KDM1A drives hepatoblastoma progression by activating the Wnt/ß-catenin pathway through inhibition of DKK3 transcription.

This study is to explore the mechanism of KDM1A-regulated hepatoblastoma (HB) development. Cancerous and paracancer tissues of 30 HB patients were collected for detection of KDM1A and DKK3 expression. HuH-6 and HepG2 cells were subjected to assays of cellular activities after treatment with sh-KDM1A, sh-DKK3, and/or XAV-939 (an inhibitor of the Wnt/ß-catenin pathway). Chromatin immunoprecipitation was used to determine the interaction of KDM1A with DKK3. Nude mice were injected with HuH-6 cells in which KDM1A was knocked down. KDM1A was highly expressed and DKK3 was lowly expressed in HB patients. Knockdown of KDM1A reduced the proliferative and invasive capabilities of HepG2 and HuH-6 cells and accelerated the cell apoptosis; these influences were nullified by knockdown of DKK3. KDM1A inhibited DKK3 transcription by reducing H3 methylation. XAV-939 treatment inhibited the development of HepG2 and HuH-6 cells in which KDM1A and DKK3 were both knocked down. Knockdown of KDM1A reduced the tumor mass, inactivated the Wnt/ß-catenin signaling, and increased the expression of DKK3 in nude mice. KDM1A stimulates HB development by activating the Wnt/ß-catenin pathway through inhibition of DKK3 transcription.

The Inhibitory Effect of Perceived Organizational Politics on Employee Voice Behavior: A Moderated Mediation Model.

Research on the mediating mechanisms and boundary conditions of perceived organizational politics' (POP) effect on employee voice is underdeveloped. Based on conservation of resources theory, we proposed a moderated mediation model in which organizational embeddedness acts as a mediator to explain why POP inhibits promotive and prohibitive voice. Additionally, we posited sense of impact as a boundary condition affecting this relationship. A time-lagged survey of 227 employed MBA students from a university in southwestern China revealed that organizational embeddedness mediates the relationship between POP and promotive and prohibitive voice, and sense of impact moderates the relationship between POP and promotive voice, such that the relationship is stronger when sense of impact is weaker. The moderating effect was not significant for prohibitive voice. These findings have implications for theory, practice, and further organizational research.

lncRNA TUG1 regulates angiogenesis via the miR­204­5p/JAK2/STAT3 axis in hepatoblastoma.

Hepatoblastoma is the most common malignant hepatic tumour type with hypervascularity in early childhood. In recent decades, emerging evidence has proven that long non­coding RNAs (lncRNAs) serve an important oncogenic role in the pathogenesis of hepatoblastoma. However, the underlying mechanism of lncRNA taurine upregulated 1 (TUG1) in the angiogenesis of hepatoblastoma remains unknown. The expression patterns of TUG1 and microRNA (miR)­204­5p were detected in hepatoblastoma tissues and cell lines via reverse transcription­quantitative PCR and were analysed using a Pearson's correlation test. A tube formation assay was performed using human umbilical vein endothelial cells to assess the vasculogenic activity of treated HuH­6 cells. ELISA was used to detect the level of the secretory proangiogenic factor VEGFA in the culture media of HuH­6 cells. A dual luciferase reporter assay was performed to validate the binding relationships of TUG1/miR­204­5p and miR­204­5p/Janus kinase 2 (JAK2). Moreover, western blotting was conducted to measure the protein expression levels of VEGFA, phosphorylated (p)­JAK2, JAK2, p­STAT3 and STAT3. It was identified that TUG1 was upregulated, while miR­204­5p was downregulated in hepatoblastoma tissues and cells. TUG1 knockdown inhibited angiogenesis induced by hepatoblastoma cells. Furthermore, miR­204­5p was identified as a target of TUG1. The results demonstrated that TUG1 attenuated the inhibitory effect of miR­204­5p on the JAK2/STAT3 pathway and promoted angiogenesis in hepatoblastoma cells. In summary, TUG1 was upregulated in hepatoblastoma and suppressed miR­204­5p, thereby activating the downstream signalling pathway of JAK2/STAT3 to facilitate angiogenesis. The present findings will provide novel targets for the treatment of hepatoblastoma.

