Misclassification of causes of death among a small all-autopsied group of former nuclear workers: Death certificates vs. autopsy reports.

The U.S. Transuranium and Uranium Registries performs autopsies on each of its deceased Registrants as a part of its mission to follow up occupationally-exposed individuals. This provides a unique opportunity to explore death certificate misclassification errors, and the factors that influence them, among this small population of former nuclear workers. Underlying causes of death from death certificates and autopsy reports were coded using the 10th revision of the International Classification of Diseases (ICD-10). These codes were then used to quantify misclassification rates among 268 individuals for whom both full autopsy reports and death certificates with legible underlying causes of death were available. When underlying causes of death were compared between death certificates and autopsy reports, death certificates correctly identified the underlying cause of death's ICD-10 disease chapter in 74.6% of cases. The remaining 25.4% of misclassified cases resulted in over-classification rates that ranged from 1.2% for external causes of mortality to 12.2% for circulatory disease, and under-classification rates that ranged from 7.7% for external causes of mortality to 47.4% for respiratory disease. Neoplasms had generally lower misclassification rates with 4.3% over-classification and 13.3% under-classification. A logistic regression revealed that the odds of a match were 2.8 times higher when clinical history was mentioned on the autopsy report than when it was not. Similarly, the odds of a match were 3.4 times higher when death certificates were completed using autopsy findings than when autopsy findings were not used. This analysis excluded cases where it could not be determined if autopsy findings were used to complete death certificates. The findings of this study are useful to investigate the impact of death certificate misclassification errors on radiation risk estimates and, therefore, improve the reliability of epidemiological studies.

Improvement of antibacterial activity of polysaccharides via chemical modification: A review.

Antibiotic residue and bacterial resistance induced by antibiotic abuse have seriously threatened food safety and human healthiness. Thus, the development and application of safe, high-efficiency, and environmentally friendly antibiotic alternatives are urgently necessary. Apart from antitumor, antivirus, anti-inflammatory, gut microbiota regulation, immunity improvement, and growth promotion activities, polysaccharides also have antibacterial activity, but such activity is relatively low, which cannot satisfy the requirements of food preservation, clinical sterilization, livestock feeding, and agricultural cultivation. Chemical modification not only provides polysaccharides with better antibacterial activity, but also promotes easy operation and large-scale production. Herein, the enhancement of the antibacterial activity of polysaccharides via acetylation, sulfation, phosphorylation, carboxymethylation, selenation, amination, acid graft, and other chemical modifications is reviewed. Meanwhile, a new trend on the application of loading chemically modified polysaccharides into nanostructures is discussed. Furthermore, possible limitations and future recommendations for the development and application of chemically modified polysaccharides with better antibacterial activity are suggested.

Custom-tailored hole transport layer using oxalic acid for high-quality tin-lead perovskites and efficient all-perovskite tandems.

All-perovskite tandem solar cells (TSCs) have exhibited higher efficiencies than single-junction perovskite solar cells (PSCs) but still suffer from the unsatisfactory performance of low-bandgap (LBG) tin-lead (Sn-Pb) subcells. The inherent properties of PEDOT:PSS are crucial to high-performance Sn-Pb perovskite films and devices; however, the underlying mechanism has not been fully explored and revealed. Here, we report a facile oxalic acid treatment of PEDOT:PSS (OA-PEDOT:PSS) to precisely regulate its work function and surface morphology. OA-PEDOT:PSS shows a larger work function and an ordered reorientation and fiber-shaped film morphology with efficient hole transport pathways, leading to the formation of more ideal hole-selective contact with Sn-Pb perovskite for suppressing interfacial nonradiative recombination losses. Moreover, OA-PEDOT:PSS induces (100) preferred orientation growth of perovskite for higher-quality Sn-Pb films. Last, the OA-PEDOT:PSS-tailored LBG PSC yields an impressive efficiency of up to 22.56% (certified 21.88%), enabling 27.81% efficient all-perovskite TSC with enhanced operational stability.

