HNF1A induces glioblastoma by upregulating EPS8 and activating PI3K/AKT signaling pathway.

Despite the exact biological role of HNF1 homolog A (HNF1A) in the regulatory mechanism of glioblastoma (GBM), the molecular mechanism, especially the downstream regulation as a transcription factor, remains to be further elucidated. Immunohistochemistry was used to detect the expression and clinical relevance of HNF1A in GBM patients. CCK8, TUNEL, and subcutaneous tumor formation in nude mice were used to evaluate the effect of HNF1A on GBM in vitro and in vivo. The correction between HNF1A and epidermal growth factor receptor pathway substrate 8 (EPS8) was illustrated by bioinformatics analysis and luciferase assay. Further mechanism was explored that the transcription factor HNF1A regulated the expression of EPS8 and downstream signaling pathways by directly binding to the promoter region of EPS8. Our comprehensive analysis of clinical samples in this study showed that upregulated expression of HNF1A was associated with poor survival in GBM patients. Further, we found that knockdown of HNF1A markedly suppressed the malignant phenotype of GBM cells in vivo and in vitro as well as promoted apoptosis of tumor cells, which was reversed by upregulation of HNF1A. Mechanistically, HNF1A could significantly activate PI3K/AKT signaling pathway by specifically binding to the promoter regions of EPS8. Moreover, overexpression of EPS8 was able to reverse the apoptosis of tumor cells caused by HNF1A knockdown, thereby exacerbating the GBM progression. Correctively, our study has clarified the explicit mechanism by which HNF1A promotes GBM malignancy and provides a new therapeutic target for further clinical application.

Necroptosis: A Pathogenic Negotiator in Human Diseases.

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Increased risk of hepatocellular carcinoma in patients with traumatic liver injury: Real-world data from a nationwide population-based study.

ABSTRACT: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and liver is one of the most commonly injured organs after blunt abdominal trauma. The traumatic liver injury-HCC risk relationship remains unclear.We extracted data of patients with traumatic liver injury between 2000 and 2013 from Taiwan National Health Insurance Research Database (n = 15,966) and those of age-, gender-, occupation-, and index year-matched individuals without traumatic liver injury from the general population (n = 63,864). Cox proportional hazard models were employed to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC occurrence in the traumatic liver injury cohort compared with that in the comparison cohort.Patients with traumatic liver injury had an increased HCC risk (adjusted HR 2.13, 95% CI 1.59-2.85); this increased risk was more pronounced within 1 year after injury (adjusted HR 8.84, 95% CI 4.29-18.2). After >1 year of injury, HCC risk remained 1.53-fold higher in patients with traumatic liver injury than in those without traumatic liver injury (95% CI 1.08-2.15).People with traumatic liver injury demonstrate a high HCC risk, particularly within the first year of the injury.

LASSO and Bioinformatics Analysis in the Identification of Key Genes for Prognostic Genes of Gynecologic Cancer.

The aim of this study is to identify potential biomarkers for early diagnosis of gynecologic cancer in order to improve survival. Cervical cancer (CC) and endometrial cancer (EC) are the most common malignant tumors of gynecologic cancer among women in the world. As the underlying molecular mechanisms in both cervical and endometrial cancer remain unclear, a comprehensive and systematic bioinformatics analysis is required. In our study, gene expression profiles of GSE9750, GES7803, GES63514, GES17025, GES115810, and GES36389 downloaded from Gene Expression Omnibus (GEO) were utilized to analyze differential gene expression between cancer and normal tissues. A total of 78 differentially expressed genes (DEGs) common to CC and EC were identified to perform the functional enrichment analyses, including gene ontology and pathway analysis. KEGG pathway analysis of 78 DEGs indicated that three main types of pathway participate in the mechanism of gynecologic cancer such as drug metabolism, signal transduction, and tumorigenesis and development. Furthermore, 20 diagnostic signatures were confirmed using the least absolute shrink and selection operator (LASSO) regression with 10-fold cross validation. Finally, we used the GEPIA2 online tool to verify the expression of 20 genes selected by the LASSO regression model. Among them, the expression of PAMR1 and SLC24A3 in tumor tissues was downregulated significantly compared to the normal tissue, and found to be statistically significant in survival rates between the CC and EC of patients (p < 0.05). The two genes have their function: (1.) PAMR1 is a tumor suppressor gene, and many studies have proven that overexpression of the gene markedly suppresses cell growth, especially in breast cancer and polycystic ovary syndrome; (2.) SLC24A3 is a sodium-calcium regulator of cells, and high SLC24A3 levels are associated with poor prognosis. In our study, the gene signatures can be used to predict CC and EC prognosis, which could provide novel clinical evidence to serve as a potential biomarker for future diagnosis and treatment.

