The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer.

Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

An immune checkpoint score system for prognostic evaluation and adjuvant chemotherapy selection in gastric cancer.

Immunosuppressive molecules are extremely valuable prognostic biomarkers across different cancer types. However, the diversity of different immunosuppressive molecules makes it very difficult to accurately predict clinical outcomes based only on a single immunosuppressive molecule. Here, we establish a comprehensive immune scoring system (ISSGC) based on 6 immunosuppressive ligands (NECTIN2, CEACAM1, HMGB1, SIGLEC6, CD44, and CD155) using the LASSO method to improve prognostic accuracy and provide an additional selection strategy for adjuvant chemotherapy of gastric cancer (GC). The results show that ISSGC is an independent prognostic factor and a supplement of TNM stage for GC patients, and it can improve their prognosis prediction accuracy; in addition, it can distinguish GC patients with better prognosis from those with high prognostic nutritional index score; furthermore, ISSGC can also be used as a tool to select GC patients who would benefit from adjuvant chemotherapy independent of their TNM stages, MSI status and EBV status.

m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling.

BACKGROUND: BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. METHODS: We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. RESULTS: BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. CONCLUSIONS: Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

CDK5RAP3 Inhibits the Translocation of MCM6 to Influence the Prognosis in Gastric Cancer.

Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) was identified as a tumor suppressor in gastric cancer, while, minichromosome maintenance complex component 6 (MCM6), which is closely related to the initiation of DNA replication, was reported to be upregulated in multiple malignancies. However, the interaction between these two proteins has not been investigated in gastric cancer. Here, we evaluate the connection between CDK5RAP3 and MCM6 using mass spectrometry and immunoprecipitation. In cells, cell growth and invasiveness indicate that CDK5RAP3 acts as a tumor suppressor by preventing the effects of MCM6. The potential mechanism was revealed using immunofluorescence and nuclear protein extraction. In patients, immunohistochemistry and immunofluorescence show that the protein levels of CDK5RAP3 were markedly decreased in most gastric tumor tissues compared with adjacent nontumor tissues, and the expression levels of MCM6 in the nucleus showed the opposite trend. Prognostic analysis showed that the combined expression of CDK5RAP3 and MCM6 was an independent prognostic factor correlating with the overall survival of gastric cancer patients. Cox regression analysis indicated that the expression of CDK5RAP3 and MCM6 corresponded to T, N, and M stages. Our results demonstrate that CDK5RAP3 can interact with MCM6 and prevent MCM6 from translocating into the nucleus, which may be a potential mechanism through which CDK5RAP3 negatively regulates the proliferation of gastric cancer.

CDK5RAP3 suppresses Wnt/ß-catenin signaling by inhibiting AKT phosphorylation in gastric cancer.

BACKGROUND: CDK5RAP3 was initially isolated as a binding protein of the CDK5 activator p35. Although CDK5RAP3 has been shown to negatively regulate the Wnt/ß-catenin signaling pathway in gastric cancer by repressing GSK-3ß phosphorylation, its in-depth mechanism has not been determined. METHODS: Following CDK5RAP3 overexpression or knock down, CDK5RAP3 signaling pathways were investigated in gastric cancer cells by Western Blotting. Cell growth, invasion and migration were also evaluated in gastric cancer cell lines. We analyzed CDK5RAP3, AKT, p-AKT (Ser473), GSK-3ß and p-GSK-3ß (Ser9) expression in gastric tumor samples and adjacent non-tumor tissues from 295 patients using immunohistochemistry and Western Blotting. The prognostic significance of CDK5RAP3 and p-AKT (Ser473) was confirmed by a Log-rank test. RESULTS: Our study demonstrated that the expression of p-AKT (Ser473) and p-GSK-3ß (Ser9) was negatively correlated with CDK5RAP3 in stable gastric cancer cell lines. CDK5RAP3 repressed AKT phosphorylation, which promoted GSK-3ß phosphorylation, thereby suppressing ß-catenin protein expression and, consequently, gastric cancer. The protein level of CDK5RAP3 was markedly decreased in most gastric tumor tissues compared with adjacent non-tumor tissues, and the levels of p-AKT (Ser473) and p-GSK-3ß (Ser9) were also negatively correlated with those of CDK5RAP3. The prognostic value of CDK5RAP3 for overall survival was found to be dependent on AKT phosphorylation. CONCLUSION: Our results demonstrated that CDK5RAP3 negatively regulates the Wnt/ß-catenin signaling pathway by repressing AKT phosphorylation, which leads to better survival of patients with gastric cancer.

[Analysis of water sources of plants in artificial sand-fixation vegetation area based on large rainfall events.] / 基于较大降水事件的人工固沙植被区植物水分来源分析.

