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Gastric cancer (GC) is a highly prevalent and aggressive malignancy with a poor prognosis. Recent evidence suggested that metallothionein 1 M (MT1M) may play a critical role in cancer development, progression, and drug resistance; however, its role in GC remains largely unknown. In this study, we investigated the expression and function of MT1M in GC both in vitro and in vivo. We found that MT1M expression was significantly downregulated in GC tissues and cell lines. Decreased expression of MT1M was associated with worse clinical prognosis, particularly in patients treated with 5-fluorouracil. Low expression of MT1M was indicative of poor overall survival (OS, HR 0.56 [95% CI 0.37-0.84], P < 0.005), first progression survival (FP, HR 0.54 [95% CI 0.36-0.79], P < 0.005), and post-progression survival (PPS, HR 0.65 [95% CI 0.45-0.94], P < 0.05). We also demonstrated that overexpression of MT1M inhibited cell proliferation and induced apoptosis in GC cells and in tumor xenografts, and it improved chemosensitivity to 5-fluorouracil. Furthermore, we found that MT1M overexpression could inhibit stem cell characteristics by targeting GLI1 and affecting GLI1 ubiquitination. Collectively, these findings indicated that MT1M may act as a tumor suppressor in GC and could serve as a potential therapeutic target to attenuate stemness and chemotherapy resistance of GC.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Proteínas Hedgehog/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Línea Celular Tumoral , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metalotioneína/genéticaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC. METHODS: Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance. RESULTS: We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells. CONCLUSION: Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC.
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Factor de Transcripción Activador 2/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Factor de Transcripción Activador 2/genética , Animales , Carcinoma Hepatocelular/patología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas de la Membrana/genética , Ratones , Ratones Desnudos , Ubiquitina-Proteína Ligasas/genética , Regulación hacia ArribaRESUMEN
DNA methyltransferase (DNMT) participates in the transformation or progression of human cancers by mediating the hypermethylation of cancer suppressors. However, the regulatory role of DNMT in pancreatic cancer cells remains poorly understood. In the present study, we demonstrated that DNMT1 repressed the expression of microRNA 34a (miR-34a) and enhanced the activation of the Notch pathway by mediating the hypermethylation of the miR-34a promoter. In patients with pancreatic cancer, the expression levels of DNMT1 were negatively related with those of miR-34a. Mechanistically, knockdown of DNMT1 decreased the methylation of the miR-34a promoter and enhanced the expression of miR-34a to inhibit the activation of the Notch pathway. Downregulation of the Notch pathway via the DNMT1/miR-34a axis significantly enhanced the sensitivity of pancreatic cells to molecular targeting agents. Therefore, the results of our study suggest that downregulation of DNMT enhances the expression of miR-34a and may be a potential therapeutic target for pancreatic cancer.
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ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Metilación de ADN/genética , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Anciano , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Regiones Promotoras Genéticas , Receptores Notch , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Liver metastases (LM) is the primary factor contributing to unfavorable outcomes in patients diagnosed with gastric cancer (GC). The objective of this study is to analyze significant prognostic risk factors for patients with GCLM and develop a reliable nomogram model that can accurately predict individualized prognosis, thereby enhancing the ability to evaluate patient outcomes. AIM: To analyze prognostic risk factors for GCLM and develop a reliable nomogram model to accurately predict individualized prognosis, thereby enhancing patient outcome assessment. METHODS: Retrospective analysis was conducted on clinical data pertaining to GCLM (type III), admitted to the Department of General Surgery across multiple centers of the Chinese PLA General Hospital from January 2010 to January 2018. The dataset was divided into a development cohort and validation cohort in a ratio of 2:1. In the development cohort, we utilized univariate and multivariate Cox regression analyses to identify independent risk factors associated with overall survival in GCLM patients. Subsequently, we established a prediction model based on these findings and evaluated its performance using receiver operator characteristic curve analysis, calibration curves, and clinical decision curves. A nomogram was created to visually represent the prediction model, which was then externally validated using the validation cohort. RESULTS: A total of 372 patients were included in this study, comprising 248 individuals in the development cohort and 124 individuals in the validation cohort. Based on Cox analysis results, our final prediction model incorporated five independent risk factors including albumin levels, primary tumor size, presence of extrahepatic metastases, surgical treatment status, and chemotherapy administration. The 1-, 3-, and 5-years Area Under the Curve values in the development cohort are 0.753, 0.859, and 0.909, respectively; whereas in the validation cohort, they are observed to be 0.772, 0.848, and 0.923. Furthermore, the calibration curves demonstrated excellent consistency between observed values and actual values. Finally, the decision curve analysis curve indicated substantial net clinical benefit. CONCLUSION: Our study identified significant prognostic risk factors for GCLM and developed a reliable nomogram model, demonstrating promising predictive accuracy and potential clinical benefit in evaluating patient outcomes.
