Does overconfident CEO lead to corporate environmental misconducts? Evidence from China.

Enterprises are drawing growing criticism for violating environmental rules. The research examines whether and how top executives' mental bias leads to corporate environmental misconduct (CEI). Drawing on upper echelon theory (UET) and agency theory, we link CEO overconfidence with CEI, and explore the boundary conditions from the perspective of management discretion at the governance level. Using a data set covering the Chinese listed enterprises from 2004 to 2016, the empirical results demonstrate that CEO overconfidence positively and markedly influenced CEI. Moreover, shareholder concentration and CEO duality reinforce the relationship between overconfidence and CEI, whereas board independence is the opposite. The findings clarify ecological outcomes of CEO overconfidence and have remarkable significance in theory and practice.

miR-493-5p Silenced by DNA Methylation Promotes Angiogenesis via Exosomes and VEGF-A-Mediated Intracellular Cross-Talk Between ESCC Cells and HUVECs.

Background: Exosomal microRNAs (miRNAs) in the tumor microenvironment play crucial roles in tumorigenesis and tumor progression by participating in intercellular cross-talk. However, the functions of exosomal miRNAs and the mechanisms by which they regulate esophageal squamous cell carcinoma (ESCC) progression are unclear. Methods: RNA sequencing and GEO analysis were conducted to identify candidate exosomal miRNAs involved in ESCC development. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of plasma exosomal miR-493-5p. EdU, tube formation and Transwell assays were used to investigate the effects of exosomal miR-493-5p on human umbilical vein endothelial cells (HUVECs). A subcutaneous xenograft model was used to evaluate the antitumor effects of miR-493-5p and decitabine (a DNA methyltransferase inhibitor). The relationship between miR-493-5p and SP1/SP3 was revealed via a dual-luciferase reporter assay. A series of rescue assays were subsequently performed to investigate whether SP1/SP3 participate in exosomal miR-493-5p-mediated ESCC angiogenesis. Results: We found that miR-493-5p expression was notably reduced in the plasma exosomes of ESCC patients, which showed the high potential value in early ESCC diagnosis. Additionally, miR-493-5p, as a candidate tumor suppressor, inhibited the proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGFA and exerted its angiostatic effect via exosomes. Moreover, we found that SP1/SP3 are direct targets of miR-493-5p and that re-expression of SP1/SP3 could reverse the inhibitory effects of miR-493-5p. Further investigation revealed that miR-493-5p expression could be regulated by DNA methyltransferase 3A (DNMT3A) and DNMT3B, and either miR-493-5p overexpression or restoration of miR-493-5p expression with decitabine increased the antitumor effects of bevacizumab. Conclusion: Exosomal miR-493-5p is a highly valuable ESCC diagnosis marker and inhibits ESCC-associated angiogenesis. miR-493-5p can be silenced via DNA methylation, and restoration of miR-493-5p expression with decitabine increases the antitumor effects of bevacizumab, suggesting its potential as a therapeutic target for ESCC treatment.

Circ_16601 facilitates Hippo pathway signaling via the miR-5580-5p/FGB axis to promote my-CAF recruitment in the TME and LUAD progression.

