Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.

Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways.

Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL­1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL­1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knocked­down Jurkat and BALL­1 cells, and the phosphorylation level of ERK was decreased in Sema4D knocked­down BALL­1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.

Inhibition of semaphorin 4D enhances chemosensitivity by increasing 5-fluorouracile-induced apoptosis in colorectal cancer cells.

Overexpression of semaphorin 4D (SEMA4D), an immune semaphorin, is found in various human malignancies, including colorectal cancer (CRC). In this study, we explored the relationship between silencing SEMA4D expression and 5-fluorouracil (5-FU) response in the colorectal cancer cell line. SW48 cells were transfected with a short interfering RNA (siRNA) in order to silence SEMA4D gene expression and then exposed to 5-FU for 48 h. The down-regulation of SEMA4D expression was confirmed by qRT-PCR and the particular concentration of 5-FU was acquired using MTT assay. Flow cytometry and western blot were used to evaluate apoptosis rate and pro- and anti-apoptotic expression levels of proteins involved in apoptosis including Bax, Bcl-2, P53, and caspase-3. Other oncogenic activities including epithelial-mesenchymal transition (EMT) process, cancer stem cell (CSC) markers, and ß-catenin pathway were investigated using qRT-PCR, and western blot. The proliferation was analyzed via colony formation test and cell invasion was assessed by transwell assay. Our data demonstrate that SEMA4D silencing results in strikingly elevated apoptosis in response to 5-FU treatment and leads to down-regulation of Bcl-2 and overexpression of Bax, P53, and caspase-3 in protein levels. Furthermore, the mRNA and protein expression levels of ß-catenin, as well as transcript expressions of CSCs and EMT markers, were remarkably diminished. However, mRNA expression of E-cadherin as an epithelial marker was significantly increased in 5-FU treatment combined with siRNA SEMA4D. This study implicates that the silencing of SEMA4D by siRNA promotes the chemosensitivity of SW48 cells to 5-FU and it may be a potential therapeutic agent for colon cancer therapy.

High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma.

BACKGROUND: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. METHODS: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Affiliated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. RESULTS: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical significance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). CONCLUSION: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.

Semaphorin 6A Attenuates the Migration Capability of Lung Cancer Cells via the NRF2/HMOX1 Axis.

Cell migration is a fundamental feature of cancer recurrence. Since recurrence is correlated with high mortality in lung cancer, it follows that reducing cell migration would decrease recurrence and increase survival rates. Semaphorin-6A (SEMA6A), a protein initially known as a regulator of axonal guidance, is down-regulated in lung cancer tissue, and low levels of SEMA6A are associated with cancer recurrence. Thus, we hypothesized that SEMA6A could suppress cancer cell migration. In this study, we found that the migration capability of H1299 lung cancer cells decreased with SEMA6A overexpression, while it increased with SEMA6A silencing. Moreover, silencing of the cellular homeostasis protein Heme-oxygenase-1 (HMOX1) and/or the transcription factor Nuclear Factor, Erythroid-2-Like-2 (NRF2) reversed the migration-suppressing effect of SEMA6A and the SEMA6A-driven alterations in expression of urokinase insulin-like-growth-factor-binding-protein-3, Matrix metalloproteinase (MMP)-1, and MMP9, the downstream effectors of HMOX1. Taken together, these results demonstrate that SEMA6A is a potential suppressor of cancer migration that functions through the NRF2/HMOX1 axis. Our results explain why low SEMA6A is linked to high recurrence in the clinical setting and suggest that SEMA6A could be useful as a biomarker or target in lung cancer therapy.

Semaphorin 4C Promotes Macrophage Recruitment and Angiogenesis in Breast Cancer.

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules that are associated with repelling axonal guidance. Intriguingly, recent researches indicate that semaphorins are involved in cancer progression. Semaphorin 4C (SEMA4C) has long been considered a neuronal migration gene, but we detected that it is also highly expressed in many malignant human cancers. During an investigation of subcutaneous tumor models, we found that SEMA4C expression promoted tumor growth and progression. We discovered that SEMA4C was involved in maintaining tumor cell self-renewal, likely by regulating the p53 pathway. Inhibiting the expression of endogenous SEMA4C in tumor cells impaired growth and induced senescence and cell-cycle arrest in the G2-phase. In addition, we found that SEMA4C induced the production of angiogenin and colony-stimulating factor-1 (CSF-1) in tumor cells by activating the NF-κB pathway in a plexinB2-dependent manner. In conclusion, SEMA4C expression in breast cancer cells promotes cancer cell proliferation, macrophage recruitment, and angiogenesis. Thus, inhibition of SEMA4C activity may be a novel therapeutic strategy for human breast cancer. IMPLICATIONS: In breast cancer, therapeutic targeting of the SEMA4C pathway may prevent tumor growth, angiogenesis, metastasis, and progression.

CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis.

Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal cancers mainly due to the high rate of metastasis. Here, we find that the expression level of CD100 in HNSCC is positively correlated with the T category, pathological grade and lymph node metastasis of the tumor. The level of soluble CD100 (sCD100) is highly increased in serum of HNSCC patients, and sCD100 markedly induces the epithelial-mesenchymal transition (EMT) of HNSCC through its receptor, Plexin-B1 (PlxnB1), and promotes the metastasis in a xenograft mouse model. Furthermore, sCD100 promotes the stabilization of Snail through the regulation of the Vav1-Rac1/RhoA-p21-activated kinase pathway for the induction of EMT. Anti-CD100 antibody abolishes the CD100-induced EMT and prevents the metastasis of HNSCC, and anti-CD100 antibody also increases the drug sensitivity of HNSCC. Taken together, our study shows for the first time that CD100 induces the EMT of HNSCC and promotes the metastasis, and CD100 would be a candidate as a novel prognostic biomarker and a potential therapeutic target for HNSCC.

Promoter hypermethylation-mediated downregulation of tumor suppressor gene SEMA3B and lncRNA SEMA3B-AS1 correlates with progression and prognosis of esophageal squamous cell carcinoma.

Frequent deletions of tumor-suppressor genes at chromosome 3p21.3 have been detected in esophageal squamous cell carcinoma (ESCC). As a candidate tumor suppressor gene, semaphorin 3B (SEMA3B) is located at 3p21.3 and is frequently inactivated in several tumors. However, the role and inactivation mechanisms of SEMA3B and its antisense long non-coding RNA (lncRNA) SEMA3B-AS1 in the carcinogenesis of ESCC have not been fully elucidated. The present study was conducted to investigate the role, epigenetic inactivation mechanisms, and prognostic value of SEMA3B and SEMA3B-AS1 in ESCC tumorigenesis and prognosis. Frequent downregulation of SEMA3B and SEMA3B-AS1 was detected in esophageal cancer cells and ESCC tissues, and the expression level of SEMA3B and SEMA3B-AS1 in ESCC tissues was correlated with TNM stage and lymph node metastasis. SEMA3B and SEMA3B-AS1 shared the same CpG island in the promoter region and the expression of both genes might be regulated by the promoter methylation status. Furthermore, transcription factor Sp1 activated SEMA3B or SEMA3B-AS1 transcription and the promoter hypermethylation of SEMA3B and SEMA3B-AS1 influenced Sp1 binding ability. Moreover, over-expression of SEMA3B and SEMA3B-AS1 suppressed the viability and invasion of esophageal cancer cells in vitro. SEMA3B-AS1 influenced the protein expression of SEMA3B. SEMA3B or SEMA3B-AS1 expression and promoter methylation status were correlated with ESCC patients' survival. Thus, these findings suggest that SEMA3B and SEMA3B-AS1 may act as tumor suppressors and may serve as potential targets for antitumor therapy.

Association between prognosis and SEMA4D/Plexin-B1 expression in various malignancies: A meta-analysis.

INTRODUCTION: SEMA4D and its high affinity receptor Plexin-B1 showed a promising prognosis prediction for carcinoma patients in recent studies, we performed a meta-analysis to evaluate the prognostic role of them in various malignancies. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and CNKI from inception till July 2017. Eligible studies were identified by different reviewers. Hazard ratios (HRs)/related ratios (RRs) and their corresponding 95% confidence intervals (CIs) were extracted to investigate the relevance between malignancies prognosis and SEMA4D/Plexin-B1. RESULTS: Around 2638 patients from 14 studies were included in this meta-analysis. High expression of SEMA4D was significantly associated with overall survival (OS) and disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) in tumors (respectively, HRos = 2.05, 95%CI: 1.68-2.50, P < .001; HRdfs/pfs/rfs = 1.59, 95%CI = 1.27-1.98, P < .001). However, the relationship between SEMA4D expression and prognosis of breast cancer patients was failed to find (HR = 0.76, 95%CI = 0.32-1.82, P = .539). Plexin-B1 level showed a significant positive correlation both with OS and DFS of Caucasian breast cancer patients (respectively, HRos = 0.56, 95%CI: 0.39-0.79, P = .001; HRdfs = 0.68, 95%CI = 0.51-0.90, P = .008) CONCLUSIONS:: SEMA4D could be a prospective biomarker for prognostic prediction of various malignancies except breast cancer. For Caucasian breast cancer patients, SEMA4D's high affinity receptor Plexin-B1 showed a significant positive correlation with survival.

