TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.
Fanconi Anemia; juvenile polyposis Smads; pancreatic cancer; squamous cell carcinomas; TGFβ signaling
Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. Immunohistochemistry (IHC) staining using human breast cancer tissue arrays revealed that 92% of invasive ductal breast cancer cases have CtBP1-positive staining compared to 4% CtBP1-positive in normal breast tissue. To explore the functional impact of CtBP1 in breast cancer, we examined CtBP1’s transcriptional regulation of known tumor suppressors, breast cancer susceptibility gene 1 (Brca1), and E-cadherin. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. Concomitantly, Brca1 loss was detected in 57% and E-cadherin loss was detected in 76% of human invasive ductal breast cancers, and correlated with CtBP1 nuclear staining in these lesions. Importantly, siRNA knock down of CtBP1 restored Brca1 and E-cadherin expression in breast cancer cell lines, implying CtBP1 down-regulates Brca1 and E-cadherin genes in human breast cancer. This study provides evidence that although genetic loss of Brca1 and E-cadherin are infrequent in breast cancer, they are downregulated at the transcriptional level by CtBP1 expression. Thus, CtBP1 activation could be a potential biomarker for breast cancer development.
Brca1; CtBP1; E-cadherin; transcription; breast cancer
TGFβ1 was initially identified as a potent chemotactic cytokine to initiate inflammation, but the autoimmune phenotype seen in TGFβ1 knockout mice reversed the dogma of TGFβ1 being a pro-inflammatory cytokine to predominantly an immune suppressor. The discovery of the role of TGFβ1 in Th17 cell activation once again revealed the pro-inflammatory effect of TGFβ1. We developed K5.TGFβ1 mice with latent human TGFβ1 overexpression targeted to epidermal keratinocytes by keratin 5. These transgenic mice developed significant skin inflammation. Further studies revealed that inflammation severity correlated with switching TGFβ1 transgene expression on and off, and genome wide expression profiling revealed striking similarities between K5.TGFβ1 skin and human psoriasis, a Th1/Th17-associated inflammatory skin disease. Our recent study reveals that treatments alleviating inflammatory skin phenotypes in this mouse model reduced Th17 cells, and antibodies against IL-17 also lessen the inflammatory phenotype. Examination of inflammatory cytokines/chemokines affected by TGFβ1 revealed predominantly Th1-, Th17-related cytokines in K5.TGFβ1 skin. However, the finding that K5.TGFβ1 mice also express Th2-associated inflammatory cytokines under certain pathological conditions raises the possibility that deregulated TGFβ signaling is involved in more than one inflammatory disease. Furthermore, activation of both Th1/Th17 cells and regulatory T cells (Tregs) by TGFβ1 reversely regulated by IL-6 highlights the dual role of TGFβ1 in regulating inflammation, a dynamic, context and organ specific process. This review focuses on the role of TGFβ1 in inflammatory skin diseases.
TGFβ1; skin inflammation
The ability to judge whether sensory stimuli match an internally represented pattern is central to many brain functions. To elucidate the underlying mechanism, we developed a neural circuit model for match/nonmatch decision making. At the core of this model is a “comparison circuit” consisting of two distinct neural populations: match enhancement cells show higher firing response for a match than a nonmatch to the target pattern, and match suppression cells exhibit the opposite trend. We propose that these two neural pools emerge from inhibition-dominated recurrent dynamics and heterogeneous top-down excitation from a working memory circuit. A downstream system learns, through plastic synapses, to extract the necessary information to make match/nonmatch decisions. The model accounts for key physiological observations from behaving monkeys in delayed match-to-sample experiments, including tasks that require more than simple feature-match (e.g. when BB in ABBA sequence must be ignored). A testable prediction is that magnitudes of match enhancement and suppression neural signals are parametrically tuned to the similarity between compared patterns. Furthermore, the same neural signals from the comparison circuit can be used differently in the decision process for different stimulus statistics or tasks; reward-dependent synaptic plasticity enables decision neurons to flexibly adjust the readout scheme to task demands, whereby the most informative neural signals have the highest impact on the decision.
delayed match-to-sample task; match enhancement and match suppression; repetition suppression; reward-dependent synaptic plasticity; fine discrimination
Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPAR) contributed background depolarization to sustain network firing. In contrast, many Response cells -which likely predominate in rodent PFC- were sensitive to AMPAR blockade and increased firing following systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s Disease profoundly impair cognition.