Correlation between cognitive impairment and serum markers in patients with obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Previous studies have revealed that sleep structure and hypoxemia are two important environmental factors for cognitive impairment in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that the pathophysiological mechanisms between these two factors may also be involved in cognitive impairment in patients with OSAHS. Previous studies have suggested that alterations in serum glucose and lipid metabolism, inflammatory responses, and astrocyte markers not only contribute to sleep structural disorders in OSAHS but also affect the occurrence and development of this disease. Therefore, we hypothesized that alterations in the abovementioned indicators may be involved in cognitive impairment in OSAHS. Additionally, obesity is an important risk factor for OSAHS. This study therefore aimed to explore the correlation between serum indicators and cognitive impairment in patients with OSAHS. METHODS: Patients with OSAHS who underwent polysomnography in our hospital were recruited in this study. The overall cognitive function of patients were evaluated using the Mini mental State Examination (MMSE). Blood biochemical indicators such as glucose (GLU), triglycerides (TG), and triglyceride glucose (TyG) index were measured. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of serum glucagon-like peptide-1 receptor (GLP-1R), fibroblast growth factor 21 (FGF21), S100 calcium binding protein B (S100B), brain derived neurotrophic factor (BDNF), inflammatory factors such as C-reactive protein (CRP), tumor necrosis factor-α (TNFα), interleukin-4 (IL-4), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Spearman correlation analysis was used to determine if the indicator was related to cognitive function, and backward linear regression analysis was used to identify the main risk factors for cognitive impairment in non-obese and obese patients with OSAHS. RESULTS: Among 34 patients, 19 were non-obese and 15 were obese. Obese patients exhibited higher AHI compared to non-obese individuals, and the difference was statistically significant (p < 0.05). In non-obese patients, Spearman correlation analysis revealed a negative correlation between serum GLU, IL-4, and MMSE scores (p < 0.05); IL-6 was positively correlated with MMSE (p < 0.05). In addition, GLU and IL-6 were independently correlated with MMSE in non-obese patients (p < 0.05). In obese patients, serum TG and TyG were positively correlated with MMSE scores (p < 0.05); age, BMI, and IL-4 were negatively correlated with MMSE scores (p < 0.05). In addition, age and IL-4 were independently correlated with MMSE in obese patients (p < 0.05). CONCLUSIONS: Our data suggested that GLU and IL-6 were independently correlated with cognitive impairment in non-obese patients with OSAHS; age and IL-4 were independently correlated with cognitive impairment in obese patients. Early detection of this difference in heterogeneity may provide theoretical support for future investigations in prevention and treatment of cognitive impairment in patients with OSAHS.

Relationship between slow-wave sleep and serum γ-glutamine transaminase in non-obese men with obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a disease characterized with intermittent hypoxia and sleep fragmentation. Obesity and gender are major risk factors for the onset of OSAHS. Previous studies on obese men with OSAHS have been performed, while few studies on non-obese men with OSAHS have been carried out. The purpose of this study was to explore the clinical characteristics of polysomnography and blood biochemical indexes in non-obese men with OSAHS and to identify the possible influencing factors. METHODS: This retrospective study included patients with OSAHS who underwent polysomnography in our hospital. General clinical data such as overnight polysomnography and biochemical indicators were recorded. The patients were divided into two groups according to the apnea-hypopnea index (AHI): mild to moderate OSAHS and severe OSAHS. The differences in biochemical parameters such as the levels of γ-glutamine transaminase (GGT), triglyceride (TG), glucose (GLU), and sleep structure parameters such as N1, N2, slow-wave sleep (SWS), and rapid eye movement (REM) sleep were compared and analyzed. Spearman correlation analysis and logistic regression were used to identify the risk factors of non-obese men with OSAHS. ROC curves were used to evaluate the predictive ability of SWS and GGT on disease severity. RESULTS: Of 94 non-obese men with OSAHS, 49 had mild to moderate OSAHS and 45 had severe OSAHS. Our data suggested that the levels of low oxygen saturation (L-SaO2), mean oxygen saturation (M-SaO2), SWS, and GGT were significantly changed in the mild to moderate OSAHS group compared with the severe group (p < 0.05). For patients with OSAHS, the proportion of SWS in the group with severe OSAHS was higher than that in the mild to moderate group (p < 0.05), and the serum GGT enzyme levels were significantly elevated in the severe group compared to the mild to moderate group (p < 0.05). Using logistic regression analyses, our data revealed that both SWS and GGT enzyme levels were independent risk factors for AHI (p < 0.05). In addition, the results of correlation analysis indicated that SWS was related to triglyceride (TG), total cholesterol (TC), apolipoprotein E (APOE), and triglyceride glucose (TyG) index (p < 0.05); GGT was related to TG, TC, APOE, and TyG index (p < 0.05). Furthermore, SWS was independently associated with GGT (p < 0.05). The area under the ROC curve plotted with the combined coefficient of SWS and serum GGT was 0.728, which was predictive of the disease severity. CONCLUSIONS: These results suggest that SWS and GGT are independent associated factors of the severity of the disease. However, TyG index was not an independent associated factor of the severity of disease in non-obese men with OSAHS. In addition, SWS and GGT were negatively correlated. SWS combined with serum GGT may be predictive of the severity of the disease. This study may have added to our understanding of the pathogenesis of OSAHS in non-obese men.

