat globule destabilization after 24 h aging. Emulsions were stable with 7S and SPHPe with high proportion of β-subunits, which were not replaced by monoglycerides. This study provided the foundation for the preparation and application of soy protein isolate with different emulsion stability requirements paired with selected enzyme treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hedgehog signaling plays very important roles in development and cancers. Vertebrates have three transcriptional factors, Gli1, Gli2 and Gli3. Among them, Gli3 is a very special transcriptional ...factor which closely resembles Cubitus interruptus (Ci, in Drosophila) structurally and functionally as a 'double agent' for Shh target gene expression. Here we show that Gli3 full-length, but not the truncated form, can be methylated at K436 and K595. This methylation is specifically catalyzed by Set7, a lysine methyltransferase (KMT). Methylation at K436 and K595 respectively increases the stability and DNA binding ability of Gli3, resulting in an enhancement of Shh signaling activation. Furthermore, functional experiments indicate that the Gli3 methylation contributes to the tumor growth and metastasis in non-small cell lung cancer in vitro and in vivo. Therefore, we propose that Set7 mediated methylation is a novel PTM of Gli3, which positively regulates the transactivity of Gli3 and the activation of Shh signaling.
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