Evolution of Network Biomarkers from Early to Late Stage Bladder Cancer Samples

We use a systems biology approach to construct protein-protein interaction networks (PPINs) for early and late stage bladder cancer. By comparing the networks of these two stages, we find that both networks showed very significantly different mechanisms. To obtain the differential network structures between cancer and noncancer PPINs, we constructed cancer PPIN and noncancer PPIN network structures for the two bladder cancer stages using microarray data from cancer cells and their adjacent noncancer cells, respectively. With their carcinogenesis relevance values (CRVs), we identified 152 and 50 significant proteins and their PPI networks (network markers) for early and late stage bladder cancer by statistical assessment. To investigate the evolution of network biomarkers in the carcinogenesis process, primary pathway analysis showed that the significant pathways of early stage bladder cancer are related to ordinary cancer mechanisms, while the ribosome pathway and spliceosome pathway are most important for late stage bladder cancer. Their only intersection is the ubiquitin mediated proteolysis pathway in the whole stage of bladder cancer. The evolution of network biomarkers from early to late stage can reveal the carcinogenesis of bladder cancer. The findings in this study are new clues specific to this study and give us a direction for targeted cancer therapy, and it should be validated in vivo or in vitro in the future.

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Applying NGS Data to Find Evolutionary Network Biomarkers from the Early and Late Stages of Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2015/391475 ◽

2015 ◽

Vol 2015 ◽

pp. 1-27 ◽

Cited By ~ 5

Author(s):

Yung-Hao Wong ◽

Chia-Chou Wu ◽

Chih-Lung Lin ◽

Ting-Shou Chen ◽

Tzu-Hao Chang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Systems Biology ◽

Liver Cancer ◽

Late Stage ◽

Early Stage ◽

Network Structures ◽

Network Biomarkers ◽

Two Stages ◽

Ngs Data ◽

Late Stages

Hepatocellular carcinoma (HCC) is a major liver tumor (~80%), besides hepatoblastomas, angiosarcomas, and cholangiocarcinomas. In this study, we used a systems biology approach to construct protein-protein interaction networks (PPINs) for early-stage and late-stage liver cancer. By comparing the networks of these two stages, we found that the two networks showed some common mechanisms and some significantly different mechanisms. To obtain differential network structures between cancer and noncancer PPINs, we constructed cancer PPIN and noncancer PPIN network structures for the two stages of liver cancer by systems biology method using NGS data from cancer cells and adjacent noncancer cells. Using carcinogenesis relevance values (CRVs), we identified 43 and 80 significant proteins and their PPINs (network markers) for early-stage and late-stage liver cancer. To investigate the evolution of network biomarkers in the carcinogenesis process, a primary pathway analysis showed that common pathways of the early and late stages were those related to ordinary cancer mechanisms. A pathway specific to the early stage was the mismatch repair pathway, while pathways specific to the late stage were the spliceosome pathway, lysine degradation pathway, and progesterone-mediated oocyte maturation pathway. This study provides a new direction for cancer-targeted therapies at different stages.

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The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside

Pharmaceutics ◽

10.3390/pharmaceutics13122066 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2066

Author(s):

Liezl Gibhard ◽

Dina Coertzen ◽

Janette Reader ◽

Mariëtte E. van der Watt ◽

Lyn-Marie Birkholtz ◽

...

Keyword(s):

Late Stage ◽

Early Stage ◽

Blood Stage ◽

Combination Therapies ◽

Prolonged Incubation ◽

Model Following ◽

Synthetic Accessibility ◽

Artemisinin Combination Therapies

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

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Continuous infusion of dexamethasone aggravates the damage of cartilage via upregulating p-AKT and impairing articular autophagy in experimental OA model

10.21203/rs.3.rs-71569/v1 ◽

2020 ◽

Author(s):

liang chen ◽

Zhenhong Ni ◽

Jinfan Zhang ◽

Junlan Huang ◽

Yangli Xie ◽

...

Keyword(s):

Articular Cartilage ◽

Continuous Infusion ◽

Late Stage ◽

Early Stage ◽

Cartilage Matrix ◽

Chondrocyte Apoptosis ◽

Western Blot Assay ◽

Akt Activation

Abstract Objective To explore the effect of dexamethasone (Dex) infusion on articular cartilage and the underlying mechanisms in vitro and in vivo. Methods Destabilization of medial meniscus (DMM)-induced OA mouse model was used in this study. The mice with Dex treatment were sacrificed and then the knee joint samples were obtained for pathological analysis. Mouse primary chondrocytes were isolated and cultured in the presence or absence of Dex, which were used for calcification analysis and western blot assay. Results Dex accelerated the loss of articular cartilage matrix in mice, while it aggravated the damage of cartilage in DMM-induced OA model at the late stage. The calcium content in calcified cartilage layer in the joints from Dex treated OA mice was significantly higher than that from control mice. Dex treatment enhanced mineralization of articular cartilage matrix and leaded to massive apoptosis of chondrocytes in OA model. In addition, Dex caused autophagy of chondrocytes in the early stage, which was decreased at the late stage of Dex treatment. Moreover, we found that the effect of Dex on the mineralization of articular cartilage matrix in mice was related to AKT activation. Conclusions Continuous infusion of Dex can enhance the calcification of cartilage via AKT activation and increase chondrocyte apoptosis through inhibiting autophagy, which aggravates the damage of articular cartilage and accelerates the progression of OA in vivo.

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Zeb1 Promotes Odontoblast Differentiation in a Stage-Dependent Manner

Journal of Dental Research ◽

10.1177/0022034520982249 ◽

2021 ◽

pp. 002203452098224

Author(s):

Y. Xiao ◽

Y.X. Lin ◽

Y. Cui ◽

Q. Zhang ◽

F. Pei ◽

...