Application value of hand-sewn anastomosis in totally laparoscopic total gastrectomy for gastric cancer.

BACKGROUND: Digestive tract reconstruction in totally laparoscopic total gastrectomy can be divided into two types: instrument anastomosis and hand-sewn anastomosis. This study explored the feasibility and safety of hand-sewn sutures in esophagojejunostomy of totally laparoscopic total gastrectomy, compared with instrument anastomosis using an overlap linear cutter. METHODS: This retrospective cohort study was conducted from January 2017 to January 2020 at one institution. The clinical data of 50 patients who underwent totally laparoscopic total gastrectomy, with an average follow-up time of 12 months, were collected. The clinicopathologic data, short-term survival prognosis, and results of patients in the hand-sewn anastomosis (n=20) and the overlap anastomosis (n=30) groups were analyzed. RESULTS: There were no significant differences between the groups in sex, age, body mass index, American Society of Anesthesiologists score, tumor location, preoperative complications, abdominal operation history, tumor size, pTNM stage, blood loss, first postoperative liquid diet, exhaust time, or postoperative length of hospital stay. The hand-sewn anastomosis group had a significantly prolonged operation time (204±26.72min versus 190±20.90min, p=0.04) and anastomosis time (58±22.0min versus 46±15.97min, p=0.029), and a decreased operation cost (CNY 77,100±1700 versus CNY 71,900±1300, p<0.0001). Postoperative complications (dynamic ileus, abdominal infection, and pancreatic leakage) occurred in three patients (15%) in the hand-sewn anastomosis group and in four patients (13.3%) in the overlap anastomosis group (anastomotic leakage, anastomotic bleeding, dynamic ileus, and duodenal stump leakage). CONCLUSION: The hand-sewn anastomosis method of esophagojejunostomy under totally laparoscopic total gastrectomy is safe and feasible and is an important supplement to linear and circular stapler anastomosis. It may be more convenient regarding obesity, a relatively high position of the anastomosis, edema of the esophageal wall, and short jejunal mesentery.

Digestive tract reconstruction of laparoscopic total gastrectomy for gastric cancer: a comparison of the intracorporeal overlap, intracorporeal hand-sewn anastomosis, and extracorporeal anastomosis.

BACKGROUND: The application of esophagojejunostomy has certain difficulties in totally laparoscopic total gastrectomy (TLTG). This is due to the higher requirement for surgical techniques and the lack of any unified standards. This study aim to explore the practicability and safety of intracorporeal overlap and intracorporeal hand-sewn anastomosis compared with extracorporeal anastomosis. METHODS: The clinical pathological data of 56 patients who underwent TLTG from March 2016 to December 2020 in the Harbin Medical University Cancer Hospital were retrospectively analyzed. According to the method of anastomosis, the patients were divided into the overlap (n=36) and the hand-sewn anastomosis (n=20). Patients who receive laparoscopic-assisted total gastrectomy (LATG; n=74) formed the control group. The basic clinical data, and intraoperative and postoperative results of the patients were assessed. RESULTS: Compared with the control group, the overlap anastomosis and hand-sewn anastomosis groups showed no significant differences in clinicopathological data and short-term postoperative recovery. There were no significant differences between the overlap and the control group in operation time nor anastomosis time. However, the anastomosis time of the hand-sewn anastomosis group was significantly prolonged compared to the control group (53.20±14.14 vs. 43.01±12.53 minutes, P=0.002). Compared with the control group, the operation cost was significantly higher in the overlap group (CNY 81,300±6,100 vs. CNY 76,600±6,800, P=0.001), but significantly lower in the hand-sewn anastomosis group (CNY 71,900±1,700 vs. CNY 76,600±6,800, P=0.003). Early postoperative complications occurred in 5 cases (13.9%) in the overlap group, 3 cases (15.0%) in the hand-sewn anastomosis group, and 11 cases (14.9%) in the control group. There were 3 cases (8.3%) of postoperative anastomotic-related complications in the overlap group. No anastomotic-related complications were observed in the hand-sewn anastomosis group. CONCLUSIONS: The overlap anastomosis and hand-sewn anastomosis are practical and safe. Furthermore, the overlap anastomosis may be more suitable for patients with lower cardia and fundic lesions. The hand-sewn method has a wider range of indications pending advanced surgical skills, and is an effective supplementary technique for instrument anastomosis.

