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Supplementary Data from MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma

Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC.Significance:This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

Background: Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical intervention, such as physical exercise has been recognized as an effective strategy to improve memory function of people with dementia. Here we investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and underlying mechanisms in 3xTg-AD mouse, a well-established rodent model of Alzheimer's disease (AD). Methods: 3xTg-AD transgenic mice with three AD mutations were used and compared with non-transgenic mice. Voluntary wheel running continued for 5 months (1 hour per day, 5 days per week) and was followed by spatial memory testing. At the end of behavior testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Results: Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by increased synapses and higher expressions of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, resulting in reduced Aβ peptides, and spatial memory performance correlated with levels of Aβ peptides Aβ1-40 and Aβ1-42. Conclusion: These data suggest that prolonged running may improve memory in preclinical AD via slowing down amyloid pathology and preventing loss of synaptic contacts.

Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. Significance: This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

This study aimed to design arterial ischemic and venous congested areas on the same multi-territory perforator flap, assessing the effects of arterial blood supply and venous return on flap survival. Totally 68 rats were randomly divided into the experimental (Exp) and control (Con) groups. In the Exp group, flaps were based on left superficial epigastric artery and right superficial epigastric vein. In the Con group, flaps were based on the left superficial epigastric artery and vein. Immediate postoperative ink-gelatin angiography, epidermal metabolite levels detection, tissue edema measurement, survival rate evaluation in half of the flaps and average microvessel density assessment were performed. Blood in the Exp group flowed through most angiosomes, but only flowed around pedicled vessels in the Con group; metabolite levels of left halves in the Con and Exp groups were comparable with those of right halves. Angiosomes with high water contents occurred in the Exp group. Survival rates of left halves in the Con and Exp groups were higher than those of right halves, and more microvessels were found in the left ventral areas of both groups compared with the right ventral area in the Exp group. These findings revealed that on the same multi-territory perforator flap, arterial blood supply, affected by venous return, is a prerequisite for flap survival.

The impacts of early-life adversity (ELA) on cognitive functions including striatal-dependent habit memory and hippocampal-dependent spatial memory were investigated in male mice. The ELA mouse model was generated via an altered cage environment with limited nesting and bedding materials during postnatal days 2-9 (P2-9). The altered cage environment affected the nesting behaviors of dams, creating a stressful condition for their offspring. The ELA mice had biased decision making and poor spatial memory when they grew into young adults (4-month-old). To explore the underlying synaptic basis of these effects, excitatory synapses represented by postsynaptic density protein-95 (PSD-95) were immunolabelled on a series of brain sections and stereologically quantified in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), as well as in area CA1 of the dorsal hippocampus. Increased PSD-95-immunoreactive synapses were observed in DLS but not DMS, whereas selective loss of PSD-95 synapses was detected in the stratum radiatum of area CA1. The spine data supported the selective effects of ELA on PSD-95 synapses. Specifically, both thin and mushroom-type spines were increased in DLS, while loss of thin spines was apparent in CA1 radiatum in ELA mice versus controls. The correlation between PSD-95 synapses and memory performances was further analyzed, and the data suggested that increased small (0.20 μm

Background: Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical intervention, such as physical exercise has been recognized as an effective strategy to improve memory function of people with dementia. Here we investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and underlying mechanisms in 3xTg-AD mouse, a well-established rodent model of Alzheimer's disease (AD).Methods: 3xTg-AD transgenic mice that bear three mutations of AD were used and compared with non-transgenic mice. Voluntary wheel running continued for 5 months (1 hour per day, 5 days per week), followed by spatial memory testing. At the end of behavior testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in dorsal hippocampus. Results: Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by increased synapses and higher expressions of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, resulting in reduced Aβ peptides, and spatial memory performance correlated with levels of Aβ peptides including Aβ1-40 and Aβ1-42. Conclusion: These data suggest that prolonged running may improve memory in preclinical AD via slowing down amyloid pathology and preventing loss of synaptic contacts.

The effects of early-life adversity (ELA) on dendritic differentiation of striatal neurons were investigated in the dorsal striatum including the dorsomedial striatum and dorsolateral striatum (DMS and DLS, respectively). An animal model of ELA was created by changing the growth environment of newborn mouse pups by giving limited bedding and nesting materials from postnatal day 2 to day 9 (P2-P9). One week after the stress paradigm (P16), the dendritic branches and spines of striatal spiny neurons as well as the synapses represented by postsynaptic density protein-95 (PSD-95) in DMS and DLS were stereologically analyzed. Adverse experience in early life selectively affected the spiny neurons in DLS, leading to abundant proximal dendritic branches and an increased number of filopodia-like protrusions, but a reduced number of dendritic spines. The selective effects of stress on neurons in DLS were further identified by reduced expression of PSD-95, including a reduced optical density of PSD-95 immunoreactivity and fewer individual PSD-95 immunoreactive synapses in this region. Notably, stress in early life affected either D1 or D2 dopamine receptor-expressing DLS neurons. These findings suggest that adverse early-life experience delayed the maturation of dendritic spines on neurons in the dorsolateral striatum. Altered dendritic differentiation provoked by stress in early life may contribute critically to the formation of proper neuronal circuits in the dorsal striatum and, therefore, affect striatum-dependent habitual behavior and emotional function later in life.

