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Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
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Objective:To promote the development of basic research, clarify the development trend of frontier biotechnology, and strengthen scientific research management in project management, resource integration, risk supervision and other aspects.Methods:Through literature study and expert discussion, this paper analyzed the hot spots of frontier biotechnology research, and put forward suggestions for optimizing strategic tasks and innovation management from the perspective of innovation management.Results:The research of frontier biotechnology in our country showed a rapid development trend, but also faced with challenges such as insufficient technological innovation ability and relatively lagging management level. It is imperative to explore and establish a new scientific research management model and optimize the operation mechanism.Conclusions:The major research achievements of frontier biotechnology are emerging constantly, showing a trend of multi-disciplinary and multi-field integration. China should actively explore innovative management models, optimize and improve strategic tasks, improve the efficiency of scientific research management, and do a good job in supporting the realization of high-level scientific and technological self-reliance.
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@#Among current novel druggable targets, protein–protein interactions (PPIs) are of considerable and growing interest. Diacylglycerol kinase α (DGKα) interacts with focal adhesion kinase (FAK) band 4.1-ezrin-radixin-moesin (FERM) domain to induce the phosphorylation of FAK Tyr397 site and promotes the malignant progression of esophageal squamous cell carcinoma (ESCC) cells. Chrysin is a multi-functional bioactive flavonoid, and possesses potential anticancer activity, whereas little is known about the anticancer activity and exact molecular mechanisms of chrysin in ESCC treatment. In this study, we found that chrysin significantly disrupted the DGKα/FAK signalosome to inhibit FAK-controlled signaling pathways and the malignant progression of ESCC cells both in vitro and in vivo, whereas produced no toxicity to the normal cells. Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGKα contributed to chrysin-mediated inhibition of the assembly of DGKα/FAK complex. This study has illustrated DGKα/FAK complex as a target of chrysin for the first time, and provided a direction for the development of natural products-derived PPIs inhibitors in tumor treatment.
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Objective To investigate the biological effects of exosomes secreted by KYSE410 cells on migration and invasion of KYSE410,KYSE510,YES2 cells and the possible mechanisms underlying the phenotype change.Methods The exosomes were isolated from the conditional supernatant of esophageal cancer cell line KYSE410 by ultracentrifugation.The morphology of exosomes was observed by transmission electron microscopy (TEM).Western blotting was used to detect the protein markers of exosomes.The uptaken of fluorescence-labeled KYSE410 exosomes by KYSE410,KYSE510 and YES2 was also recorded under confocal microscopy.Migration and invasion ability of the three esophageal carcinoma cell lines and the effects of exosomes from KYSE410 on migration and invasion of KYSE410,KYSE510 and YES2 cells were analyzed by Transwell chamber,respectively.The alteration of Wnt/β-catenin and PI3K/Akt pathway-related proteins were detected by Western blotting.Results The membrane structure of KYSE410 derived exosomes could be observed with its diameter ranged between 30-100nm.The invasion and migration ability of three esophageal cancer cells are KYSE410＞ KYSE510＞ YES2.KYSE410 exosomes promoted the migration and invasion of KYSE410,KYSE510 and YES2 cells.Conclusions Concentrated exosomes derived from the highly migratory and invasive esophageal cancer cell line KYSE410 promoted the migration and invasion potentials of itself and esophageal cancer cell lines KYSE510 and YES2,which possibly exerted the effects by activating Wnt/β-catenin and PI3K/Akt signaling pathways.
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Precision medicine is a new developing area of medical research and clinical practice, which is stemmed from the urgent need for high-profile medical health care and fast emergence of exquisite biological and medical technologies.Precision medicine, mainly based on the individualized molecular medicine and sophisticated medical techniques, offers multiple dimensional imaging examinations and biological molecular assays to make subsequent therapeutic strategies much more optimized to the personal disease characteristics than the traditional regimes, hence pursuing maximized efficacy and minimized side effects.The precision medicine in China is stepping into a vigorously developing stage after its first official initiation.This review summarized the development and program design of precision medicine in China to shed light on this growingly progressing area.
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Objective To screen the genes most relevant to lymph node metastasis of cervical cancer and identify the genes at the key knots of the regulatory network to provide the potential targets for cervical cancer intervention.Methods The transcriptional profiling database of TCGA was used, and random forests algorithm was adopted to rank the genes related to lymph node metastasis extracted from GeneCards database.STRING and Cytospace tolls were used to build the interactive regulatory network and identify the most weighted genes localized in the central of the network.DAVID platform was used to perform a functional annotation for the whole geneset.Results We ranked 2784 genes in respect to their potential contributions to lymph node metastasis of cervical cancer and identified the genes at the key knob.The genes related to cancer metastasis were enriched to cytokines pathway, MAPK pathway, wnt pathway, intercellular interaction, adhesive conjunction, cellular skeleton regulation, etc.Some of the identified key genes, like EGFR, NOTCH1, RHOA, etc. have been verified to be closely related cervical cancer metastasis in the basic and clinical research. Conclusion Random forests algorithm is useful, taking advantages of TCGA database, in enriching the genes playing significant role in cervical cancer metastasis.A majority of the genes in the analyzed geneset were indicated to be significantly correlated with lymph node metastasis.