Synchronous rhythms represent a core mechanism for sculpting temporal coordination of neural activity in the brainwide network. This review focuses on oscillations in the cerebral cortex that occur during cognition, in alert behaving conditions. Over the last two decades, experimental and modeling work has made great strides in elucidating the detailed cellular and circuit basis of these rhythms, particularly gamma and theta rhythms. The underlying physiological mechanisms are diverse (ranging from resonance and pacemaker properties of single cells, to multiple scenarios for population synchronization and wave propagation), but also exhibit unifying principles. A major conceptual advance was the realization that synaptic inhibition plays a fundamental role in rhythmogenesis, either in an interneuronal network or in a recipropocal excitatory-inhibitory loop. Computational functions of synchronous oscillations in cognition are still a matter of debate among systems neuroscientists, in part because the notion of regular oscillation seems to contradict the common observation that spiking discharges of individual neurons in the cortex are highly stochastic and far from being clock-like. However, recent findings have led to a framework that goes beyond the conventional theory of coupled oscillators, and reconciles the apparent dichotomy between irregular single neuron activity and field potential oscillations. From this perspective, a plethora of studies will be reviewed on the involvement of long-distance neuronal coherence in cognitive functions such as multisensory integration, working memory and selective attention. Finally, implications of abnormal neural synchronization are discussed as they relate to mental disorders like schizophrenia and autism.
Dysregulation of transformation growth factor β (TGFβ) signaling has been reported in human psoriasis. However, the causal role of TGFβ in psoriasis has not been given attention until our recent report that the transgenic mice expressing wild-type TGFβ1 in the epidermis using a keratin 5 promoter (K5.TGFβ1wt) developed psoriasis-like skin inflammation. Additional experimental data further support the causal role of TGFβ1 overexpression in psoriasis. First, we temporally induced TGFβ1 expression in keratinocytes in our gene-switch-TGFβ1wt transgenic mice and found that inflammation severity correlated with on-and-off switch of TGFβ1wt transgene expression. Second, deletion of T cells in K5.TGFβ1wt mice significantly delayed the development of psoriatic lesions. Third, therapeutic approaches effective for human psoriasis, i.e. Enbrel and Rosiglitazone (Avandia®), are also effective in relieving the symptoms seen in K5.TGFβ1wt mice. Future studies will dissect specific mechanisms and identify key factors in the TGFβ1-induced skin inflammation. Our mouse models will provide a useful tool to test novel therapeutic interventions and help to design specific therapeutic approaches for inflammatory skin disorders, including human psoriasis.
Systems capable of targeting genetic manipulations to keratin-positive airway basal cells are more poorly developed than systems targeting other airway epithelial cell populations and this has likely hindered development of animal models of diseases such as lung squamous cell carcinoma. Although keratin promoter driven-Cre recombinase constructs are potentially useful for targeting these cells, these constructs have substantially higher activity in the skin and oral epithelium than in the airways. We developed a method for delivering RU486, the conditional activator of Cre recombinase progesterone receptor (CrePR) fusion proteins to the lung and then examined the activity of three keratin-driven CrePR constructs in the conducting airways. We also developed a technique for survival bronchioalveolar lavage on non-ventilated animals to examine the effects of the acetone/oil vehicle required to deliver RU486 to the lung. K5CrePR1 and K14CrePR1 constructs differ only in the keratin promoter used to target CrePR1 expression while K5Cre*PR contains a truncated progesterone receptor designed to reduce RU486-independent Cre activity. While all three constructs demonstrate RU486-inducible Cre activity in the conducting airways, both construct activity and tightness of regulation vary considerably. K5Cre*PR is the most tightly regulated Cre driver making it ideal for targeting somatic mutations to the airway epithelia while K5CrePR1 and K14CrePR1 may be better suited to studying diseases of the conducting airways where gene targeting of keratin expressing cells and their derivatives is desired.