Alzheimer’s disease (AD) is the most common form of dementia which mostly affects persons younger than 65 years old. Mounting findings showed that amyloid-β (Aβ) peptides, oxidative stress, neuroinflammation and insulin resistance may play central role in the pathogenesis of AD. There are very many methods to slow it through affecting these aforementioned factors. However, more efficient prevention of the progression of AD is still ambiguous. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is expressed by several organs. It increases insulin sensitivity and regulates lipid metabolism and energy homeostasis. Emerging evidence demonstrates that FGF21 has potential effects in the brain involving metabolic regulation, neuroprotection and cognition. Hence, we hypothesize that FGF21 may be a protective factor in AD by attenuating Aβ generation, inflammation, oxidative stress, and insulin resistance. Our hypothesis will shed new light on the understanding of pathogenesis of AD and help to find a new way to prevent the genesis and progress of AD.

The effects of prolonged physical training on memory performance and underlying synaptic mechanisms were investigated in old C57BL/6 mice. Training via voluntary running wheels was initiated at 16 months of age and continued for 5 months (1 hour per day and 5 days per week), followed by learning and memory test and spine/synapse analysis. Trained old mice were compared with their age-matched sedentary controls and aged adult controls. This training improved hippocampal-dependent spatial learning and memory function in old mice, and enhanced cognition was accompanied by increased density of spines on CA1 pyramidal cells in the hippocampus. Particularly, the training selectively affected thin spines that carry small synapses in the stratum radiatum, the target area of CA3 Schaffer pathway. Furthermore, increased density of thin spines positively correlates with improved memory performance. Finally, the training prevented age-related loss of postsynaptic density protein-95 in the Schaffer pathway. These data suggest that the preservation of thin spines carrying small synapses in specific hippocampal region contributes critically to running-related improvement of learning and memory function.

The effects of prolonged physical training on memory performance and underlying presynaptic mechanisms were investigated in old C57BL/6 mice. Training via voluntary running wheels was initiated at 16 months of age and continued for 5 months (1 h per day, 5 days per week), followed by testing of learning and memory functions and counting of presynaptic puncta and cholinergic inputs in the hippocampus. Trained old mice were compared to their age-matched sedentary controls and adult controls. This training strategy improved hippocampal-dependent spatial memory function tested via a novel location task, and enhanced memory was accompanied by restored presynaptic puncta and cholinergic fibers in area CA1 and DG of the hippocampus in old mice. Particularly, the training selectively affected presynaptic vesicle protein synaptophysin but not growth associated protein GAP-43, and the increased number of synaptophysin puncta positively correlates with improved memory performance. To better understand the neurochemical mechanisms by which prolonged physical training protects against aging-related memory deficits, the cholinergic inputs to the hippocampus were compared among the three groups of mice and correlated with memory performance. While the running prevented age-related loss of cholinergic inputs, it has limited impact on the projection source cells in the medial septum-diagonal band (MS-DB). Importantly, cholinergic fibers in area CA1 and DG positively correlated with spatial memory function. These data suggest that the preservation of presynaptic inputs, particularly those involved in the integrity of memory performance, contributes critically to the beneficial effects of physical running initiated at an older age.

The design and synthesis of passivation materials are of significant importance to reducing surface charge recombination in quantum dot-sensitized solar cells (QDSCs). In this study, the systematic characterization and comparison of the optical and electrochemical properties of ZnS and ZnSe passivation layers and their impacts on the performance of the resulting QDSCs have been investigated. The ZnS and ZnSe passivation layers were all deposited via a reproducible and controlled successive ionic layer adsorption and reaction method. QDSCs with a ZnSe passivation layer demonstrated strongly inhibited interfacial charge recombination and greatly enhanced light harvesting, resulting in a power conversion efficiency of up to 6.4%, which is appreciably higher than 4.9% for the solar cells with a ZnS passivation layer and 3.4% for the solar cells without a passivation layer.