Sema4A Responds to Hypoxia and Is Involved in Breast Cancer Progression.

Semaphorin4A (Sema4A) is a family member of semaphorins expressed in immune cells and is also related with disease progression of tumor disease. In this study, we investigate the expression and pathological role of Sema4A in breast cancer (BCa). Our data showed that the expression of Sema4A increased in the tissues and serum of BCa patients when compared with normal controls. The expression of Sema4A in BCa cells could be induced by hypoxic treatment, whereas silencing hypoxia-inducible factor (HIF)-1α could attenuate the above induced. Furthermore, chromatin immunoprecipitation (ChIP) analysis demonstrated that HIF-1α could regulate the expression of Sema4A through directly binding to the promoter of Sema4A gene, whose enrichment could be further enhanced by hypoxic stimulation. In addition, silencing Sema4A could inhibit the proliferation, vascular endothelial growth factor (VEGF) production and the phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and signal transduction and activator of transcription (STAT)3, but induce apoptosis of BCa cells in the presence of hypoxia. In contrast, recombinant human Sema4A treatment showed the opposite effects. Taken together, these results suggest that Sema4A could promote progression of BCa in the presence of hypoxia and it may hold potential for treatment target for BCa.

Semaphorin-7A contributes to growth, migration and invasion of oral tongue squamous cell carcinoma through TGF-ß-mediated EMT signaling pathway.

OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) is the most frequently encountered malignant epithelial tumors. Semaphorin-7A is a membrane-associated/secreted protein that plays an essential role in the migration and progression of human malignancies. We aimed to investigate the mechanisms of Semaphorin-7A in the growth and migration of OTSCC. MATERIALS AND METHODS: The expressions of Semaphorin-7A in cells were tested by RT-PCR, Western blot, and Immunofluorescence, separately. The activities of OTSCC cells (HSC-3 and Tca8113) were analyzed by MTT, following treatment with Semaphorin-7A or PBS. The migration, invasion, and apoptosis of cells were also determined. The protein expressions of epithelial mesenchymal transition (EMT) pathway were analyzed by Western blot, after treated with Semaphorin-7A in vitro and in vivo. Finally, the mouse model of OTSCC was treated with antibody target for Semaphorin-7A (AntiSema-7A), Semaphorin-7A or PBS, then the tumor size was determined, and histopathological examination and western blot was applied for further confirmation. RESULTS: In OTSCC cells, Semaphorin-7A was highly expressed, and Semaphorin-7A promoted growth in multiple metastatic OTSCC cell lines. Further study indicated that Semaphorin-7A resulted in up-regulation of Snail, N-cadherin and Vimentin expression, and downregulating of E-cadherin. In addition, The Ets2-repressor factor (ERF) expression was down-regulated, and transforming growth factor (TGF-ß)-induced EMT was promoted in OTSCC cells. Then, the proteins of collagen types I (CT-I) and fibronectin (FIB) were also up-regulated after Semaphorin-7A treatment. Furthermore, our results indicated that inhibition of Semaphorin-7A by antibody target for Semaphorin-7A (AntiSema-7A) suppressed OTSCC growth and increased survival in a mouse model of OTSCC. Histopathological examination confirmed the inhibitory effects in vivo. CONCLUSIONS: Semaphorin-7A promoted growth and migration of OTSCC by regulating TGF-ß-induced EMT signaling pathway in OTSCC cells, which provided a new interconnection between the Semaphorin-7A and TGF-ß-induced EMT signaling pathway.

The miR-608 rs4919510 polymorphism may modify cancer susceptibility based on type.

Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00-1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted.

Use of NRP1, a novel biomarker, along with VEGF-C, VEGFR-3, CCR7 and SEMA3E, to predict lymph node metastasis in squamous cell carcinoma of the tongue.