Keratins; Cre recombinase; basal cells
We have previously shown that keratinocyte-specific deletion of Smad4, a TGFβ/Activin/BMP signaling mediator, results in a progressive alopecia. To further assess the molecular mechanisms of Smad4 loss-mediated alopecia, we examined expression levels of key molecules associated with hair follicle differentiation in Smad4-deleted skin. Among them, Desmoglein 4 (Dsg4) was down-regulated in Smad4-deleted skin prior to the onset of hair follicle abnormalities with gradual depletion coinciding with hair follicle degeneration. Chromatin immunoprecipitation (ChIP) assay showed that Smad4, together with the BMP mediators Smad1 and Smad5, but not the TGFβ/Activin mediators Smad2 or Smad3, bound to the Smad Binding Element (SBE) of the Dsg4 promoter. A Dsg4 reporter assay revealed that Smad4 was required for the maximal transactivation of Dsg4 in cooperation with Smad1 and Smad5. Mutating the SBE of the Dsg4 promoter abrogated Smad4 transactivation of Dsg4. Furthermore, BMP ligands, but not ligands of TGFβ and Activin, induced endogenous Dsg4 expression. Our data demonstrate that in the presence of Smad4, BMP signaling participated in transcriptional regulation of Dsg4. Thus, Smad4 loss-associated Dsg4 depletion contributed, at least in part, to hair follicles degeneration in Smad4 deficient skin.
Smad4; Hair Follicle; Desmoglein-4; TGFβ; BMP
Neurons show diverse timescales, so that different parts of a network respond with disparate temporal dynamics. Such diversity is observed both when comparing timescales across brain areas and among cells within local populations; the underlying circuit mechanism remains unknown. We examine conditions under which spatially local connectivity can produce such diverse temporal behavior.
In a linear network, timescales are segregated if the eigenvectors of the connectivity matrix are localized to different parts of the network. We develop a framework to predict the shapes of localized eigenvectors. Notably, local connectivity alone is insufficient for separate timescales. However, localization of timescales can be realized by heterogeneity in the connectivity profile, and we demonstrate two classes of network architecture that allow such localization. Our results suggest a framework to relate structural heterogeneity to functional diversity and, beyond neural dynamics, are generally applicable to the relationship between structure and dynamics in biological networks.
Many biological systems can be thought of as networks in which a large number of elements, called ‘nodes’, are connected to each other. The brain, for example, is a network of interconnected neurons, and the changing activity patterns of this network underlie our experience of the world around us. Within the brain, different parts can process information at different speeds: sensory areas of the brain respond rapidly to the current environment, while the cognitive areas of the brain, involved in complex thought processes, are able to gather information over longer periods of time. However, it has been largely unknown what properties of a network allow different regions to process information over different timescales, and how variations in structural properties translate into differences in the timescales over which parts of a network can operate.
Now Chaudhuri et al. have addressed these issues using a simple but ubiquitous class of networks called linear networks. The activity of a linear network can be broken down into simpler patterns called eigenvectors that can be combined to predict the responses of the whole network. If these eigenvectors ‘map’ to different parts of the network, this could explain how distinct regions process information on different timescales.
Chaudhuri et al. developed a mathematical theory to predict what properties would cause such eigenvectors to be separated from each other and applied it to networks with architectures that resemble the wiring of the brain. This revealed that gradients in the connectivity across the network, such that nodes share more properties with neighboring nodes than distant nodes, combined with random differences in the strength of inter-node connections, are general motifs that give rise to such separated activity patterns. Intriguingly, such gradients and randomness are both common features of biological systems.
