Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene (VHL), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia. Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients. Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/- cells. VEGFC-/- cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients. Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.
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PMID:VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. 3080

Busulfan and other chemotherapeutic drugs used in the treatment of cancer may result in temporary or even permanent damage to spermatogenesis. During spermatogenesis, the rapidly dividing spermatogonia are highly susceptible to chemotherapy. Consequently, there is significant interest in developing an approach that could provide stimulation and regenerate spermatogenesis after chemotherapy. In a previous study, we suggested the potential application for vascular endothelial growth factor C (VEGFC) because of its key role in stimulating the proliferation of spermatogonia. However, methods to facilitate the recovery of spermatogenesis in such patients using VEGFC, or other regulatory factors, are sorely lacking because of the rapid degradation of these proteins and restrictions created by the blood-testis-barrier. To this end, we loaded VEGFC into polyanion dextran sulfate incorporated in a polycation chitosan shell to produce VEGFC sustained-release ultrafine particles (UFPs, CS-DS-VEGFC). We tested such particles in an azoospermic mouse model, created using busulfan. For each mouse, CS-DS-VEGFC was injected into the seminiferous tubules of one testis, while unloaded UFPs (CS-DS), or the VEGFC protein alone, was injected into the opposite testis as a control. All mice were sacrificed and evaluated 5 weeks later. Spermatogenesis in the tubules that were injected with CS-DS-VEGFC was clearly better than those injected with controls, and contained more spermatogonia and spermatocytes, along with Ki67 and PCNA positive-cells per tubule. In addition, the phosphorylation levels of AKT and MAPK in these tubules were also higher than in controls, indicating that CS-DS-VEGFC could induce the sustained activation of these pathways. In conclusion, CS-DS-VEGFC, combined with the efferent tubule injection technique, is a feasible approach with which to improve the regeneration of spermatogenesis in busulfan-induced azoospermic mice.
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PMID:Intra-Seminiferous Tubular Injection of Vascular Endothelial Growth Factor C Sustained-Release Ultrafine Particles: A Novel Method for Improving the Regeneration of Spermatogenesis After Chemotherapy. 3174 18