Inhibition of TGFß1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy.

Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFß1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFß1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFß1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFß1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFß1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFß1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFß1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFß1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFß1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.

ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway.

BACKGROUND: ATP binding cassette subfamily A member 8 (ABCA8) belongs to the ATP binding cassette (ABC) transporter superfamily. ABCA8 is a transmembrane transporter responsible for the transport of organics, such as cholesterol, and drug efflux. Some members of the ABC subfamily, such as ABCA1, may inhibit cancer development. However, the mechanism of ABCA8 in the process of cancer activation is still ambiguous. METHODS: The expression of ABCA8 in human hepatocellular carcinoma (HCC) tissues and cell lines was examined using qPCR, immunoblotting, and immunohistochemical staining. The effects of ABCA8 on the proliferation and metastasis of HCC were examined using in vitro and in vivo functional tests. A luciferase reporter assay was performed to explore the binding between microRNA-374b-5p (miR-374b-5p) and the ABCA8 3'-untranslated region (UTR). RESULTS: ABCA8 was frequently down-regulated in HCC and this down-regulation was negatively correlated with prognosis. The overexpression of ABCA8 inhibited growth and metastasis in HCC, whereas the knockdown of ABCA8 exerted the antithetical effects both in vivo and in vitro. ABCA8 was down-regulated by miR-374b-5p; this down-regulation can induce epithelial transformation to mesenchyme via the ERK/ZEB1 signaling pathway and promote HCC progression. CONCLUSION: We exposed the prognostic value of ABCA8 in HCC, and illuminated a novel pathway in ABCA8-regulated inhibition of HCC tumorigenesis and metastasis. These findings may lead to a new targeted therapy for HCC through the regulation of ABCA8, and miR-374b-5p.

Highly Thermal Conductivities, Excellent Mechanical Robustness and Flexibility, and Outstanding Thermal Stabilities of Aramid Nanofiber Composite Papers with Nacre-Mimetic Layered Structures.

Aramid nanofiber (ANF) paper has shown potential applications in flexible electronics. However, its inherent low thermal conductivity coefficient (λ) values might threaten the safety of devices under a high-power working condition. In this work, polydopamine-functionalized boron nitride nanosheet (BNNS@PDA)/ANF thermally conductive composite papers with nacre-mimetic layered structures were prepared via highly efficient vacuum-assisted filtration followed by hot pressing. For a given BNNS loading, the surface functionalization of BNNS could further enhance the thermal conductivities and mechanical properties of BNNS@PDA/ANF composite papers. BNNS@PDA/ANF composite papers presented anisotropic thermal conductivities, and the through-plane (λ⊥) and in-plane (λ∥) values of the 50 wt % BNNS@PDA/ANF composite papers reached 0.62 and 3.94 W/mK, 181.8 and 196.2% higher than those of original ANF paper, respectively, which were also higher than those of 50 wt % BNNS/ANF composite papers (λ⊥ = 0.52 W/mK and λ∥ = 3.33 W/mK). The tensile strength of the 50 wt % BNNS@PDA/ANF composite papers reached 36.8 MPa, 30.5% higher than that of 50 wt % BNNS/ANF composite papers (28.2 MPa). In addition, the heat resistance index (THRI) of the 50 wt % BNNS@PDA/ANF composite papers was further increased to 223.1 °C. Overall, our fabricated BNNS@PDA/ANF composite papers possess highly thermal conductivities, excellent mechanical robustness and flexibility, and outstanding thermal stabilities, showing great potential applications in the fields of intelligent wearable equipment, flexible supercapacitors, and flexible electronics.

A Novel Oxoglutarate Dehydrogenase-Like Mediated miR-214/TWIST1 Negative Feedback Loop Inhibits Pancreatic Cancer Growth and Metastasis.

PURPOSE: As a main rate-limiting subunit of the 2-oxoglutarate dehydrogenase multienzyme complex, oxoglutarate dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. EXPERIMENTAL DESIGN: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. RESULTS: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF1α and regulating AKT pathways. A combination of OGDHL downregulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. CONCLUSIONS: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.

Upregulation of cystatin SN promotes hepatocellular carcinoma progression and predicts a poor prognosis.