Transcriptome and DNA methylation analysis reveals molecular mechanisms underlying intrahepatic cholangiocarcinoma progression.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with increasing incidence. It has been suggested that DNA methylation drives cancer development. However, the molecular mechanisms underlying iCCA progression and the roles of DNA methylation still remain elusive. In this study, weighted correlation networks were constructed to identify gene modules and hub genes associated with the tumour stage. We identified 12 gene modules, two of which were significantly positively or negatively related to the tumour stage， respectively. Key hub genes SLC2A1, CDH3 and EFHD2 showed increased expression across the tumour stage and were correlated with poor survival, whereas decrease of FAM171A1, ONECUT1 and PHYHIPL was correlated with better survival. Pathway analysis revealed hedgehog pathway was activated in CDH3 up-regulated tumours, and chromosome separation was elevated in tumours expressing high EFHD2. JAK-STAT pathway was overrepresented in ONECUT1 down-regulated tumours, whereas Rho GTPases-formins signalling was activated in PHYHIPL down-regulated tumours. Finally, significant negative associations between expression of EFHD2, PHYHIPL and promoter DNA methylation were detected, and alterations of DNA methylation were correlated with tumour survival. In summary, we identified key genes and pathways that may participate in progression of iCCA and proposed putative roles of DNA methylation in iCCA.

Long Non-Coding RNA CRNDE Regulates Angiogenesis in Hepatoblastoma by Targeting the MiR-203/VEGFA Axis.

OBJECTIVE: MiR-203 has been shown to participate in multiple malignancies, but the role of miR-203 in hepatoblastoma (HB) remains unclear. The aim of our study was to investigate the effects of miR-203 in HB. METHODS: A total of 15 pairs of HB tissues and para-tumour normal tissues were collected for the experiments. RT-qPCR and Western blotting were performed to detect the expression of CRNDE, miR-203, and VEGFA at the mRNA and/or protein levels, respectively. A dual luciferase assay verified the target relationship between miR-203 and the 3'UTR of VEGFA as well as miR-203 and CRNDE. In addition, MTT, wound healing, and tube formation assays were performed to assess the effects of miR-203, VEGFA, and CRNDE on cell proliferation, migration, and angiogenesis, respectively. RESULTS: Our data revealed that miR-203 expression was decreased in HB tissues, while long non-coding RNA (lncRNA) CRNDE expression was increased. The dysregulation of miR-203 and CRNDE was closely related to tumour size and stage. Moreover, overexpression of miR-203 inhibited angiogenesis. A dual luciferase assay verified that VEGFA is a direct target of miR-203 and that CRNDE binds to miR-203. Furthermore, our results showed that miR-203 suppressed cell viability, migration, and angiogenesis by regulating VEGFA expression. Additionally, it was confirmed that CRNDE promoted angiogenesis by negatively regulating miR-203 expression. CONCLUSION: lncRNA CRNDE targets the miR-203/VEGFA axis and promotes angiogenesis in HB. These results provide insight into the underlying mechanisms of HB and indicate that CRNDE and miR-203 might be potential targets for HB therapy.

Ethical Leadership as the Reliever of Frontline Service Employees' Emotional Exhaustion: A Moderated Mediation Model.

Based on the conservation of resources theory, this study aims to create new knowledge on the antecedents of emotional exhaustion. We explore the internal mechanism and boundary conditions of the impact of ethical leadership on emotional exhaustion, using data gathered from 460 frontline service employees at an airport in China. Employees completed questionnaires regarding ethical leadership, emotional exhaustion, organizational embeddedness, job satisfaction, and demographic variables. After controlling for the effects of demographic variables and company tenure, ethical leadership was found to have a negative impact on emotional exhaustion ( = -0.128, p < 0.01), and to be positively related to organizational embeddedness ( = 0.518, p < 0.01). After adding in the mediating variable (organizational embeddedness), the effect of ethical leadership on emotional exhaustion was no longer significant ( = 0.012, ns), while organizational embeddedness emerged as significantly related to emotional exhaustion ( = -0.269, p < 0.01), implying that the effect of ethical leadership on emotional exhaustion was completely mediated by organizational embeddedness. Simultaneously, the results suggested that job satisfaction could strengthen the mediating effect of organizational embeddedness on emotional exhaustion (the difference in the mediating effect between the groups with respective high and low job satisfaction was -0.096, p < 0.05). This study proposed and validated a moderated mediation model, the implications of which are that ethical leadership is an effective way to alleviate frontline service employees' emotional exhaustion.