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Thrombospondin-2 (THBS2), a secreted extracellular matrix protein, plays a crucial role in various biological processes including angiogenesis, tissue remodeling, and inflammation. Our study focuses on its function in human gastric cancer (GC). Through bioinformatics and tumor tissue analysis, we compared THBS2 expression in GC tissues and adjacent tissues, and predicted regulatory upstream and downstream molecules. The direct regulatory effect of miR-29b-3p on THBS2 was evaluated through dual-luciferase reporter assays, showing that miR-29b-3p targets the 3'-UTR of THBS2 mRNA, reducing its expression in GC cells. The influence of THBS2 on tumorigenesis and stemness was examined on protein expression levels via Western blot. In vivo, THBS2's role was investigated through xenograft and metastasis assays in nude mice, demonstrating that downregulation of THBS2 impairs GC tumorigenesis and liver metastasis. Our study identified THBS2 as a highly expressed prognostic factor in GC patients. Functionally, THBS2 promotes GC progression through the Notch signaling pathway by regulating Notch3, NEY1, and HES1 proteins, and sustains cancer stem cell-like characteristics by Notch3, including the expression of CD44, Nanog, OCT4, and SOX2. In sum, our study reveals that THBS2 promotes GC progression and stemness, modulated negatively by miR-29b-3p. This suggests potential therapeutic targets within the THBS2/Notch signaling axis for combating gastric cancer.
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BACKGROUND: To explore the risk factors for preoperative massive cerebral infarction (MCI) in pediatric patients with moyamoya disease (MMD). METHODS: Pediatric patients with MMD treated between 2017 and 2022 were enrolled. Logistic regression analysis was performed to identify risk factors for MCI among the patients, and a nomogram was constructed to identify potential predictors of MCI. Receiver operating characteristic (ROC) curves and areas under the curves were calculated to determine the effects of different risk factors. RESULTS: This study included 308 pediatric patients with MMD, including 36 with MCI. The MCI group exhibited an earlier age of onset than the non-MCI group. Significant intergroup differences were observed in familial MMD history, postcirculation involvement, duration from diagnosis to initiation of treatment, Suzuki stage, magnetic resonance angiography (MRA) score, collateral circulation score, and RNF213 p.R4810K variations. Family history, higher MRA score, lower collateral circulation score, and RNF213 p.R4810K variations were substantial risk factors for MCI in pediatric patients with MMD. The nomogram demonstrated excellent discrimination and calibration capabilities. The integrated ROC model, which included all the abovementioned four variables, showed superior diagnostic precision with a sensitivity of 67.86%, specificity of 87.01%, and accuracy of 85.11%. CONCLUSIONS: This study showed that family history, elevated MRA score, reduced collateral circulation score, and RNF213 p.R4810K variations are risk factors for MCI in pediatric patients with MMD. The synthesized model including these variables demonstrated superior predictive efficacy; thus, it can facilitate early identification of at-risk patients and timely initiation of appropriate interventions.