BACKGROUND: Lung cancer represents a significant public health issue in China, given its high incidence and mortality rates. Circular RNAs (circRNAs) have been recently proposed to participate in the development and progression of tumors. Nevertheless, their particular roles in the pathogenesis of lung adenocarcinoma (LUAD), the tumor microenvironment (TME), and the underlying molecular mechanisms are still not well understood. METHODS: High-throughput sequencing was used to analyze the circRNAs expression profiles in 7 pairs of human LUAD tissues. shRNA was used to knockdown the YAP1 and FGB genes. RNA sequencing and RT-qPCR were performed to classify the regulatory effects of circ_16601 in LUAD cells. The progression effect of circ_16601 on lung cancer was investigated in vitro and in vivo. RESULTS: The circ_16601 is significantly elevated in LUAD tissues compared to adjacent normal lung tissues, and its high expression is positively associated with poor prognosis in LUAD patients. Additionally, circ_16601 overexpression promotes LUAD cell proliferation in vitro and increases xenograft tissue growth in mice in vivo; circ_16601 also could recruit fibroblasts to cancer associate fibroblasts. Mechanistically, circ_16601 can directly bind to miR-5580-5p, preventing its ability to degrade FGB mRNA and enhancing its stability. Subsequently, circ_16601 promotes the activation of the Hippo pathway in a YAP1-dependent manner, leading to LUAD progression. CONCLUSIONS: Our findings shed valuable insights into the regulatory role of circ_16601 in LUAD progression and highlight its potential as a diagnostic and therapeutic target in LUAD. Overall, this study provides theoretical support to improve the prognosis and quality of life of patients suffering from this devastating disease.

Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA.

Increasing evidence has shown that circular RNAs (circRNAs) interact with RNA-binding proteins (RBPs) and promote cancer progression. However, the function and mechanism of the circRNA/RBP complex in esophageal squamous cell carcinoma (ESCC) are still largely unknown. Herein, we first characterized a novel oncogenic circRNA, circ-FIRRE, by RNA sequencing (Ribo-free) profiling of ESCC samples. Furthermore, we observed marked circ-FIRRE overexpression in ESCC patients with high TNM stage and poor overall survival. Mechanistic studies indicated that circ-FIRRE, as a platform, interacts with the heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein to stabilize GLI2 mRNA by directly binding to its 3'-UTR in the cytoplasm, thereby resulting in elevated GLI2 protein expression and subsequent transcription of its target genes MYC, CCNE1, and CCNE2, ultimately contributing to ESCC progression. Moreover, HNRNPC overexpression in circ-FIRRE knockdown cells notably abolished circ-FIRRE knockdown-mediated Hedgehog pathway inhibition and ESCC progression impairment in vitro and in vivo. Clinical specimen results showed that circ-FIRRE and HNRNPC expression was positively correlated with GLI2 expression, which reveals the clear significance of the circ-FIRRE/HNRNPC-GLI2 axis in ESCC. In summary, our results indicate that circ-FIRRE could serve as a valuable biomarker and potential therapeutic target for ESCC and highlight a novel mechanism of the circ-FIRRE/HNRNPC complex in ESCC progression regulation.

CircABCA13 acts as a miR-4429 sponge to facilitate esophageal squamous cell carcinoma development by stabilizing SRXN1.

Circular RNAs (circRNAs) play a pivotal role in the tumorigenesis and progression of various cancers. However, the role and mechanisms of circABCA13 in esophageal squamous cell carcinoma (ESCC) are largely unknown. Here, we reported that circABCA13, a novel circular RNA generated by back-splicing of the intron of the ABCA13 gene, is highly expressed in ESCC tumor tissues and cell lines. Upregulation of circABCA13 correlated with TNM stage and a poor prognosis in ESCC patients. While knockdown of circABCA13 in ESCC cells significantly reduced cell proliferation, migration, invasion, and anchorage-independent growth, overexpression of circABCA13 facilitated tumor growth both in vitro and in vivo. In addition, circABCA13 directly binds to miR-4429 and sequesters miR-4429 from its endogenous target, SRXN1 mRNA, which subsequently upregulates SRXN1 and promotes ESCC progression. Consistently, overexpression of miR-4429 or knockdown of SRXN1 abolished malignant behavior promotion of ESCC results from circABCA13 overexpression in vitro and in vivo. Collectively, our study uncovered the oncogenic role of circABCA13 and its mechanism in ESCC, suggesting that circABCA13 could be a potential therapeutic target and a predictive biomarker for ESCC patients.

Exosomal miR-10527-5p Inhibits Migration, Invasion, Lymphangiogenesis and Lymphatic Metastasis by Affecting Wnt/ß-Catenin Signaling via Rab10 in Esophageal Squamous Cell Carcinoma.