Water is a major limiting factor for plant growth in arid and semi-arid regions. To find out the main sources of water for two artificial sand-fixation plants (Caragana korshinskii and Artemisia ordosica), we analyzed the characteristics of hydrogen and oxygen stable isotopes in water molecules of rainfall, soil water and xylem water. To analyze water sources of these two plants, we used a direct comparison method and a multi-variate mixed linear model. The results showed that an equation of local meteoric water line in Shapotou was δD=7.83δ18O+5.64 (R2=0.91). The value for rainfall δ18O varied during plant-growing season, which was higher in the beginning and end of growing season, and lower in the peak of growing season. The value for soil water δ18O in the upper layers changed dramatically. The change range became smaller in the deeper soil layer. C. korshinskii had a greater efficiency (56.1%) in utilizing soil water in 40-80 cm soil layer. A. ordosica had a utilizing efficiency of 56.4% in 20-60 cm soil layer. A week after rain event, C. korshinskii and A. ordosica showed a higher efficiency in upper soil water. C. korshinskii showed an increase of 12.5% in utilizing soil water in 0-40 cm soil layer and A. ordosicas showed an increase of 10% in utilizing soil water in 0-20 cm layer. These results suggested that C. korshinskii and A. ordosica changed their water use strategy after large rainfall events, which might enable them to more easily adapt to arid environment.

The effect of the structure of polychlorinated biphenyls on their hydroxylation, oxidation, and glutathionyl conjugation reactions.

OBJECTIVE: To compare the nature of the metabolites formed from the phase I metabolism (hydroxylation and oxidation) and phase II metabolism (glutathionyl conjugation) of PCBs that have different chlorine substitution patterns. To discuss the structure-activity relationships and metabolic mechanisms of PCBs. METHODS: 4-Cl-biphenyl (PCB3), 4,4'-Cl-biphenyl (PCB15), 3,4,3',4'-Cl-biphenyl (PCB77) were used for in vitro metabolic study. LC/MS and UV-Vis studies were performed for metabolites identification. RESULTS: The cytochrome P-450 catalyzed hydroxylation rate decreased as the number of chlorine substitutions increased. In this reaction, PCB3 was fully metabolized, approximately half of the PCB15 was metabolized and PCB77 was not metabolized at all. The oxidation rate of PCB15-HQ was higher than that of PCB3-HQ under various oxidation conditions. The LC/MS and UV-Vis data suggest that in the conjugation reaction of PCB15-Q and GSH, the Michael addition reaction occurs preferentially over the displacement reaction. CONCLUSION: The metabolic profiles of polychlorinated biphenyls (PCBs) are dramatically affected by chlorine substitution patterns. It is suggested that the metabolic profiles of PCBs are related to their chlorine substitution patterns, which may have implications for the toxicity of PCB exposure.

[Composition and seasonal variations of carbon isotopes in aerosols of Lhasa, Tibet].

A total of 30 samples of total suspended particles were collected at an urban site in western of Lhasa city, Tibet from August 2006 to July 2007 for investigating carbonaceous aerosol features. 14C was taken as a reference to quantitatively distinguish the fossil and biogenic-derived origins along with the characteristics of seasonal variations of all carbonaceous materials in Lhasa are discussed. The results showed that the f(c) values in Lhasa ranged from 0.357 to 0.702, with an average of 0.493, which is higher than Beijing and Tokyo, but are far lower than that of remote/rural regions such as Launceston, indicating a major biogenic influence in Lhasa. Values of f(c) displayed clear seasonal variations with higher mean value in winter, a decreasing trend in spring, while relatively lower values in summer and autumn. Higher f(C) values in winter demonstrate that carbonaceous aerosol is mainly dominated by wood burning and incineration of agricultural wastes during the winter. The lower f(c) values in summer and autumn might be caused by increased diesel engines, motor vehicles emissions, which are related to the tourism in Lhasa. delta13C values ranged from -26.40% per hundred to approximately -25.10% per hundred, with an average of -25.8% per hundred, and showed no clear seasonal variation. The relative higher values in summer reflected the increment of fossil carbon emissions. 13C(TC) values are relatively homogeneous at -25.8% per hundred, considering the characteristics of seasonal variations of f(c) values, it can be concluded that carbonaceous aerosol of Lhasa was mainly influenced by a constant mixing of several pollution sources such as motor vehicles and wood burning emissions.

Distribution, biomass, and dynamics of roots in a revegetated stand of Caragana korshinskii in the Tengger Desert, northwestern China.

A field experiment was conducted to investigate root distribution, biomass, and seasonal dynamics in a revegetated stand of Caragana korshinskii Kom. in the Tengger Desert. We used soil profile trenches, soil core sampling, and minirhizotron measurements to measure root dynamics. Results showed that the roots of C. korshinskii were distributed vertically in the uppermost portion of the soil profile, especially the coarse roots, which were concentrated in the upper 0.4 m. The horizontal distribution of the root length and weight of C. korshinskii coarse roots was concentrated within 0.6 and 0.4 m of the trunk, respectively. The lateral distribution of fine roots was more uniform than coarse roots. Total-root and fine-root biomasses were 662.4 +/- 45.8 and 361.1 +/- 10.3 g m(-2), accounting for about two-thirds and one-third of the total plant biomass, respectively. Fine-root turnover is closely affected by soil water, and both of these parameters showed synchronously seasonal trends during the growing season in 2004 and 2005. The interaction between fine-root turnover and soil water resulted in the fine-root length densities and soil water content in the 0- to 1.0-m soil layer having similar trends, but the soil water peaks occurred before those of the fine-root length densities.