Keyword(s):

Late Stage ◽

Tooth Development ◽

Early Stage ◽

Rna Seq ◽

Cis Elements ◽

Odontoblast Differentiation ◽

Odontoblastic Differentiation ◽

Accessible Chromatin

A comprehensive study of odontoblastic differentiation is essential to understand the process of tooth development and to achieve the ability of tooth regeneration in the future. Zinc finger E-box-binding homeobox 1 ( Zeb1) is a transcription factor expressed in various neural crest–derived tissues, including the mesenchyme of the tooth germ. However, its role in odontoblastic differentiation remains unknown. In this study, we found the expression of Zeb1 gradually increased during odontoblast differentiation in vivo, as well as during induced differentiation of cultured primary murine dental papilla cells (mDPCs) in vitro. In addition, the differentiation of mDPCs was repressed in Zeb1-silenced cells. We used RNA sequencing (RNA -seq) to identify the transcriptome-wide targets of Zeb1 and used assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to explore the direct targets of Zeb1 in both the early stage (embryonic day 16.5; E16.5) and the late stage (postnatal day 0; PN0) of tooth development. We identified the motifs of transcription factors enriched in Zeb1-dependent accessible chromatin regions and observed that only in the early stage of mDPCs could Zeb1 significantly change the accessibility of chromatin regions. In vivo and in vitro experiments confirmed that silencing of Zeb1 at E16.5 inhibited dentinogenesis. Analysis of RNA-seq and ATAC-seq resulted in the identification of Runx2, a gene directly regulated by Zeb1 during early odontoblast differentiation. Zeb1 enhances the expression of Runx2 by binding to its cis-elements, and ZEB1 interacts with RUNX2. In the late stage of tooth development, we found that ZEB1 could directly bind to and increase the enhancer activity of an element upstream of Dspp and promote dentinogenesis. In this study, for the first time, we revealed that ZEB1 promoted odontoblast differentiation in the early stage by altering chromatin accessibility of cis-elements near genes such as Runx2, while in the late stage, it directly enhanced Dspp transcription, thereby performing a dual role.

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Surface Labeling with Adhesion Protein FimH Improves Binding of Immunotherapeutic Agent Salmonella Ty21a to the Bladder Epithelium

Bladder Cancer ◽

10.3233/blc-200382 ◽

2020 ◽

pp. 1-12

Author(s):

Maroeska J. Burggraaf ◽

Lisette Waanders ◽

Mariska Verlaan ◽

Janneke Maaskant ◽

Diane Houben ◽

...

Keyword(s):

Bladder Cancer ◽

Antitumor Activity ◽

Bladder Wall ◽

Bladder Epithelium ◽

Modest Improvement ◽

Adhesion Protein ◽

Survival Experiment ◽

Muscle Invasive

BACKGROUND: Bladder cancer is the ninth most common cancer in men. 70% of these tumors are classified as non-muscle invasive bladder cancer and those patients receive 6 intravesical instillations with Mycobacterium bovis BCG after transurethral resection. However, 30% of patients show recurrences after treatment and experience severe side effects that often lead to therapy discontinuation. Recently, another vaccine strain, Salmonella enterica typhi Ty21a, demonstrated promising antitumor activity in vivo. Here we focus on increasing bacterial retention in the bladder in order to reduce the number of instillations required and improve antitumor activity. OBJECTIVE: To increase the binding of Ty21a to the bladder wall by surface labeling of the bacteria with adhesion protein FimH and to study its effect in a bladder cancer mouse model. METHODS: Binding of Ty21a with surface-labeled FimH to the bladder wall was analyzed in vitro and in vivo. The antitumor effect of a single instillation of Ty21a+FimH in treatment was determined in a survival experiment. RESULTS: FimH-labeled Ty21a showed significant (p < 0.0001) improved binding to mouse and human cell lines in vitro. Furthermore, FimH labeled bacteria showed ∼5x more binding to the bladder than controls in vivo. Enhanced binding to the bladder via FimH labeling induced a modest improvement in median but not in overall mice survival. CONCLUSIONS: FimH labeling of Ty21a significantly improved binding to bladder tumor cells in vitro and the bladder wall in vivo. The improved binding leads to a modest increase in median survival in a single bladder cancer mouse study.

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The oncogenic role of the cerebral endothelial cell adhesion molecule (CERCAM) in bladder cancer cells in vitro and in vivo

Cancer Medicine ◽

10.1002/cam4.3955 ◽

2021 ◽

Author(s):

Yali Zuo ◽

Xiaoliang Xu ◽

Minfeng Chen ◽

Lin Qi

Keyword(s):

Bladder Cancer ◽

Cell Adhesion ◽

Endothelial Cell ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Bladder Cancer Cells ◽

Endothelial Cell Adhesion

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Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽

10.3390/cancers13163975 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3975

Author(s):

Marco A. De Velasco ◽

Yurie Kura ◽

Naomi Ando ◽

Noriko Sako ◽

Eri Banno ◽

...

Keyword(s):

Prostate Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Late Stage ◽

Early Stage ◽

Castration Resistant Prostate Cancer ◽

Akt Inhibitor ◽

Molecular Features ◽

Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

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RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Oncogene ◽

10.1038/s41388-021-01666-z ◽

2021 ◽

Author(s):

Qiuxia Yan ◽

Peng Zeng ◽

Xiuqin Zhou ◽

Xiaoying Zhao ◽

Runqiang Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Alternative Splicing ◽

Rna Binding ◽

Aerobic Glycolysis ◽

Histological Grade ◽

Migration And Invasion ◽

Binding Motif ◽

Hnrnp A1

AbstractThe prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

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