Celecoxib suppresses proliferation and metastasis of pancreatic cancer cells by down-regulating STAT3 / NF-kB and L1CAM activities.

OBJECTIVE: To explore the molecular mechanisms of celecoxib-induced pancreatic cancer suppression in vivo and in vitro. METHODS: The anti-pancreatic cancer activities of celecoxib (0, 20, 60 and 100 µmol/L) were investigated by cell viability and migration of Panc-1 and Bxpc-3 cells in vitro. The expression of L1CAM in pancreatic cancer and adjacent tissues was compared using immunohistochemistry. The expressions of L1CAM, STAT3, p-STAT3, NF-κB, p-NF-κB were determined by western blotting, and cell invasive ability was determined by wound healing assay in L1CAM-silenced and over-expressed Panc-1and Bxpc-3 cells. RESULTS: The expression of L1CAM in pancreatic carcinoma was stronger than that in the adjacent tissues and L1CAM could increase the growth and invasion of pancreatic cancer cells. Over-expression of L1CAM activated the STAT3/NF-κB signaling pathway in Panc-1 and Bxpc-3 pancreatic cancer cells and celecoxib inhibited their viability and the expressions of STAT3, p-STAT3, NF-κB, p-NF-κB as well as full length L1CAM in a concentration dependent manner. CONCLUSIONS: L1CAM was highly expressed in pancreatic cancer tissue and positively correlated with age, TNM staging and tumor differentiation. L1CAM activated the STAT/NF-κB signaling pathway and celecoxib could inhibit the activity of L1CAM, STAT3 and the NF-κB signaling pathway resulting in decreased growth and invasion of pancreatic cancer cells.

MicroRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells.

Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potential target for cancer therapy. However, many cancer cells are resistant to TRAIL-induced apoptosis and its mechanism is not well understood. In this study, to identify potential therapeutic targets for TRAIL-resistant cancer cells, we compared the expression levels of interferon-stimulated gene 15 in TRAIL-sensitive and TRAIL-resistant hepatocellular carcinoma cell lines. Western blot analysis showed that interferon-stimulated gene 15 expression levels were significantly higher in resistant HLCZ01and Huh7 cells than in sensitive LH86 and SMMC-7721 cells. Interferon-stimulated gene 15 knockdown in resistance cells led to TRAIL sensitivity. Conversely, interferon-stimulated gene 15 overexpression in sensitive cells resulted in TRAIL resistance. Our bioinformatics search detected a putative target sequence for microRNA miR-138 in the 3' untranslated region of the interferon-stimulated gene 15. Real-time quantitative polymerase chain reaction analysis demonstrated that miR-138 was significantly downregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. Forced expression of miR-138 in resistant cells decreased both messenger RNA and protein levels of interferon-stimulated gene 15, and when exposed to TRAIL, activated poly(adenosine diphosphate-ribose) polymerase, indicating sensitization to TRAIL. The results suggested that miR-138 regulates the interferon-stimulated gene 15 expression by directly targeting the 3' untranslated region of interferon-stimulated gene 15 and modulates the sensitivity to TRAIL-induced apoptosis. MiR-138 may be a target for therapeutic intervention in TRAIL-based drug treatments of resistant hepatocellular carcinoma or could be a biomarker to select patients who may benefit from the treatment.

ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system.

The interferon-stimulated gene 15 ubiquitin-like modifier (ISG15) encodes an IFN-inducible, ubiquitin-like protein. The ISG15 protein forms conjugates with numerous cellular proteins that are involved in a multitude of cellular functions, including interferon-induced immune responses and the regulation of cellular protein turnover. The expression of ISG15 and ISG15-mediated conjugation has been implicated in a wide range of human tumors and cancer cell lines, but the roles of ISG15 in tumorigenesis and responses to anticancer treatments remain largely unknown. In this review, we discuss the findings of recent studies with regard to the role of ISG15 pathways in cancers of the digestive system.