Background: Cancer cell-derived exosomal microRNAs (miRNAs) play critical role in orchestrating intercellular communication between tumor cells and tumor microenvironmental factors, including lymphatic endothelial cells (LECs). Nevertheless, the functions and underlying mechanisms of exosomal miRNAs in lymphatic metastasis and lymphangiogenesis in esophageal squamous cell carcinoma (ESCC) remain unclear. Methods: Small RNA sequencing, Gene Expression Omnibus (GEO) analysis and qRT‒PCR were performed to identify the candidate exosomal miRNAs involved in ESCC metastasis. Receiver operating characteristic curve analysis was conducted to evaluate the diagnostic potential of exosomal miR-10527-5p in predicting lymph node metastasis (LNM) status. An in vitro coculture system was used to investigate the effects of exosomal miR-10527-5p on ESCC cells and human LECs (HLECs), followed by a popliteal LNM assay in vivo. The relationship between miR-10527-5p and Rab10 was identified by dual-luciferase reporter, fluorescence in situ hybridization and qRT‒PCR assays. Then, a series of rescue assays were performed to further investigate whether Rab10 is involved in exosomal miR-10527-5p mediated ESCC metastasis. Results: MiR-10527-5p was found to be notably reduced in both the plasma exosomes and tumor tissues of ESCC patients with LNM, and plasma exosomal miR-10527-5p had a high sensitivity and specificity for discrimination of LNM status. Moreover, exosome-shuttled miR-10527-5p suppressed the migration, invasion and epithelial-to-mesenchymal transition (EMT) of ESCC cells as well as the migration and tube formation of HLECs via Wnt/ß-catenin signaling in vitro and in vivo. Further investigation revealed that Rab10 was a direct target of miR-10527-5p, and re-expression of Rab10 neutralized the inhibitory effects of exosomal miR-10527-5p. Conclusion: Our study demonstrated that exosomal miR-10527-5p had a strong capability to predict preoperative LNM status and anti-lymphangiogenic effect. Exosomal miR-10527-5p inhibited lymphangiogenesis and lymphatic metastasis of ESCC in a vascular endothelial growth factor-C (VEGF-C)-independent manner, showing potential as a therapeutic target for ESCC patients.

USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP.

Esophageal squamous carcinoma (ESCC) is the major subtype of esophageal cancer in China, accounting for 90% of cases. Recent studies revealed that abnormalities in the Hippo/YAP axis are pervasive in ESCC and are recognized as the important driver of ESCC progression. Since the activity of Hippo signaling is controlled by phosphorylation cascade, it is a mystery why the major effector YAP is still over-activated when the cascade is inhibited. Several studies suggested that in addition to phosphorylation, other protein modifications such as ubiquitination also play important roles in manipulating Hippo/YAP signaling activity. Since YAP protein stability is controlled via an appropriate balance between E3 ubiquitin ligases and deubiquitinases, we performed deubiquitinase siRNA screening and identified USP36 as a deubiquitinase significantly related to Hippo/YAP signaling activity and ESCC progression. USP36 expression was elevated in ESCC samples and correlated with poor differentiation. USP36 expression was correlated with YAP protein levels in ESCC samples. Molecular studies demonstrated that USP36 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. In conclusion, our study revealed a novel deubiquitinase in regulating Hippo signaling in ESCC, which could be an encouraging drug target for Hippo-driven ESCC.

Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/ß-catenin signaling pathway in taxol-resistant human lung adenocarcinoma.

BACKGROUND: Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance. METHODS: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot. Expression of ß-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/ß was evaluated by western blot and IHC. RESULTS: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxol-resistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelial-mesenchymal transition (EMT) through repression of the p70S6K/GSK3/ß-catenin signaling pathway. CONCLUSIONS: Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/ß-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

RUNX3 inhibits the invasion and migration of esophageal squamous cell carcinoma by reversing the epithelial­mesenchymal transition through TGF­ß/Smad signaling.