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Dysregulated cell cycle-mediated cell transformation and uncontrolled cell growth are some of the fundamental biolog-ical features of malignant tumors. Thus, understanding the mechanism(s) involved in the cell cycle will facilitate the discovery of the na-ture of tumor initiation and progression as well as the molecular mechanism of tumor malignancy. Consequently, biomarkers and drug targets for early diagnosis and treatment would be obtained. This study was designed to analyze in detail the key regulators of cell cycle and their importance in carcinogenesis and clinical prevention, diagnosis and treatment, and anti-cancer drug discovery. The biological impact of the dysregulated cell cycle on tumor occurrence and malignancy development is systematically described. The theoretical and practical significance of the cell cycle regulation in tumor diagnosis and therapy are also provided.
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Objective Mitotic spindle and midbody are both microtubule-based temporary structures during cell growth and play essential roles in mitosis.The purpose of this study was to establish a mature and efficient method to extract mitotic spindle and midbody.Methods Through the cell cycle synchronization method,mitotic spindle or midbody was made appear inside cells.Low permeability swelling and glycerol gradient centrifugation principles were then used to extract spindle and midbody.Results By Western Blot and immunofluorescence staining,the extracts were identified as mitotic spindle and midbody.Conclusions The successful extraction of mitotic spindle and midbody from synchronized Hela cells will provide foundation for identifying the proteins located in cell during mitosis,and be of great significance to the study of molecular regulation mechanisms of mitosis and tumorigenesis.
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The human Gadd45 protein family plays critical roles in DNA repair, negative growth control, genomic stability, cell cycle checkpoints and apoptosis. Here we report the crystal structure of human Gadd45γ [corrected], revealing a unique dimer formed via a bundle of four parallel helices, involving the most conserved residues among the Gadd45 isoforms. Mutational analysis of human Gadd45γ [corrected] identified a conserved, highly acidic patch in the central region of the dimer for interaction with the proliferating cell nuclear antigen (PCNA), p21 and cdc2, suggesting that the parallel dimer is the active form for the interaction. Cellular assays indicate that: (1) dimerization of Gadd45γ [corrected] is necessary for apoptosis as well as growth inhibition, and that cell growth inhibition is caused by both cell cycle arrest and apoptosis; (2) a conserved and highly acidic patch on the dimer surface, including the important residues Glu87 and Asp89, is a putative interface for binding proteins related to the cell cycle, DNA repair and apoptosis. These results reveal the mechanism of self-association by Gadd45 proteins and the importance of this self-association for their biological function.
Subject(s)
Animals , Humans , Mice , Amino Acid Motifs , Apoptosis , Radiation Effects , CDC2 Protein Kinase , Cell Cycle , Cell Survival , Crystallography, X-Ray , Cyclin B , Metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Metabolism , Cyclin-Dependent Kinases , HeLa Cells , Intracellular Signaling Peptides and Proteins , Chemistry , Genetics , Metabolism , Mutagenesis, Site-Directed , Mutation, Missense , Proliferating Cell Nuclear Antigen , Metabolism , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization , Protein Structure, Quaternary , Ultraviolet RaysABSTRACT
Objective To indentify the gene expression on different fractionated radiation regimens with the same total radiation dose in xenografts with human lung adenocareinoma. Methods Forty-eight BALB/c-nu mice, implanted with human lung adenocarcinoma (Anip973), were randomized into 4 groups: normal control greup,60 Gy in 30 fractions conventional radiation group (2 Gy group) ,60 Gy in 10 fractions hypofractionated radiation group (6 Gy group) ,60 Gy in 6 fractions hypofractionaed radiation group (10 Gy group). Gene alterations were investigated with the microchip analytical procedures covering the entire genome. Genes with significantly different expression were further validated by the quantitative real-time polymerase chain reaction (RT-PCR). Results Compared to the 2 Gy group, the expression of the genes related with the cell growth inhibition and apoptesis was increased, while the genes related with the cell proliferation, anti-apoptosis and DNA damage repair were decreased in the 6 Gy and 10 Gy groups. Confirmed by RT-PCR, c-myc gene was distinctly suppressed in the 6 Gy group (2. 9%) comparing with 2 Gy (5.6%) group and 10 Gy (4.8%) group (P=0. 000,P=0. 002) , and was slightly suppressed in the 10 Gy group comparing with 2 Gy group (P = 0. 069). Conclusions In the BALB/c-nu mice implanted with human lung adenocarcinoma, the hypofractionated radiation regimens clearly inhibit the tumor growth more than conventional fractionation group, though with the same total dose. The 6 Gy group seem to be more effective than 10 Gy group in the inhibition of tumor growth.
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Gadd45a, a p53 and BRCA1-regulated growth arrest and DNA damage gene, plays important roles in suppressing cell transformation and tumor malignancy. Gadd45a maintains the genomic stability through inhibiting the cell growth and promoting the DNA repair etc, by which it suppresses the tumor development. Additionally, Gadd45a is involved in some important signaling pathway, contributing to its function in tumor suppressing.