timescales; network dynamics; neural networks; None
Noise can degrade memories by causing transitions from one memory state to another. For any biological memory system to be useful, the time scale of such noise-induced transitions must be much longer than the required duration for memory retention. Using biophysically-realistic modeling, we consider two types of memory in the brain: short-term memories maintained by reverberating neuronal activity for a few seconds, and long-term memories maintained by a molecular switch for years. Both systems require persistence of (neuronal or molecular) activity self-sustained by an autocatalytic process and, we argue, that both have limited memory lifetimes because of significant fluctuations. We will first discuss a strongly recurrent cortical network model endowed with feedback loops, for short-term memory. Fluctuations are due to highly irregular spike firing, a salient characteristic of cortical neurons. Then, we will analyze a model for long-term memory, based on an autophosphorylation mechanism of calcium/calmodulin-dependent protein kinase II (CaMKII) molecules. There, fluctuations arise from the fact that there are only a small number of CaMKII molecules at each postsynaptic density (putative synaptic memory unit). Our results are twofold. First, we demonstrate analytically and computationally the exponential dependence of stability on the number of neurons in a self-excitatory network, and on the number of CaMKII proteins in a molecular switch. Second, for each of the two systems, we implement graded memory consisting of a group of bistable switches. For the neuronal network we report interesting ramping temporal dynamics as a result of sequentially switching an increasing number of discrete, bistable, units. The general observation of an exponential increase in memory stability with the system size leads to a trade-off between the robustness of memories (which increases with the size of each bistable unit) and the total amount of information storage (which decreases with increasing unit size), which may be optimized in the brain through biological evolution.
Previous studies have shown that non-human primates can generate highly stochastic choice behavior, especially when this is required during a competitive interaction with another agent. To understand the neural mechanism of such dynamic choice behavior, we propose a biologically plausible model of decision making endowed with synaptic plasticity that follows a reward-dependent stochastic Hebbian learning rule. This model constitutes a biophysical implementation of reinforcement learning, and it reproduces salient features of behavioral data from an experiment with monkeys playing a matching pennies game. Due to interaction with an opponent and learning dynamics, the model generates quasi-random behavior robustly in spite of intrinsic biases. Furthermore, non-random choice behavior can also emerge when the model plays against a non-interactive opponent, as observed in the monkey experiment. Finally, when combined with a meta-learning algorithm, our model accounts for the slow drift in the animal’s strategy based on a process of reward maximization.
Decision making; Reward-dependent stochastic Hebbian learning rule; Reinforcement learning; Meta-learning; Synaptic plasticity; Game theory
Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.
schizophrenia; pharmacology; functional connectivity; computational modeling; thalamus; NMDA receptors; glutamate
A considerable body of evidence has accumulated over recent years on the functions of the default-mode network (DMN) – a set of brain regions whose activity is high when the mind is not engaged in specific behavioral tasks and low during focused attention on the external environment. In this review, we focus on DMN suppression and its functional role in health and disease, summarizing evidence that spans several disciplines, including cognitive neuroscience, pharmacological neuroimaging, clinical neuroscience, and theoretical neuroscience. Collectively, this research highlights the functional relevance of DMN suppression for goal-directed cognition, possibly by reducing goal-irrelevant functions supported by the DMN (e.g., mind- wandering), and illustrates the functional significance of DMN suppression deficits in severe mental illness.
default-mode network; suppression; cognition; schizophrenia; computational modeling
Histone modifications play important roles in the tumorigenesis and progression of prostate cancer (PCa) and genes involved in histone modifications are seemed as ideal targets for treatment of PCa patients. However, clinical trials have shown that those existing drugs exert the minimal antitumor activity and excess adverse effects on PCa patients. Therefore, it is of great interest to figure out novel specific biomarkers to guide the development of new drugs. In present study, an RNAi screening with 44 genes involved in histone modifications was applied to a PCa cell line, Du145. The results showed that nine genes were in positive regulation of Du145 cell growth. Then four selected genes (KAT2B, KAT5, KAT6B and HDAC1) were found to exert this effect by a gene-specific manner when silenced. And then KAT5 or KAT6B silenced cells were subjected to DNA microarray analysis. The common differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) and found that PDEF signaling, EIF2 signaling and PI3K signaling was suppressed following by KAT5 or KAT6B silencing. Subsequent immunoblotting assay showed that AKT signaling was inhibited, which suggested that KAT5 or KAT6B regulates cancer cell growth through PI3K-AKT signaling. Together with our published data  that AURKA inhibitoin increased drug sensitivity of DU145, our work demonstrated the underlying mechanism that how the acetylation enzyme regulates cancer cells survial and might provide potential therapeutic targets for prostate cancer patients in future epigenetic drug development.