Cystatin SN, a specific cysteine protease inhibitor, is thought to be involved in various malignant tumors. Therefore, we evaluated the role of cystatin SN in hepatocellular carcinoma (HCC). Notably, cystatin SN was elevated in tumorous samples and cells. Moreover, overexpression of cystatin SN was correlated with tumor diameter and TNM stage. Cox multivariate analysis displayed that cystatin SN was an independent prognosis indicator and that high cystatin SN level was associated with a dismal prognosis. Moreover, cystatin SN enhancement facilitated the proliferation, migratory, and invasive potential of Huh7 and HCCLM3 cells, whereas cystatin SN knockdown caused the opposite effect. Cystatin SN also modulated the epithelial-mesenchymal transition progression through the PI3K/AKT pathway. In vivo cystatin SN promoted HCCLM3 cell growth and metastasis in xenograft mice model. Thus, cystatin SN was involved in HCC progression and could be a latent target for HCC treatment.

KIFC1 regulated by miR-532-3p promotes epithelial-to-mesenchymal transition and metastasis of hepatocellular carcinoma via gankyrin/AKT signaling.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. The poor survival may be due to a high proportions of tumor recurrence and metastasis. Kinesin family member C1 (KIFC1) is highly expressed in a variety of neoplasms and is a potential marker for non-small cell lung cancer or ovarian adenocarcinoma metastasis. Nevertheless, the role of KIFC1 in HCC metastasis remains obscure. We investigated this in the present study using HCC cell lines and clinical specimens. Our results indicated that increased levels of KIFC1 were associated with poor prognosis and metastasis in HCC. In addition, KIFC1 induced epithelial-to-mesenchymal transition (EMT) and HCC metastasis both in vitro and in vivo. This tumorigenic effect depended on gankyrin; inhibiting gankyrin activity reversed EMT via activation of protein kinase B (AKT)/Twist family BHLH transcription factor 1 (AKT/TWIST1). We also found that KIFC1 was directly regulated by the microRNA miR-532-3p, whose downregulation was associated with metastatic progression in HCC. These results denote that a decrease in miR-532-3p levels results in increased KIFC1 expression in HCC, leading to metastasis via activation of the gankyrin/AKT/TWIST1 signaling pathway.

Tetraspanin 1 promotes epithelial-to-mesenchymal transition and metastasis of cholangiocarcinoma via PI3K/AKT signaling.

BACKGROUND: Numerous studies have demonstrated that tetraspanin 1 (TSPAN1), a transmembrane protein, functions as an oncoprotein in many cancer types. However, its role and underlying molecular mechanism in cholangiocarcinoma (CCA) progression remain unclear. METHODS: In the present study, the expression of TSPAN1 in human CCA and adjacent nontumor tissues was examined using real-time PCR, western blot and immunohistochemistry. The effect of TSPAN1 on proliferation and metastasis was evaluated by functional assays both in vitro and in vivo. A luciferase reporter assay was performed to investigate the interaction between microRNA-194-5p (miR-194-5p) and TSPAN1 3'-untranslated region. Co-immunoprecipitation (co-IP) was used to confirm the interaction between TSPAN1 protein and integrin α6ß1 and western blot was used to explore TSPAN1 mechanism. RESULTS: We found that TSPAN1 was frequently upregulated in CCA and high levels of TSPAN1 correlated with TNM stage, especially metastasis in CCA. TSPAN1 overexpression promoted CCA growth, metastasis, and induced epithelial-to-mesenchymal transition (EMT), while its silencing had the opposite effect both in vitro and in vivo. To explore the differential expression of TSPAN1, we screened miR-194-5p as the upstream regulator of TSPAN1. A combination of high-level TSPAN1 and low-level miR-194-5p predicted poor prognosis in patients with CCA. Furthermore, in accordance with the functional characteristics of the TSPAN superfamily, we proved that TSPAN1 interacted with integrin α6ß1 to amplify the phosphoinositide-3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3ß/Snail family transcriptional repressor (Snail)/phosphatase and tensin homolog (PTEN) feedback loop. CONCLUSION: The results indicate that TSPAN1 could be a potential therapeutic target for CCA.

Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation.

