To investigate the differential proteins and related molecular mechanism of CDA-II (cell differentiation agent-II) induced therapy on a human hepatocellular carcinoma model in nude mice with high metastatic potential (LCI-D20). After tumors were transplanted 11 days, mice were intraperitoneally injected with CDA-II (1,800 mg/kg) for 20 days continuously. The tumor growth-inhibitory efficiency in CDA-II treated groups was calculated. Proteins extracted from tumor tissue were separated by two-dimensional gel electrophoresis (2DE) and the differential proteins were identified by matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Western blotting (WB) was performed to verify the expression of certain candidate proteins. Reverse transcription-polymerase chain reaction (RT-PCR) was engaged to study the molecular mechanism of the therapy. CDA-II suppressed the growth and metastasis of tumor. The tumor growth-inhibitory efficiency was 41.8%. In total, 27 differentially expressed proteins were identified, including HSP27, UGDH, CK8, Hsp60, ENOA and AnxA5, with functions involved in oncogene expression and/or cell differentiation. In addition, apparent alternations of HSP60 and β-actin expression levels and their different posttranslational modifications (PTMs) were investigated. RT-PCR analysis confirmed that the cancer related genes c-myc, N-ras and MMP-9 were significantly down-regulated. Our results demonstrate that CDA-II presence can change the proteome profiling and favors of the tumor suppression in LCI-D20 cell differentiation. Our results also suggest that the dynamic PTM of HSP60 expression levels could be used to predict HCC and might be a promising and useful biomarker to prognosticate CDA-II therapeutic efficacy.

Comparative proteomics and molecular mechanical analysis in CDA-II induced therapy of LCI-D20 hepatocellular carcinoma model

Cell differentiation agent II (CDA‑II) is a DNA methyltransferase inhibitor isolated from healthy human urine. In the present study, the antitumor activity of CDA‑II on human multiple myeloma (MM) cell lines via the mitochondrial pathway was first revealed. The human MM cell lines were exposed to CDA‑II. Cytotoxicity, caspase activation, apoptosis and the effects on the mitochondrial pathway were assessed. CDA‑Ⅱ was capable of decreasing the depolarized mitochondrial membranes and activating caspase‑3 and ‑9 and poly (ADP‑ribose) polymerase in MM cells treated with CDA‑II. CDA‑II induced caspase‑dependent cell death accompanied by a significant decrease in X-linked inhibitor of apoptosis protein (XIAP), survivin and Mcl‑1 levels. The caspase‑3 inhibitor, Z‑DEVD‑FMK, inhibited CDA‑II‑induced apoptosis. CDA‑II potently increased the Bax levels, decreased the Bcl‑2/Bax ratio and decreased the expression of the downstream targets of NF‑κB. In conclusion, the results of the present study demonstrated that CDA‑II treatment leads to the inhibition of p65 nuclear localization and potently induces caspase‑dependent apoptosis in MM cells mediated through the mitochondrial pathway at low nanomolar concentrations. These results indicate that CDA‑II is a novel inhibitor of NF‑κB activity, with notable antimyeloma efficacy. This study provides a rationale for the clinical investigation of CDA‑Ⅱ in human MM.

https://www.spandidos-publications.com/10.3892/mmr.2014.1911/download

Antitumor activity of CDA-II, a urinary preparation, on human multiple myeloma cell lines via the mitochondrial pathway.