Prostate cancer; histone modifications; RNAi screening; KAT5; KAT6B; PI3K-AKT signaling
Carboxyl-terminal binding protein 1 (CtBP1) has been shown to suppress the transcription of several tumor suppressors in vitro. Paradoxically, a previous report showed that CtBP1 mRNA was down-regulated in melanoma. Using immunostaining, we found that a large percentage of human melanomas were positive for CtBP1 protein. Further, we demonstrated that CtBP1 expression in melanoma cells contributes to cell proliferation and genome instability, two aspects promoting melanoma initiation and progression. Breast Cancer Susceptibility Gene 1(Brca1), a core protein in DNA damage repair, was repressed by CtBP1 in melanoma cells. Consistently, Brca1 loss was found in human malignant melanoma tissues inversely correlated with CtBP1 expression levels. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well. Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1, with CtBP1 over-expression potentially contributing to increased proliferation and DNA damage in melanoma.
Brca1; CtBP1; p16INK4a; transcription; tumor suppressor; melanoma
We report that K5.Smad7 mice, which express Smad7 transgene by a keratin-5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to NF-κB activation known to contribute to oral mucositis, we found activated TGF-β signaling in oral mucositis. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor CtBP1 transcriptionally repressed Rac1, and Smad7 abrogated this repression. Knocking down Rac1 in mouse keratinocytes abrogated Smad7-induced migration. Topically applying Smad7 protein with a cell permeable Tat-tag (Tat-Smad7) to oral mucosa showed preventive and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified novel molecular mechanisms involved in oral mucositis pathogenesis and our data suggest an alternative therapeutic strategy to block multiple pathological processes of oral mucositis.
Rituximab, a monoclonal antibody against CD20+ antigen specific B cell, has been increasingly used in the treatment of non-Hodgkin’s lymphoma and some other autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. It is noted that Rituximab could enhanced the efficacy of CHOP-based chemotherapy. Meanwhile it could increase the opportunity of lung infection. Pneumocystis jiroveci pneumonia (PCP), a rare opportunistic infection that was not reported in the large-scale clinical trials of Rituximab, was found recently in patients with non-Hodgkin’s lymphoma treated with remedy containing Rituximab. We herein report two cases of PCP in lymphoma patients after Rituximab-containing chemotherapy. Both patients were successfully treated, with trimethoprim-sulfamethoxazole (TMP-SMX) in one case and Caspofungin alone in the other. We also reviewed the literature and concluded that PCP is an infrequent but potentially life-threatening infection in patients with non-Hodgkin’s lymphoma subjected to Rituximab-containing regimen. Therefore, adequate prophylaxis, timely diagnosis and treatment are necessary.
Rituximab; non-Hodgkin’s lymphoma; pneumocystis jiroveci pneumonia (PCP); Caspofungin
Oral leukoplakia (OL) is the most common premalignancy in the oral cavity and can progress to oral squamous cell carcinoma (OSCC). SMAD4 is a tumor suppressor implicated in multiple cancer types including OSCC. To assess the role of SMAD4 in oral leukoplakia malignant transformation, the authors investigated SMAD4 expression patterns in OL and OSCC using a highly specific antibody and correlated the patterns with the risk of malignant transformation oral leukoplakia. Immunohistochemistry and a quantitative imaging system were used to measure SMAD4 expression in OL from 88 OL patients, including 22 who later went through malignant transformation, and their OSCC counterpart. Forty-three (48.9%) of the 88 OL patients had strong SMAD4 expression. SMAD4 expression had no significant correlation with patients' clinicopathological parameters. Interestingly, 17 (39.5%) of the 43 OL lesions with strong SMAD4 expression went through malignant transformation whereas only 5 (11.1%) of the 45 OL lesions with weak SMAD4 expression did so (p = 0.002). The SMAD4 expression in OL was much higher than that in their OSCC counterpart. Kaplan-Meier analysis revealed that the combination of SMAD4 expression and histological grade of dysplasia (p = 0.007) is a better predictor for the malignant transformation of oral leukoplakia. In the multivariate analysis, both SMAD4 expression and grade of dysplasia were identified as independent factors for OL malignant transformation risk (p = 0.013 and 0.021, respectively). It was concluded that high SMAD4 expression may be indicative of an early carcinogenic process in OL and serve as an independent biomarker in assessing malignant transformation risk in patients with OL, and the combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia.