Runt­related transcription factor 3 (RUNX3) is a candidate tumor suppressor, and its inactivation may play a crucial role in the carcinogenesis process of numerous cancer types, including esophageal squamous cell carcinoma (ESCC). We previously revealed that RUNX3 inactivation was correlated with lymph node metastasis (LNM) and ESCC recurrence. However, the exact mechanisms of this process are still under investigation. The aim of the present study was to examine the potential roles and underlying molecular mechanisms of RUNX3 in ESCC metastasis and the epithelial­mesenchymal transition (EMT). According to the results, RUNX3 expression in ESCC tissue was significantly reduced compared with that in adjacent normal tissue (0.50±0.20 vs. 0.83±0.16; P<0.001). In addition, statistical analysis revealed a close association between decreased RUNX3 expression and T status (P=0.027) and LNM (P=0.017) in ESCC patients. Pearson's correlation coefficient analysis was then used to evaluate correlations between RUNX3 and EMT­related marker expression. The results revealed that RUNX3 expression in ESCC tissues was negatively correlated with the expression of N­cadherin (r=­0.429; P<0.01) and Snail (r=­0.364; P<0.01) and positively correlated with the expression of E­cadherin (r=0.580; P<0.01). Moreover, Eca109 and EC9706 cell invasion, migration, MMP­9 expression and EMT were significantly inhibited by RUNX3 overexpression. Notably, further analysis revealed that RUNX3 overexpression markedly inhibited the phosphorylation of Smad2/3; RUNX3­overexpressing cells also displayed less sensitivity to TGF­ß1­induced EMT than control cells. Thus, RUNX3 may inhibit the invasion and migration of ESCC cells by reversing EMT through TGF­ß/Smad signaling and may be useful as a therapeutic target.

A dual-responsive colorimetric probe for the detection of Cu2+ and Ni2+ species in real water samples and human serum.

The monitoring of heavy transition metals has increasingly attracted great attention because they pollute the environment and have unique physiological functions. Chemosensors are useful tools for monitoring heavy transition metals due to their simple visualization, excellent sensitivity and high selectivity. Herein, we have developed a novel chemosensor for the detection of water-soluble Cu2+ and Ni2+ species with different mechanisms, and low detection limits of 2.1 nM for Cu2+ and 1.2 nM for Ni2+ were obtained. The colorimetric probe CPH has been applied to qualitative and quantitative detection of Cu2+ and Ni2+ species in real samples.

[Pyrexia and hemoptysis for eight days in a school-age child].

A girl was diagnosed with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) due to pyrexia and hemoptysis for eight days. The girl was a school-age child with major clinical manifestations of pyrexia, skin rash, enlargement of bilateral cervical lymph nodes, conjunctival hyperaemia, red and cracked lips and strawberry-like tongue, followed by swelling of both hands and feet. Laboratory examination showed significant increases in white blood cell count, platelet count, C-reactive protein, erythrocyte sedimentation rate and liver enzymes, a significant reduction in albumin, and the presence of aseptic pyuria. After the first course of IVIG treatment, the girl still had recurrent pyrexia, with hemoptysis on day 2 after admission, and lung CT showed uneven luminance and patchy shadow. The symptoms were quickly alleviated after the second course of IVIG treatment combined with methylprednisolone and aspirin treatment. KD is a febrile disease characterized by multiple systemic vasculitis in childhood and can involve various organ systems such as the heart, lungs, kidneys and the nervous system. Therefore, it is necessary to carefully monitor and recognize the rare symptoms of KD, and early recognition of pulmonary complications of KD can avoid delay in diagnosis, prevent the development of more serious complications, and help with early treatment and disease recovery.

CEP55 promotes the proliferation, migration and invasion of esophageal squamous cell carcinoma via the PI3K/Akt pathway.