OBJECTIVE It is unclear whether differentiation disturbances or deregulation of neural stem cells (NSCs) are the early key steps for gliomagenesis and tumor development. Furthermore, relevant molecular changes and gene-regulation pathways are unknown. This study focused on screening and validating differentiation-associated genes from both human NSCs and glioma cells with malignant progression, for the purpose of offering an experimental basis for the cellular origin of gilomas and molecular pathology of gliomagenesis. METHODS The differential-gene expression profiles of malignant progression of gliomas were established, then the differentiation related genes were screened out with a bioinformatics analysis. Expression levels of these genes was further analyzed in cultured human fetal NSCs undergoing differentiation processes with a semi-quantitative RT-PCR assay. RESULTS Eight genes were screened out from the gene-expression profiling of which the expression levels were associated with the differentiation processes of NSCs, namely CXCR4, TN-C, GLT1, IL1-RI, EGFR-8, CDC2, Ndr3 and MAPKK4. Three of them, ie., GLT1, CDC2 and MAPKK4, were further analyzed, showing that expression levels decreased with the differentiation processes of NSCs, and increased with the malignant progression of ganglioglioma. CONCLUSION Three differentiation associated genes were found negatively associated with NSCs differentiation and positively associated with malignant progression of gliomas, suggesting that differentiation disturbances of neural stem cells may be involved in oncogenesis, and that further studies on their roles in gliomagenesis should be conducted.

http://www.cancerbiomed.org/index.php/cocr/article/download/806/851

Molecular Study on Differentiation-Associated Genes Involved in Both Malignant Progression of Glioma and Differentiation of Human Fetal Neural Stem Cells

Objective: To establish gene expression profiles associated with malignant progression of ganglioglioma. Methods: The primary and two recurrent glioma specimens were collected intraoperatively from the same patient who experienced tumor transformation into anaplastic astrocytoma and glioblastoma multiform for the first and second recurrence respectively. Gene expression was assayed through cDNA array and bioinformatics analysis. Results: A total of 197 differentially expressed genes with differential ratio value more than 3 compared with normal brain tissue were obtained. Among 109 functionally denned genes, those associated with development ranked the first by frequency, followed by genes associated with metabolism, differentiation, signal transduction and so on. As a result of cluster analysis among 368 genes, eleven genes were up regulated with malignant progression, while six genes were down regulated. Conclusion: Gene expression profiles associated with malignant progression of glioma were successfully established, which provides a powerful tool for research on molecular mechanisms of malignant progression of gliomas.

GENE EXPRESSION PROFILING OF GANGLIOGLIOMA MALIGNANT PROGRESSION BY cDNA ARRAY

OBJECTIVE: Establishment of a gene expression profile associated with differentiation inducing the glioma cells was made possible. METHOD: The expression level of 18 000 genes in glioma cells was evaluated before and after induction with sodium phenyl-butyrate for 2 hours or 6 days by cDNA array technique, with the results proved by multi-dot blot. RESULTS: Ninety-eight gene expressions in the glioma cells were changed after the induction, with some genes in transcription and translation systems down-regulated, some oncogenes down-regulated, and some differentiation or apoptosis genes up-regulated. Eighteen unknown EST fragments were changed also. CONCLUSION: A gene expression profile associated with differentiation-inducing the glioma cells including 98 genes has been established.

cDNA array in the establishment of a gene expression profile associated with differentiation inducing the glioma cells

Objective: To analyze the changes of gene expression in phenylbutyrate induced differentiation of glioma cells. Methods: The expression levels of 14000 genes in glioma cells before and after inducement with sodium phenylbutyrate for 2 h or 6 days were evaluated by cDNA array technique and proved by multi-dot blotting. Results: expression of 98 genes in glioma cells showed changes after the inducement. Some genes involved in transcription and translation and some oncogenes are down-regulated, while some gene involved in differentiation or apoptosis are up-regulated. 18 unknown expression sequencing tag (EST) changed too. Conclusion: A gene expression profile associated with differentiation of glioma cells was established.

Gene expression profiling of phenylbutyrate induced differentiation of glioma cells by cDNA array

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cDNA array in the establishment of a gene expression profile associated with differentiation inducing the glioma cells

GENE EXPRESSION PROFILING OF GANGLIOGLIOMA MALIGNANT PROGRESSION BY cDNA ARRAY

Gene expression profiling of phenylbutyrate induced differentiation of glioma cells by cDNA array