RESUMO
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC. SIGNIFICANCE: PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Asparagina/genética , Asparagina/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/metabolismo , Neoplasias Hepáticas/patologia , Prognóstico , Serina-Treonina Quinases TOR/metabolismoRESUMO
STUDY OBJECTIVE: Hypoxemia is one of the most frequent adverse events during sedated gastroscopy, and there is still no effective means to prevent and cure it. Therefore, we conducted this randomized trial to confirm our hypothesis that, compared with the nasal cannula group, bilevel positive airway pressure (BPAP) would decrease the incidence of hypoxemia in patients with obstructive sleep apnea (OSA) or overweight status undergoing gastroscopy. DESIGN: In a single-center, prospective, randomized controlled clinical trial, 80 patients aged 18-65 years and with OSA or overweight status who underwent gastroscopy with sedation were randomly assigned to two groups: the nasal cannula and BPAP groups. The primary outcome was the incidence of hypoxemia (75% < peripheral oxygen saturation [SpO2] < 90% for >5 sand <60 s). MAIN RESULTS: Compared to the nasal cannula group, BPAP therapy significantly decreased the incidence of hypoxemia from 40.0% to 2.5% (absolute risk difference [ARD], 37.5% [95% confidence interval (CI), 21.6 to 53.4], p < 0.001), decreased subclinical respiratory depression from 52.5% to 22.5% (ARD, 30.0% [95% CI, 9.8 to 50.2], p = 0.006), and decreased severe hypoxemia from 17.5% to 0% (ARD, 17.5% [95% CI, 5.7 to 29.3], p = 0.006). The BPAP intervention also decreased the total propofol dosage and operation time and improved anesthesiologist's satisfaction. CONCLUSION: BPAP therapy significantly decreased the incidence of hypoxemia in patients with OSA or overweight status who underwent gastroscopy.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Apneia Obstrutiva do Sono , Humanos , Pressão Positiva Contínua nas Vias Aéreas/efeitos adversos , Gastroscopia/efeitos adversos , Sobrepeso/complicações , Estudos Prospectivos , Hipóxia/diagnóstico , Hipóxia/epidemiologia , Hipóxia/etiologia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/complicaçõesRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs) show great potential as diagnostic tools in many diseases. We aimed to develop sensitive and noninvasive biomarkers in saliva for detecting early hepatocellular carcinoma (HCC). METHODS: Candidate lncRNA biomarkers identified by Agilent microarray were subjected to validation using qPCR for the quantification of their expression levels in independent tissue, plasma and saliva sample sets, including healthy controls, HBsAg carriers, patients with chronic Hepatitis B, liver cirrhosis, early HCC, and advanced HCC. Levels of candidate biomarkers were also measured in totally 108 saliva samples from patients with any one of other nine leading causes of cancer death in men and women. FINDINGS: Lnc-PCDH9-13:1 was significantly elevated in HCC tissues, plasma and saliva of HCC patients compared with healthy controls and groups of several benign liver diseases and other leading cancers. Its level was significantly reduced after curative hepatectomy but significantly elevated again if HCC recurrence occurred. Salivary lnc-PCDH9-13:1 showed reasonable specificities and sensitivities for detecting HCC compared with several control groups. Furthermore, the overexpression of lnc-PCDH9-13:1 promotes cell proliferation and migration in vitro. INTERPRETATION: Salivary lnc-PCDH9-13:1 is a desirable biomarker for early HCC. It may help warrant prospective validation with larger sample sizes in multi-centers.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Regulação para Cima , Idoso , Linhagem Celular Tumoral , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , Saliva/químicaRESUMO
Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. ß-Arrestins (ß-arrestin-1 and ß-arrestin-2) are well-established mediators of endocytosis of G-protein-coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of ß-arrestin-1 (ß-arr1) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of ß-arr1 in PHG via its regulation of endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) apoptotic signaling. Gastric mucosal injury and apoptosis were studied in PHG patients and in PHG mouse models. The induction of ß-arr1 and the ER stress/PUMA signaling pathway were investigated, and the mechanisms of ß-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments. ß-arr1 and ER stress/PUMA signaling elements were markedly induced in the gastric mucosa of PHG patients and mouse models. Blockage of ER stress demonstrably attenuated the mucosal apoptosis of PHG, while targeted deletion of ß-arr1 significantly aggravated the injury and ER stress/PUMA-mediated apoptosis. ß-arr1 limited the activation of p65 to repress TNF-α-induced inducible nitric oxide synthase (iNOS) expression and NO release, which could regulate ER stress/PUMA-mediated mucosal apoptosis in PHG. In vivo and in vitro experiments further demonstrated that ß-arr1 protected against mucosal apoptosis by repressing TNF-α-induced iNOS expression via inhibiting the activation of p65. These results indicated that ß-arr1 regulated ER stress/PUMA-induced mucosal epithelial apoptosis through suppression of the TNF-α/p65/iNOS signaling pathway activation and that ß-arr1 is a potential therapeutic target for PHG.
Assuntos
Arrestinas/genética , Hipertensão Portal/genética , Óxido Nítrico Sintase Tipo II/biossíntese , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Animais , Apoptose/genética , Arrestinas/biossíntese , Endocitose/genética , Estresse do Retículo Endoplasmático/genética , Mucosa Gástrica/lesões , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Hemorragia/metabolismo , Hemorragia/patologia , Humanos , Hipertensão Portal/patologia , Masculino , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais , Fator de Transcrição RelA/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Proteína Supressora de Tumor p53/metabolismo , beta-Arrestina 1 , beta-Arrestina 2 , beta-ArrestinasRESUMO
BACKGROUND AND AIM: Methyl or 1, N(6) -ethenoadenine base lesions are frequent and highly-mutagenic or -carcinogenic events in mammalian DNA. Human AlkB homologue-2 (hABH2), a homologue of the Escherichia coli AlkB protein, has been found to be the principal dioxygenase for the repair of these lesions. Mounting evidence indicates that impaired DNA repair contributes to gastric cancer induction and progression. Whether hABH2 is involved in this malignancy is unknown. The present study was aimed to investigate the expression profile of hABH2 in gastric cancer and the effect of hABH2 on cancer cell growth. METHODS: The expression of hABH2 in 35 pair-matched gastric neoplastic and adjacent non-neoplastic tissues, and in five gastric cancer cell lines, was examined by real-time polymerase chain reaction (PCR), immunohistochemistry, or Western blot. The cell growth was determined using cell-counting kit-8 assay. The apoptosis or cell-cycle analysis was determined using flow cytometry. RESULTS: The hABH2 expression was downregulated in 68% (24/35) of primary gastric cancers, as determined by real-time PCR; the hABH2 expression was also substantially decreased in gastric cancer cell lines. Immunohistochemical or Western blot analysis further confirmed the downregulation of hABH2 expression in gastric cancers. The overexpression of hABH2 significantly inhibited the proliferation of gastric cancer cells, and induced G(1) arrest of the cell cycle, while hABH2 knockdown promoted cell growth and cell-cycle progression of gastric cancer cells. CONCLUSIONS: These results suggest that hABH2 is downregulated in a subset of gastric cancers, and might be involved in the molecular mechanism of gastric cancer through inhibiting the proliferation of gastric cancer cells.