BACKGROUND: Centrosomal protein 55 (CEP55) is an important prognostic biomarker that plays an essential role in the proliferation, migration and invasion of multiple tumors. We aimed to investigate the prognostic value of CEP55 in pN0 esophageal squamous cell carcinoma (ESCC) and explore its biological function in ESCC cells. METHODS: We used immunohistochemistry and Western blot analysis to detect the expression of CEP55 in ESCC. Furthermore, both in vitro and in vivo assays were used to determine the effect of CEP55 on malignant behavior in ESCC cells. RESULTS: As expected, we found that CEP55 was overexpressed in ESCC. Univariate and multivariate analyses demonstrated that patients with CEP55 overexpression had a poor prognosis. Additionally, the abilities of proliferation, migration and invasion of cells, as well as the epithelial-mesenchymal transition markers, were all altered with the changed CEP55 expression levels in ESCC cells. Further study elucidated that CEP55 facilitated ESCC via the PI3K/Akt pathway. Blockade of this pathway markedly attenuated CEP55-mediated proliferation, migration, invasion and epithelial-mesenchymal transition of ESCC cells. CONCLUSION: Oncogenic CEP55 correlates with a poor prognosis by regulating tumor cell proliferation, migration and invasion via the PI3K/Akt pathway. It can serve as a promising prognostic biomarker and therapeutic target of pN0 ESCC after Ivor-Lewis esophagectomy.

FOXM1: A potential indicator to predict lymphatic metastatic recurrence in stage IIA esophageal squamous cell carcinoma.

BACKGROUND: Previous studies have elucidated that FOXM1 may predict poor prognosis in patients with multiple solid malignant tumors. In this study we explored the differential expression of FOXM1 in stage IIA esophageal squamous cell carcinoma (ESCC) and investigated its prognostic value. METHODS: Immunohistochemistry (IHC) and Western blot were used to detect FOXM1 expression in ESCC. Correlations between FOXM1 expression and clinicopathological variables, and five-year lymphatic metastatic recurrence (LMR) and overall survival (OS) of patients were analyzed. RESULTS: FOXM1 was aberrantly expressed in ESCC. Statistical analysis revealed a close relationship between FOXM1 expression and tumor size (P = 0.024), depth of invasion (P = 0.048), and degree of differentiation (P = 0.043). The five-year LMR of patients in the FOXM1 overexpression group was significantly increased compared to the low expression group (P = 0.001). The five-year OS of patients in the FOXM1 overexpression group was significantly reduced compared to the low expression group (P = 0.007). Log-rank tests demonstrated that large tumor size (P = 0.044), poor differentiation degree (P = 0.005), deep invasion (P = 0.000), and FOXM1 overexpression (P = 0.007) may indicate poor prognosis in stage IIA ESCC. Cox multivariate regression analysis revealed that all of these variables were independent predictors of unfavorable outcome (P < 0.05). CONCLUSION: FOXM1 could be a predictor of lymphatic metastatic recurrence in stage IIA ESCC after Ivor Lewis esophagectomy.

Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

PURPOSE: To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC). METHODS: Five hundred fifty-six ESCC patients undergoing curative resection of ESCC were retrospectively studied. FGFR1 gene copy number was determined in microarrayed tumor samples using fluorescent in situ hybridization (FISH) analysis. FGFR1 gene amplification status was prespecified as copy number ≥ 6 or FGFR1/CEN 8 ratio ≥ 2.2. FGFR1 expression was evaluated by immunohistochemistry. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method followed by the log rank test. Correlation with survival was examined using multivariate Cox regression. RESULTS: FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification. Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001). Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression. The frequency of FGFR1 amplification was significantly higher in heavy drinkers than in moderate and light drinkers. CONCLUSION: FGFR1 amplification is an independent adverse prognostic factor in surgically resected ESCC. FGFR1 may be a promising therapeutic target in patients with ESCC.

VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant disease characterized by poor prognosis. Chemoresistance remains a major cause of ESCC relapse. Vaccinia-related kinase 1 (VRK1) has previously been identified as a cancer-related gene. However, there is little research demonstrating an association between VRK1 and ESCC. In this study, we show that VRK1 is overexpressed in ESCC primary tumor samples and cell lines. VRK1 expression was significantly correlated with clinical characteristics and predicted poor outcomes in ESCC patients. Functionally, knockdown of VRK1 inhibited ESCC cell proliferation, survival, migration and invasion; conversely, VRK1 overexpression produced the opposite effects. Furthermore, we found that up-regulation of VRK1 promoted cisplatin (CDDP) resistance in ESCC both in vitro and in vivo, whereas knockdown of VRK1 reduced this resistance. Further studies verified that VRK1 phosphorylated c-Jun and that the VRK1/c-Jun pathway contributed to CDDP resistance in ESCC. Mechanistically, a dual luciferase reporter assay revealed that c-Jun transcriptionally activated the expression of c-MYC. Silencing c-MYC abolished the c-Jun-mediated CDDP resistance of ESCC cells. A Kaplan-Meier analysis indicated that c-MYC is a potential prognostic factor in ESCC. Finally, luteolin, a VRK1 inhibitor, attenuated the malignant biological behaviors and CDDP resistance in ESCC cells. Collectively, we conclude that VRK1 promotes CDDP resistance through c-MYC by activating c-Jun and potentiating a malignant phenotype in ESCC. Our studies provide novel insight into the role of VRK1 in carcinogenesis and indicate that VRK1 can serve as a potential therapeutic target in ESCC.

Overexpression of IFITM3 predicts poor prognosis in stage IIA esophageal squamous cell carcinoma after Ivor Lewis esophagectomy.

BACKGROUND: Recent research has shown that IFITM3 plays an important role in the tumorigenesis of many malignancies. We investigated the clinicopathological variables and prognostic value of IFITM3 in stage IIA esophageal squamous cell carcinoma (ESCC) patients. METHODS: Immunohistochemistry and Western blot analysis were used to examine IFITM3 expression in tumor specimens. The relationships between IFITM3 expression and clinicopathological variables, as well as the five-year survival and recurrence status of patients, were analyzed. RESULTS: IFITM3 was aberrantly expressed in tumor tissue. Statistical analysis showed a close correlation of IFITM3 expression with T tumor status (P = 0.004). Additionally, IFITM3 overexpression, advanced T status, poor degree of differentiation, and large tumor size were not only associated with poor survival but were high lymphatic metastatic recurrence predictors in ESCC patients (P < 0.05). CONCLUSION: Our data indicated that IFITM3 overexpression may predict poor prognosis in stage IIA ESCC patients after Ivor Lewis esophagectomy.

The effect of IL-1ß on synaptophysin expression and electrophysiology of hippocampal neurons through the PI3K/Akt/mTOR signaling pathway in a rat model of mesial temporal lobe epilepsy.

BACKGROUND: The inflammation induced by interleukin-1ß (IL-1ß) is a critical factor in the pathogenesis of mesial temporal lobe epilepsy (MTLE). Synaptophysin (SYN) and other changes, including neuron electrophysiology, participate in the pathophysiological processes of MTLE. Phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling pathway may play a critical role in regulating SYN expression and electrophysiology of hippocampal neurons. METHODS: We used lithium-pilocarpine-treated rats as model of human MTLE, detecting epileptic seizures with digital video-EEG, and evaluating the proteins related to the PI3K/Akt/mTOR signaling pathway by western blot (WB). Then, we cultured primary neuron and established a neuronal epilepsy model using Mg2+-free media. Immunocytochemistry and WB were used to investigate SYN expression, and whole-cell current clamp recording techniques were used to detect the electrophysiological properties of cultured neurons. RESULTS: We have demonstrated that IL-1ß can activate the PI3K/Akt/mTOR signaling pathway in primary hippocampal neurons, and we speculate that IL-1ß may affect SYN expression and neuron electrophysiology through PI3K/Akt/mTOR signaling pathway. CONCLUSION: We confirmed that IL-1ß stimulated SYN expression and epileptiform discharges, and that blocking the PI3K/Akt/mTOR pathway alleviated these phenomena. Therefore, activation of the PI3K/Akt/mTOR signaling pathway by IL-1ß contributes to the pathogenesis of MTLE, and modulating this pathway is a promising strategy of study for therapies to prevent or reverse the cellular and molecular mechanisms of epileptogenesis in MTLE.