BACKGROUND: Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of the lipolytic pathway in HCC has not been elucidated. METHODS: We compared levels of adipose triglyceride lipase (ATGL) in human HCC and healthy liver tissues by real time PCR, western blot and immunohistochemistry. We measured diacylglycerol(DAG) and free fatty acid (FFA) levels in HCC cells driven by the NEAT1-ATGL axis and in HCC tissues. We also assessed the effects of ATGL, DAG, FFA, and NEAT1 on HCC cells proliferation in vitro and in an orthotopic xenograft HCC mouse model. We also performed a luciferase reporter assay to investigate the interaction between NEAT1/ATGL and miR-124-3p. RESULTS: We found that the lipolytic enzyme, ATGL is highly expressed in human HCC tissues and predicts poor prognosis. We also found that high levels of DAG and FFA are present in HCC tissues. Furthermore, the lncRNA-NEAT1 was found to modulate ATGL expression and disrupt lipolysis in HCC cells via ATGL. Notably, ATGL and its products, DAG and FFA, were shown to be responsible for NEAT1-mediated HCC cell growth. NEAT1 regulated ATGL expression by binding miR-124-3p. Additionally, NEAT1 knockdown attenuated HCC cell growth through miR-124-3p/ATGL/DAG+FFA/PPARα signaling. CONCLUSION: Our results reveal that NEAT1-modulates abnormal lipolysis via ATGL to drive HCC proliferation.

STK17B promotes carcinogenesis and metastasis via AKT/GSK-3ß/Snail signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide with frequent intrahepatic and distant metastasis. Elucidating the underlying molecular mechanism that modulates HCC progression is critical for exploring novel therapeutic strategies. Serine/Threonine Kinase 17B (STK17B) is upregulated in HCC tissues, but its role in HCC progression remains elusive. In the present studies, we reported that STK17B had a critical role in HCC progression. STK17B was significantly upregulated in HCC cell lines and specimens, and patients with ectopic STK17B expression characterized with poor clinicopathological features. In vitro and in vivo assay demonstrated that inhibition of STK17B markedly inhibits HCC tumorigenesis and metastasis, while STK17B overexpression promoted these processes. Furthermore, we found that STK17B promoted EMT process via activating AKT/GSK-3ß/Snail signal pathway, and miR-455-3p was identified as the upstream regulator of STK17B. Combination of high level of STK17B and low level of miR-455-3p predicted poor prognosis with higher accuracy for HCC patients. In conclusion, our research demonstrated that STK17B promotes HCC progression, induces EMT process via activating AKT/GSK-3ß/Snail signal and predicts poor prognosis in HCC.

Deregulated AJAP1/ß-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis.

Adherens junctions-associated protein 1 (AJAP1) is an integral membrane protein that is thought to function as a tumor suppressor in various malignancies. Downregulation of AJAP1 mRNA levels may predict recurrence in hepatocellular carcinoma (HCC) patients, but the underlying molecular mechanism is unknown. This was addressed in the present study by examining the role of AJAP1 in HCC cell proliferation, migration, and invasion in vitro as well as in human specimens and mouse xenograft model. We found that AJAP1 expression was reduced in HCC cells and human HCC tissue, which was associated with metastasis. AJAP1 overexpression inhibited HCC progression and metastasis, while its silencing had the opposite effect both in vitro and in vivo. Furthermore, AJAP1 blocked epithelial-to-mesenchymal transition by interacting with ß-catenin and inhibiting its nuclear translocation, which suppressed zinc finger E-box binding homeobox 1 (ZEB1) transcription. These results indicate that AJAP1 inhibits HCC metastasis, and is thus a potential therapeutic target for HCC treatment.

N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway.

Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).

FCN2 inhibits epithelial-mesenchymal transition-induced metastasis of hepatocellular carcinoma via TGF-ß/Smad signaling.

Hepatocellular carcinoma (HCC) is currently still a major cause of cancer-related deaths. Identifying early metastatic biomarkers and therapeutic targets for HCC is of great importance. Emerging evidence suggest that epithelial-mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is crucial for improving HCC. In this study, we find Ficolin-2 (FCN2) plays an essential role in metastasis and EMT of HCC. FCN2 expression is downregulated in HCC cells and tissues. Low level of FCN2 in HCCs is correlated with aggressive metastatic features, and would be a prognostic factor for overall disease-free survival of HCC patients. Ectopic expression of FCN2 markedly inhibits HCC cells migration, invasion as well as EMT in vitro and in vivo. Moreover, TGF-ß is found contribute to the function of FCN2 in suppressing metastasis and EMT of HCC. Collectively, our data suggest that FCN2 may have prognostic value in HCC metastasis. Additionally, the FCN2/ TGF-ß/EMT axis identified in this study provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.