The present study examined the downregulation of survivin expression by hypoxia-inducible factor-1α (HIF-1α) miRNA and its effect in the inhibition of A549 cell growth in vitro and in vivo. Survivin expression, apoptosis, proliferation and migration under normoxic and hypoxic conditions were assessed by standard methods. Cotransfection and chromatin immunoprecipitation were used to observe the effects of HIF-1α on survivin transcription. HIF-1α knockdown in A549 cells were injected into nude mice to examine survivin expression and suppression of tumorigenicity. Transfection of A549 cells with HIF-1α miRNA led to decreased expression of HIF-1α and survivin mRNA and protein. Survivin overexpression is mediated by HIF-1α by direct binding to a putative binding site in the survivin core promoter. HIF-1α-miRNA induced apoptosis and inhibited proliferation of A549 cells under hypoxic, but not normoxic, conditions, whereas transfection by survivin expression vectors partly rescued the apoptotic phenotype and revived cell proliferation under hypoxic conditions. However, cell migration was substantially suppressed by HIF-1α silencing under normoxic and hypoxic conditions. After A549 cells were xenografted in nude mice, survivin expression in mice treated with HIF-1α miRNA was downregulated, and tumor growth was significantly inhibited. Silenced HIF-1α gene expression induced apoptosis and suppressed growth of A549 cells by downregulating survivin expression in vitro and in vivo. Our results also provide a basis to target the HIF-1α pathway in lung cancer therapy.
Hypoxia-inducible factor-1α; miRNA; survivin; lung cancer
Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long.
The palliative therapy effect by docetaxel for CRPC patients makes it urgent to improve the therapy. It was suggested that PI3K and androgen receptor-directed combination therapy may be effective for prostate cancer (PCa) patients PTEN negative. However, for those patients PTEN positive, the mechanism of anti-apoptosis survival of cancer cells is not yet well defined. Amplification of AURKA has been detected in 5% of PCa. In this work, Du145, a PTEN positive PCa cell model, was employed to investigate the role of aurora kinase a (AURKA) on cell growth. Inhibition of AURKA expression by shRNA markedly reduced prostate cancer cell viability. Furthermore, we demonstrate that AURKA inhibition induced a remarkable downregulation of AKT activity and Bax induction. Moreover, specific inhibition of the activity of AURKA, but not other aurora family members, by small molecular chemical inhibitors induced significant cell killing effects. Notably, AURKA inhibition sensitized prostate cancer cells to docetaxel treatment. Our work suggests that AURKA-directed monotherapy or combination therapy with docetaxel could be a potent treatment for PCa patients in future.
Prostate cancer; AURKA; p53; docetaxel; castration-resistant prostate cancer; aurora kinases
Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of transforming growth factor β type II receptor (TGFβRII) promotes lung AdC and SCC carcinogenesis.
We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinico-pathologic parameters. To determine if sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic KrasG12D to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase.
Reduced TGFβRII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGFβRII deletion in mouse airway epithelia increases the size and number of KrasG12D-initiated AdC and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion.
Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is at least partially mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes AdC and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII demonstrates haploid insufficiency, suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.
lung adenocarcinoma; lung squamous cell carcinoma; TGFβ; tumor progression; mouse model