ABSTRACT
This paper is step forward to establish an exponential synchronization criterion for discrete-time complex-valued neural networks (CVNNs) having time-varying delays subject to randomly occurring uncertain weighting parameters, in order to overcome the fluctuation when the output-feedback controller imposes on its dynamics. To achieve this, Jensen's weighted summation inequalities (WSIs) and an extended reciprocal convex matrix inequality (ERCMI) are extended into the domain of complex field. By introducing some augmented vectors, a Lyapunov-Krasovskii functional (LKF) is constructed to attain an improved delay-dependent linear matrix inequalities (LMIs) constraint for the exponential synchronization phenomenon of the desired master-slave neuronal system model. For instance, the upper bound of the quadratic summation terms occurred in the finite difference of the LKF have been obtained from its linearization that has been made by the developed complex-valued WSIs and complex-valued ERCMI. The proposed results are less restrictive with the minimum number of decision variables than those obtained using existing inequalities. The designed output-feedback control gain has been determined by solving a set of complex-valued LMIs and it has been enforced with a prescribed exponential decay rate. Finally, in sight of MATLAB software, the established results have been examined via a numerical example supported by the simulation results.
Subject(s)
Algorithms , Neural Networks, Computer , Feedback , Computer Simulation , SoftwareABSTRACT
Semaphorin 3A (Sema 3A), a member of semaphorin family, serves as a guidance clue during embryonic development and is known as a candidate tumor suppressor that attenuates breast tumor progression by binding with its co-receptor, neuropilin-1 (NRP-1). However, the underlying mechanism by which Sema 3A suppresses breast tumor growth is still unexplored. In this study, we report that Sema 3A regulates phosphorylation and nuclear translocation of phosphatase and tensin homolog (PTEN) and FOXO 3a. Moreover, Sema 3A controls NRP-1-mediated PTEN-dependent FOXO 3a activation. Overexpression of PTEN and FOXO 3a enhances Sema 3A-induced attenuation of breast cancer cell migration. Chromatin immunoprecipitation and electrophoretic mobility shift assay data revealed that FOXO 3a regulates MelCAM at the transcriptional level. Furthermore, Sema 3A induces NRP-1-mediated MelCAM expression through PTEN and FOXO 3a. The data also showed that vascular endothelial growth factor-induced angiogenesis is inhibited by Sema 3A. Loss of or gain in function study revealed that Sema 3A modulates phosphorylation of PTEN and FOXO 3a and expression of MelCAM, leading to suppression of tumor growth and angiogenesis using in vivo mice model. Clinical specimen analysis revealed that reduced expression of Sema 3A and p-PTEN are correlated with enhanced breast cancer progression, further strengthening our in vitro and in vivo findings. Correlation of relapse-free survival of breast cancer patients (n=2878) with expression levels of Sema 3A, NRP-1, FOXO 3a and MelCAM were studied by Kaplan-Meier analysis. Statistical analysis revealed a close association between reduced expression of Sema 3A and MelCAM with that of poor patient's survival. Our study demonstrated a novel mechanism of regulation of tumor suppression by Sema 3A in coordination with a chain of tumor-suppressor genes, which in turn inhibits breast cancer cell migration, tumor growth and angiogenesis.
Subject(s)
Breast Neoplasms/pathology , Forkhead Transcription Factors/metabolism , PTEN Phosphohydrolase/metabolism , Semaphorin-3A/metabolism , Animals , Breast/blood supply , Breast/pathology , Breast Neoplasms/metabolism , CD146 Antigen/metabolism , Cell Line, Tumor , Female , Forkhead Box Protein O3 , Human Umbilical Vein Endothelial Cells , Humans , MCF-7 Cells , Mice , Mice, SCID , Neoplasm Transplantation , Neovascularization, Pathologic , Phosphorylation , Signal TransductionABSTRACT
Hypoxia is a salient feature of most solid tumors, and hypoxic adaptation of cancer cells has crucial implications in propagation of malignant clonal cell population. Osteopontin (OPN) has been identified as a hypoxia-responsive gene, but the mechanistic and regulatory role of OPN under hypoxia is less characterized. The present study identifies the existence of a positive inter-regulatory loop between hypoxia and OPN. We have shown that hypoxia induces OPN expression in breast cancer cells; however, the expression was found to be HIF1α independent. OPN enabled transcriptional upregulation of HIF1α expression both under normoxia and hypoxia, whereas stability of HIF1α protein in breast cancer cells remained unaffected. Moreover, we have shown that OPN induces integrin-linked kinase (ILK)/Akt-mediated nuclear factor (NF)-κB p65 activation leading to HIF1α-dependent vascular endothelial growth factor (VEGF) expression and angiogenesis in response to hypoxia. These in vitro data are biologically important as OPN expressing cells induce greater tumor growth and angiogenesis through enhanced expressions of proangiogenic molecules as compared with control. Immunohistochemical analysis of human breast cancer specimens revealed significant correlation between OPN and HIF1α but not HIF2α. Elevated expression of HIF1α and OPN was observed in pre-neoplastic and early stage infiltrating ductal carcinoma implicating the role of these proteins in neoplastic progression of breast cancer. Together, our results substantiate the prime role of OPN in cellular adaptation through ILK and NF-κB-mediated HIF1α-dependent VEGF expression in response to hypoxia that ultimately controls breast cancer progression and angiogenesis. Our study reinforces the fact that targeting OPN and its regulated signaling network hold important therapeutic implications.
Subject(s)
Breast Neoplasms/metabolism , Cell Proliferation , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neovascularization, Pathologic/metabolism , Osteopontin/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Hypoxia , Cell Line, Tumor , Cells, Cultured , Embryo, Mammalian/cytology , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , MCF-7 Cells , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , NF-kappa B/genetics , NF-kappa B/metabolism , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Osteopontin/genetics , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Xenograft Model Antitumor Assays/methodsABSTRACT
Tumor-associated macrophages (TAMs) have multifaceted roles in tumor development, particularly linked with tumor angiogenesis and invasion, but the molecular mechanism underlying this association remains unclear. In this study, we report that lack of osteopontin (OPN) suppresses melanoma growth in opn(-/-) mice and macrophages are the crucial component responsible for OPN-regulated melanoma growth. In tumor microenvironment, OPN activates macrophages and influences angiogenesis by enhancing cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in an autocrine manner. Furthermore, we identify α9ß1 integrin as a functional receptor for OPN that mediates its effect and activates ERK and p38 signaling, which ultimately leads to COX-2 expression in macrophages. The major role played by OPN and PGE2 in angiogenesis are further amplified by upregulation of MMP-9. OPN-activated macrophages promote the migration of endothelial and cancer cells via PGE2. These findings provide evidence that TAMs serve as source of key components such as OPN and COX-2-derived PGE2 and MMP-9 in melanoma microenvironment. Clinical specimens analyses revealed that increased infiltration of OPN-positive TAMs correlate with melanoma growth and angiogenesis. These data provide compelling evidence that OPN and COX-2 expressing macrophages are obligatory factors in melanoma growth. We conclude that OPN signaling is involved in macrophage recruitment into tumor, and our results emphasize the potential role of macrophage in modulation of tumor microenvironment via secretion of OPN, PGE2 and MMP-9, which trigger angiogenesis and melanoma growth. Thus, blockade of OPN and its regulated signaling network provides unique strategy to eradicate melanoma by manipulating TAMs.