Exosomal tumor necrosis factor-α from hepatocellular cancer cells (Huh-7) promote osteoclast differentiation.

Bone is the common extra-hepatic site for cancer metastasis. Hepatic cancer is associated with a higher incidence of pathological fracture. However, this important regulatory mechanism remains unexplored. Thus, exosome-mediated cell-cell communication between hepatocellular cancer and bone might be key to osteolytic bone destruction. Huh-7 exosomes were characterized for size and exosome marker expressions (CD63, Alix). Exosome mediated osteoclast differentiation in the RAW 264.7 cells was monitored from day 1 to 6 and multinucleated osteoclast formation and bone resorption activity were analyzed. The osteoclastogenic factor expressions in the exosomes and osteoclast differentiation markers such as tumor necrosis factor receptor 6 (TRAF6), nuclear factor κB (NF-κB), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and cathepsin K (CTSK) were analyzed using western blot. Exosomes released by liver cancer cells (Huh-7) promoted osteoclast differentiation in RAW 264.7 cells. Analysis of osteoclastogenic factors in the exosomes showed that exosomes were specifically enriched with tumor necrosis factor α (TNF-α). Huh-7 exosomes promoted osteoclast differentiation by significantly increasing the number of TRAP-positive multi nucleated osteoclasts and resorption pits. Importantly, exosomes upregulated osteoclast markers TRAF6, NF-κB, and CTSK expressions. Further, neutralizing exosomal TNF-α reverted exosome-mediated osteoclast differentiation in RAW 264.7 cells. Collectively, our findings show that cellular communication of exosomal TNF-α from hepatocellular cancer cells (Huh-7) regulates osteoclast differentiation through NF-κB/CTSK/TRAP expressions. Thus, exosomal TNF-α might act as an important therapeutic target to prevent hepatocellular cancer mediated pathological bone disease.

Human antigen R regulates hypoxia-induced mitophagy in renal tubular cells through PARKIN/BNIP3L expressions.

Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular homeostasis. RNA-binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we aimed to understand the role of human antigen R (HuR) in hypoxia-induced mitophagy process in the renal tubular cells. Mitophagy marker expressions (PARKIN, p-PARKIN, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. Immunofluorescence studies were performed to analyze mitophagosome, mitolysosome, co-localization of p-PARKIN/TOMM20 and BNIP3L/TOMM20. HuR-mediated regulation of PARKIN/BNIP3L expressions was determined by RNA-immunoprecipitation analysis and RNA stability experiments. Hypoxia induced mitochondrial dysfunction by increased ROS, decline in membrane potential and activated mitophagy through up-regulated PARKIN, PINK1, BNIP3 and BNIP3L expressions. HuR knockdown studies revealed that HuR regulates hypoxia-induced mitophagosome and mitolysosome formation. HuR was significantly bound to PARKIN and BNIP3L mRNA under hypoxia and thereby up-regulated their expressions through mRNA stability. Altogether, our data highlight the importance of HuR in mitophagy regulation through up-regulating PARKIN/BNIP3L expressions in renal tubular cells.

The functional interplay of lncRNA EGOT and HuR regulates hypoxia-induced autophagy in renal tubular cells.

Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK-2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia-induced autophagy in HK-2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy-associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia-induced autophagy. Gain- and loss-of-EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA-binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia-induced autophagy in renal tubular cells.

N-acetylcysteine for the prevention of contrast-induced nephropathy in the emergency department.

OBJECTIVE: To evaluate the use of N-acetylcysteine (NAC), a potent antioxidant, to prevent contrast-induced nephropathy (CIN). METHODS: We prospectively studied 209 patients (106 in the NAC group and 103 in the control group) who received contrast-enhanced computed tomography (CECT) in the emergency department (ED). The NAC group received intravenous NAC (600 mg) before CECT imaging to prevent CIN. Both the NAC and control groups were treated using a standardized hydration strategy, where clinically feasible. RESULTS: The patients' mean age was 79.6±9.8 years. The prevalence of hypertension, diabetes, and chronic kidney disease (CKD) were 63.2%, 27.3%, and 21.5%, respectively. The baseline clinical characteristics were similar between the two groups except for their body weight (p=0.011), amount of contrast material administered (p=0.049) and prevalence of CKD (p=0.002). The incidence of CIN was 7.5% in the NAC group and 14.6% in the control group. The adjusted odds ratio was 0.305 (95% confidence interval: 0.097 to 0.960, p=0.042). All-cause mortality was 7.5% in the NAC group and 12.6% in the control group, which was not significantly different. Temporary hemodialysis was required in 0% of subjects in the NAC group and 1.0% in the control group, which was not a statistically significant difference. CONCLUSION: A single dose of NAC before CECT imaging can prevent CIN in an ED setting. However, it does not improve the mortality rate or the need for dialysis.