Lymph node (LN) metastasis has been suggested as a major prognostic factor for oral cancer. Knockdown of the growth factors and receptors involved in these metastatic mechanisms could significantly reduce LN metastasis and improve the survival of oral cancer patients after treatment. The present study, therefore, aimed to evaluate the expression levels of the following growth factors and receptors in squamous cell carcinoma (SCC) of the tongue: the vascular endothelial growth factor (VEGF)­C and VEGF­D, which bind to the cell surface tyrosine kinase receptor VEGF receptor­3 (VEGFR­3); C­C motif chemokine receptor 7 (CCR7); neuropilin (NRP)1 and NRP2; and semaphorin 3E (SEMA3E). Furthermore, we assessed microvessel density (MVD) and lymphatic vessel density (LVD) to demonstrate the correlation between these factors and regional LN metastasis, with respect to the clinicopathological features. Finally, we analyzed the correlation between these proteins and overall or disease­free survival, in order to demonstrate their prognostic value. Univariate analysis revealed a significant association between LN metastasis and the expression levels of VEGF­C, VEGFR­3, CCR7, NRP1, and SEMA3E, as well as LVD, in SCC cells. In contrast, multivariate analysis identified associations between LN metastasis and NRP1 expression, as well as between LN metastasis and LVD; however, no correlation was found between LN metastasis and the expression levels of the other proteins. The expression levels of VEGF­C, VEGFR­3, NRP1, and SEMA3E, as well as LVD, were correlated with disease­free survival time. These results indicate that LN metastasis is associated with poor survival in SCC. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in SCC of the tongue, whereas the expression of VEGF­C, VEGFR­3, CCR7, and SEMA3E are non­independent predictive factors.

Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target.

Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor-specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES:GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target.

Semaphorins and neuropilins expression in salivary gland tumors.

BACKGROUND: Salivary gland tumors (SGT) account for 3-10% of all head and neck neoplasms, and little is known about their angiogenic properties. Despite semaphorins and neuropilins have been demonstrated to be prognostic determinants in many human cancers, they remain to be investigated in SGT. Therefore, the objective of this study was to analyze the clinical significance of the expression of class 3 semaphorins A (Sema3A) and B (Sema3B) and neuropilins-1 (Np-1) and neuropilins-2 (Np-2), in SGT. METHODS: Two hundred and forty-eight SGT were organized in tissue microarray paraffin blocks and expression of CD34, Sema3A, Sema3B, Np-1, and Np-2 was determined through immunohistochemistry. The immunoreactions were quantified using digital algorithms and the results correlated with clinicopathological parameters. RESULTS: Malignant tumors had an increased vascular density than their benign counterparts and their increased vascular area significantly correlated with recurrences (P < 0.05). Patients older than 40 years and the presence of recurrences determined an inferior survival rate (P = 0.0057 and P = 0.0303, respectively). In normal salivary glands, Np-1 and Np-2 expression was restricted to ductal cells, whereas Sema3A and Sema3B were positive in the serous acinar compartment. Tumors were positive for all markers and the co-expression of Np-1/Np-2 significantly correlated with the presence of paresthesia and advanced stages of the tumors (P = 0.01 and P = 0.04, respectively). CONCLUSION: Sema3A, Sema3B, Np-1, and Np-2 may be involved in the pathogenesis of SGT, but their expression did not present a statistically significant prognostic potential in this study.

IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils.

IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines, such as IL-5, IL-3, and GM-CSF, are typically present in atopic diseases, including allergic asthma. As a result of the functional redundancy of these three cytokines on eosinophils and the loss of IL-5R on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these three cytokines signal through a common ß-chain receptor but yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce the production of proteins, such as semaphorin-7A, without affecting mRNA levels suggests a unique influence of IL-3 on translation. The purpose of this study was to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared with IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF, or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein S6 (RPS6) and the upstream kinase 90-kDa ribosomal S6 kinase (p90S6K). Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3-enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared with circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations identify IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions.

Epigenetically downregulated Semaphorin 3E contributes to gastric cancer.