Han Li,1,* Weijing Zhang,1,* Xiaoying Sun,1,* Jueming Chen,1 Yue Li,1 Chunhao Niu,2 Benke Xu,3 Yanna Zhang1 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; 2Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, China; 3Department of Anatomy, Medical School of Yangtze University, Jingzhou, China *These authors contributed equally to this work Background: KIF20A plays an indispensable role in cytokinesis regulation, which is important for tumor proliferation and growth. Recently, the oncogenic role of KIF20A has been well documented in several cancers. However, its clinical role in epithelial ovarian cancer (EOC) remains not reported yet. We investigated its expression and its role in promoting invasion and chemoresistance in EOC cells.Patients and methods: KIF20A transcription and translation levels were investigated in normal ovarian epithelial cell, ovarian cancer cells, and 10 pairs of fresh EOC tissues and adjacent normal ovarian tissues by real-time quantitative polymerase chain reaction and Western blots. Moreover, KIF20A protein level was also examined by immunohistochemistry in 150 EOC tissues. The correlation between KIF20A expression and clinical variables was analyzed by statistical methods. We also used wound healing assay, transwell assay MTT, and Annexin V/PI to explore KIF20A functions.Results: KIF20A expression was obviously elevated at both mRNA and protein levels in EOC cell lines and clinical cancer tissues compared with normal ovarian epithelial cell and adjacent normal ovarian tissues. KIF20A protein expression was highly correlated with International Federation of Gynecology and Obstetrics stage (P=0.008), lymph node metastasis (P=0.002), intraperitoneal metastasis (P

Aging is a normal physiological process associated with impairments in cognitive function, including learning and memory. Here, the underlying synaptic mechanisms by which aging leads to the decline of spatial learning and memory function were investigated in 25-month-old aged mice versus 2-month-old young mice. Deficits of spatial learning and memory, as well as selective loss of thin spines, but not mushroom-type spines on apical dendrites of CA1 pyramidal cells were found in aged mice. Specifically, loss of thin spines in aged mice with memory deficits was primarily found on dendritic segments located in the Schaffer pathway, and the density of thin spines significantly correlated with spatial memory performance. The loss of thin spines was evidenced by a decrease in small synapses that express diminutive amounts of postsynaptic density protein-95 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1. Furthermore, mushroom-type spines and GluR1-expressed large synapses were not affected in aged mice with impaired memory. Taken together, these data suggest that the selective loss of those highly plastic thin spines with sparse postsynaptic density protein-95 and GluR1 receptors may significantly contribute to cognitive deficits in aged individuals.

TRPC6 plays a critical role in proteinuric kidney diseases, and TRPC3 is involved in tubulointerstitial damage and renal fibrosis in obstructed kidneys. Podocyte loss is a characteristic event in diabetic nephropathy (DN). The aim of this study was to examine whether deletion of the closely related diacylglycerol (DAG)-responsive TRPCs in mice (TRPC3/6/7-/-) affects diabetes-induced renal dysfunction and podocyte loss. We compared urine volume, kidney hypertrophy, glomerular enlargement, albuminuria and podocyte loss between wild type (WT) and TRPC3/6/7-/- diabetic mice. Finally, we examined whether the TGFβ1 signaling pathway is changed in diabetic WT and TRPC3/6/7-/- mice. TRPC6 protein in the renal cortex was increased in WT diabetic mice. High glucose (HG) treatment increased TRPC6 expression in human podocytes. TRPC3 protein, however, was not altered in either diabetic mice or HG-treated human podocytes. Although diabetic WT and TRPC3/6/7-/- mice had similar levels of hyperglycemia, the TRPC3/6/7-/- diabetic mice showed less polyuria, kidney hypertrophy, glomerular enlargement, albuminuria, and had lost less podocytes compared with WT diabetic mice. In addition, we observed decreased expression of anti-apoptotic Bcl2 and increased expression of pro-apoptotic cleaved caspase 3 in WT diabetic mice, but such changes were not significant in TRPC3/6/7-/- diabetic mice. Western blot and immunohistochemistry revealed that TGFβ1, p-Smad2/3, and fibronectin were upregulated in WT diabetic mice; however, expression of these signaling molecules was not changed in TRPC3/6/7-/- diabetic mice. In conclusion, deletion of DAG-responsive TRPCs attenuates diabetic renal injury via inhibiting the upregulation of TGFβ1 signaling in diabetic kidneys.

Background The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown. Methods The expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway. Results NUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway. Conclusion These findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma. Electronic supplementary material The online version of this article (10.1186/s13046-017-0597-y) contains supplementary material, which is available to authorized users.

Clinicopathological characteristics of studied patients and expression of NUSAP1 in 221 glioma specimens. Table S2. Correlation between NUSAP1 expression and clinicopathological characteristics of 221 glioma specimens. Table S3. Univariate and multivariate analyses of various prognostic parameters in patients with glioma by Cox-regression analysis (DOCX 21Â kb)