Interleukin-1ß Plays a Pivotal Role via the PI3K/Akt/mTOR Signaling Pathway in the Chronicity of Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy. It is often associated with hippocampal sclerosis, which is histopathologically characterized by selective neuron loss, mossy fiber sprouting, and synapse reconstruction, and is the primary cause of refractory epilepsy. Its mechanism has not been fully elucidated. Substantial evidence now supports that inflammatory pathways are activated in epilepsy foci. We have confirmed that the interleukin-1ß (IL-1ß) level is involved in the epileptogenesis of MTLE, and we further investigated how it works in its chronicity in this study. METHODS: The MTLE model was induced by pilocarpine, and Western blot and co-immunoprecipitation were used to detect proteins related to the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway in the hippocampi of MTLE rats and MTLE children. Meanwhile, primary hippocampal neurons were cultured and transfected by lentivirus, and the same methods were used to test the related protein expression; fluorescent dye FM4-64 was used to measure synaptic vesicle endocytosis (SVE) of neurons. RESULTS: We revealed that mTOR is continuously activated in the rat MTLE model and children with MTLE, and it correlated with the IL-1ß level. We further proved that IL-1ß activates neurons via the PI3K/Akt/mTOR signaling pathway, accompanied by the upregulation of MAP2 and the enhancement of SVE in hippocampal neurons. CONCLUSION: Our findings suggest that IL-1ß can activate mTOR, followed by activated neurons, which is critical in the pathogenesis of MTLE chronicity. These findings contribute to the understanding of the pathogenesis of MTLE, and targeting inflammation modulators in MTLE may provide new pathways for therapy of refractory epilepsy.

Interleukin-1ß plays a role in the pathogenesis of mesial temporal lobe epilepsy through the PI3K/Akt/mTOR signaling pathway in hippocampal neurons.

Recently, the role of inflammation in the pathogenesis of mesial temporal lobe epilepsy (MTLE) has garnered great attention. Increasing evidence indicated that interleukin-1ß (IL-1ß) plays a critical role in the pathogenesis of MTLE. In this study, we cultured primary hippocampal neurons, using IL-1ß to mimic the process of inflammatory reaction in neurons, then inhibited the inflammation using inhibitors of the PI3K/Akt/mTOR signaling pathway. The expression of proteins related to the PI3K/Akt/mTOR signaling pathway in rat hippocampal neurons was detected by western blot, and similar methods were applied to the hippocampi obtained from children with MTLE and normal controls. Neuronal somatic size and dendritic length were measured by immunohistochemistry and digital imaging. We observed that stimulation with IL-1ß in neuron led to the up-regulation of p-Akt and p70S6K and promoted the growth of cell somatic size and dendritic length via the PI3K/Akt/mTOR signaling pathway. Pre-treatment with inhibitors of the pathway, LY294002 and rapamycin, decreased the expression of p-Akt and p70S6K and alleviated the morphological changes induced by IL-1ß in hippocampal neurons. We further verified the increasement of P-Akt and p70S6K in the hippocampi of children with MTLE. These data are the first to demonstrate that the inflammatory response induced by IL-1ß promotes seizures and plays an important role in the pathogenesis of MTLE via the PI3K/Akt/mTOR signaling pathway. Therefore, modulation of the PI3K/Akt/mTOR signaling pathway may be a novel therapeutic target for the treatment of MTLE.