Axon guidance protein Semaphorin 3E (Sema3E) promotes tumor metastasis and suppresses tumor cell death. Here, we demonstrated that Sema3E was decreased in gastric cancer. Its levels were inversely associated with tumor progression. Levels of Sema3E were associated with low p300 and high class I histone deacetylase (class I HDAC). Ectopic expression of Sema3E inhibited proliferation and colony formation of gastric cancer cell lines in vitro and xenografts in vivo. Sema3E overexpression inhibited migration and invasion of gastric cancer cells, which was associated with induction of E-cadherin and reduction of Akt and ERK1/2 phosphorylation. We suggest that silencing of Sema3E contributes to the pathogenesis of gastric cancer.

SEMA6A is a prognostic biomarker in glioblastoma.

Glioblastoma multiforme (GBM) is one of the most aggressive tumors in the central nervous system. SEMA6A, the first identified class 6 semaphorin, is contributed to regulate vascular development and adult angiogenesis. However, the function of SEMA6A in GBM is still undefined. In the present study, we investigated the expression of SEMA6A protein in 200 GBM tissues using immunohistochemistry (IHC). SEMA6A expression was associated with time to progression (P = 0.001) and mean tumor diameter (P = 0.038). Kaplan-Meier analysis revealed that patients expressing high SEMA6A protein levels had a significantly longer overall survival (OS, P = 0.013) and progression-free survival (PFS, P = 0.005) compared to those with low SEMA6A expression level. Cox multivariate regression analysis confirmed that low SEMA6A expression was an independent unfavorable prognostic factors for PFS (HR, 1.896; 95% CI, 1.147-2.768; P = 0.009) and OS (HR, 1.712; 95% CI, 1.011-2.657; P = 0.012). Furthermore, in vitro experiments showed that SEMA6A could inhibit proliferation, migration, and invasion in different glioma cell lines. In conclusion, our findings indicated that SEMA6A may be a potential prognostic biomarker in the treatment of GBM.

Expression and clinical significance of Semaphorin4D in non-small cell lung cancer and its impact on malignant behaviors of A549 lung cancer cells.

This study aimed to explore Semaphrin4D (Sema4D) expression and clinical significance in non-small cell lung cancer (NSCLC), and to define the roles and mechanisms of Sema4D in regulating the malignant behaviors of A549 cells by small interfering RNA (siRNA). Firstly, immunohistochemistry revealed that Sema4D was more frequently expressed in NSCLC than in lung benign lesion (P<0.05) and its overexpression was associated with low differentiation (P<0.05), poor pTNM staging (P<0.05) and occurrence of lymph node (LN) metastasis (P<0.05). Endogenous Sema4D expression was suppressed by Sema4D siRNA in A549 cells overexpressing Sema4D. Protein levels of Sema4D, total Akt and p-Akt were examined by Western blotting. Cell proliferation, migration and invasion abilities were measured by MTT assay and Transwell assay respectively. Results showed that Sema4D siRNA significantly suppressed phosphorylation of AKT in A549 cells, but it did not alter total AKT expression. In addition, efficient down-regulation of SemaD significantly inhibit cell proliferation (P<0.05), migration (P<0.05) and invasion (P<0.05) in A549 cells. These findings suggest that Sema4D might serve as a reliable tool for early prediction of NSCLC poor prognosis. Sema4D could play an important role in promoting tumor proliferation, migration and metastasis in the NSCLC, by influencing the Akt protein phosphorylation. Inhibition of Sema4D may be a useful approach for the treatment of NSCLC.

A comprehensive analysis of the human placenta transcriptome.

As the conduit for nutrients and growth signals, the placenta is critical to establishing an environment sufficient for fetal growth and development. To better understand the mechanisms regulating placental development and gene expression, we characterized the transcriptome of term placenta from 20 healthy women with uncomplicated pregnancies using RNA-seq. To identify genes that were highly expressed and unique to the placenta we compared placental RNA-seq data to data from 7 other tissues (adipose, breast, hear, kidney, liver, lung, and smooth muscle) and identified several genes novel to placental biology (QSOX1, DLG5, and SEMA7A). Semi-quantitative RT-PCR confirmed the RNA-seq results and immunohistochemistry indicated these proteins were highly expressed in the placental syncytium. Additionally, we mined our RNA-seq data to map the relative expression of key developmental gene families (Fox, Sox, Gata, Tead, and Wnt) within the placenta. We identified FOXO4, GATA3, and WNT7A to be amongst the highest expressed members of these families. Overall, these findings provide a new reference for understanding of placental transcriptome and can aid in the identification of novel pathways regulating placenta physiology that may be dysregulated in placental disease.