ABSTRACT
Rho GDP dissociation inhibitor 2 (RhoGDI2) expression is correlated with tumor growth, metastasis and chemoresistance in gastric cancer. However, the mechanisms by which RhoGDI2 promotes tumor cell survival and metastasis remain unclear. In this study, we clearly demonstrate that RhoGDI2 upregulates VEGF-C expression and RhoGDI2 expression is positively correlated with VEGF-C expression in human gastric tumor tissues as well as parental gastric cancer cell lines. VEGF-C depletion suppressed RhoGDI2-induced gastric cancer metastasis and sensitized RhoGDI2-overexpressing cells to cisplatin-induced apoptosis in vitro and in vivo. Secreted VEGF-C enhanced gastric cancer cell invasion and conferred cisplatin resistance to RhoGDI2-overexpressing cells. We also show that RhoGDI2 positively regulates Rac1 activity in gastric cancer cells. Inhibition of Rac1 expression suppressed RhoGDI2-induced VEGF-C expression, and this inhibition was associated with decreased invasiveness and increased sensitivity to cisplatin in RhoGDI2-overexpressing cells. Our results indicate that RhoGDI2 might be a potential therapeutic target for simultaneously reducing metastasis risk and enhancing chemotherapy efficacy in gastric cancer.
Subject(s)
Cisplatin/pharmacology , Drug Resistance, Neoplasm , Lung Neoplasms/secondary , Stomach Neoplasms/pathology , Vascular Endothelial Growth Factor C/metabolism , rho Guanine Nucleotide Dissociation Inhibitor beta/metabolism , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Blotting, Western , Cell Proliferation/drug effects , Chromatin Immunoprecipitation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Immunoenzyme Techniques , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/drug therapy , Stomach Neoplasms/metabolism , Tissue Array Analysis , Tumor Cells, Cultured , Vascular Endothelial Growth Factor C/genetics , Xenograft Model Antitumor Assays , rho Guanine Nucleotide Dissociation Inhibitor beta/antagonists & inhibitors , rho Guanine Nucleotide Dissociation Inhibitor beta/geneticsABSTRACT
The pace of research and development in neuroscience, neurotechnology, and neurorehabilitation is rapidly accelerating, with the number of publications doubling every 4.2 years. Maintaining this progress requires technological standards and scientific reporting guidelines to provide frameworks for communication and interoperability. The present lack of such neurotechnology standards limits the transparency, repro-ducibility, and meta-analysis of this growing body of literature, posing an ongoing barrier to research, clinical, and commercial objectives. Continued neurotechnological innovation requires the development of some minimal standards to promote integration between this broad spectrum of technologies and therapies. To preserve design freedom and accelerate the translation of research into safe and effective technologies with maximal user benefit, such standards must be collaboratively co-developed by the full range of neuroscience and neurotechnology stakeholders. This paper summarizes the preliminary recommendations of IEEE P2794 Standards Working Group, developing a Reporting Standard for in-vivo Neural Interface Research (RSNIR).
ABSTRACT
We have recently demonstrated the effectiveness of an influenza A virus (IAV) subunit vaccine based on biodegradable polyanhydride nanoparticles delivery in mice. In the present study, we evaluated the efficacy of â¼200nm polyanhydride nanoparticles encapsulating inactivated swine influenza A virus (SwIAV) as a vaccine to induce protective immunity against a heterologous IAV challenge in pigs. Nursery pigs were vaccinated intranasally twice with inactivated SwIAV H1N2 (KAg) or polyanhydride nanoparticle-encapsulated KAg (KAg nanovaccine), and efficacy was evaluated against a heterologous zoonotic virulent SwIAV H1N1 challenge. Pigs were monitored for fever daily. Local and systemic antibody responses, antigen-specific proliferation of peripheral blood mononuclear cells, gross and microscopic lung lesions, and virus load in the respiratory tract were compared among the groups of animals. Our pre-challenge results indicated that KAg nanovaccine induced virus-specific lymphocyte proliferation and increased the frequency of CD4+CD8αα+ T helper and CD8+ cytotoxic T cells in peripheral blood mononuclear cells. KAg nanovaccine-immunized pigs were protected from fever following SwIAV challenge. In addition, pigs immunized with the KAg nanovaccine presented with lower viral antigens in lung sections and had 6 to 8-fold reduction in nasal shedding of SwIAV four days post-challenge compared to control animals. Immunologically, increased IFN-γ secreting T lymphocyte populations against both the vaccine and challenge viruses were detected in KAg nanovaccine-immunized pigs compared to the animals immunized with KAg alone. However, in the KAg nanovaccine-immunized pigs, hemagglutination inhibition, IgG and IgA antibody responses, and virus neutralization titers were comparable to that in the animals immunized with KAg alone. Overall, our data indicated that intranasal delivery of polyanhydride-based SwIAV nanovaccine augmented antigen-specific cellular immune response in pigs, with promise to induce cross-protective immunity.