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Enfermedad de Moyamoya , Humanos , Niño , Enfermedad de Moyamoya/complicaciones , Enfermedad de Moyamoya/diagnóstico por imagen , Predisposición Genética a la Enfermedad , Adenosina Trifosfatasas , Ubiquitina-Proteína Ligasas/genética , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/etiología , Factores de RiesgoRESUMEN
Background: Bromodomain-containing protein 9 (BRD9) has been reported to be upregulated in multiple malignancies and facilitate cancer progression. However, there is a paucity of data relating to its expression and biological role in colorectal cancer (CRC). Therefore, this current study examined the prognostic role of BRD9 in CRC and the underlying mechanisms involved. Methods: Real-time polymerase chain reaction (PCR) and Western blotting were used to examine the expression of BRD9 in paired fresh CRC and para-tumor tissues from colectomy patients (n=31). Immunohistochemistry (IHC) was performed to assess BRD9 expression in 524 paraffin-embedded archived CRC samples. The clinical variables are including age, sex, carcinoembryonic antigen (CEA), location of tumor, T stage, N stage, and TNM classification. The effect of BRD9 on the prognosis of CRC patients was explored by Kaplan-Meier and Cox regression analyses. Cell counting kit 8 (CCK-8), clone formation assay, transwell assay, and flow cytometry were used to determine CRC cell proliferation, migration, invasion, and apoptosis, respectively. Xenograft models in nude mice were established to investigate the role of the BRD9 in vivo. Results: BRD9 mRNA and protein expression levels were significantly upregulated in CRC cells compared to normal colorectal epithelial cells (P<0.001). IHC analysis of 524 paraffin-embedded archived CRC tissues showed that high BRD9 expression was significantly associated with TNM classifications, CEA, and lymphatic invasion (P<0.01). Univariate and multivariate analyses indicated that BRD9 [hazard ratio (HR): 3.04, 95% confidence interval (CI): 1.78-5.20; P<0.01] expression and sex (HR: 6.39, 95% CI: 3.94-10.37; P<0.01) were independent prognostic factors for overall survival in the entire cohort. Overexpressing BRD9 promoted CRC cell proliferation, while silencing BRD9 inhibited the proliferation of CRC cells. Furthermore, we showed that BRD9 silencing significantly inhibited epithelial-mesenchymal transition (EMT) via the estrogen pathway. Finally, we demonstrated that silencing BRD9 significantly inhibited the proliferation and tumorigenicity of SW480 and HCT116 cells in vitro and in vivo in nude mice (P<0.05). Conclusions: This study demonstrated that BRD9 high could be an independent prognostic risk factor for CRC. Furthermore, the BRD9/estrogen pathway may contribute to the proliferation of CRC cells and EMT, suggesting that BRD9 may be a novel molecular target in the therapeutic treatment of CRC.
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Postoperative nausea and vomiting (PONV) is a common side effect after laparoscopic surgery. The aim of the study is to investigate the variables that could predict PONV in patients who underwent laparoscopic gastrectomy. We divided patients who underwent laparoscopic gastrectomy into PONV and No-PONV groups. Propensity score matching (PSM) was applied to adjust confounding factors for further validation, and ordinal logistic regression analysis was used to identify predictors for PONV. In the ordinal logistic regression analysis, the preoperative neutrophil-to-lymphocyte ratio (NLR) (odds ratio [OR]: 3.19, 95% confidence interval [CI]: 1.38-7.38; p < 0.01) was identified as an independent risk factor for the presence of PONV and a predictor of the severity of PONV (OR: 3.44, 95% CI: 1.67-5.20; p < 0.01) in 94 PSM patients. Besides, NLR was positively correlated with the PONV score (r = 0.534, p < 0.001). In the receiver-operating characteristic (ROC) curve analysis, an NLR with an optimal cutoff value of 1.59 predicted severe PONV with a sensitivity of 72% and specificity of 81%. The NLR was an independent risk factor for the presence of PONV, and a high NLR tends to be positively associated with the severity of PONV after laparoscopic gastrectomy.
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Laparoscopía , Náusea y Vómito Posoperatorios , Humanos , Náusea y Vómito Posoperatorios/epidemiología , Náusea y Vómito Posoperatorios/etiología , Puntaje de Propensión , Laparoscopía/efectos adversos , Factores de Riesgo , Gastrectomía/efectos adversosRESUMEN
BACKGROUND: The liver hemodynamic changes caused by portal hypertension (PH) are closely related to various complications such as gastroesophageal varices and portosys-temic shunts, which may lead to adverse clinical outcomes in these patients, so it is of great clinical significance to find treatment strategies with favorable clinical efficacy and low risk of complications. AIM: To study the clinical efficacy of total laparoscopic splenectomy (TLS) for PH and its influence on hepatic hemodynamics and liver function. METHODS: Among the 199 PH patients selected from October 2016 to October 2020, 100 patients [observation group (OG)] were treated with TLS, while the remaining 99 [reference group (RG)] were treated with open splenectomy (OS). We observed and compared the clinical efficacy, operation indexes [operative time (OT) and intraoperative bleeding volume], safety (intraperitoneal hemorrhage, ascitic fluid infection, eating disorders, liver insufficiency, and perioperative death), hepatic hemodynamics (diameter, velocity, and flow volume of the portal vein system), and liver function [serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum total bilirubin (TBil)] of the two groups. RESULTS: The OT was significantly longer and intraoperative bleeding volume was significantly lesser in the OG than in the RG. Additionally, the overall response rate, postoperative complications rate, and liver function indexes (ALT, AST, and TBil) did not differ significantly between the OG and RG. The hepatic hemodynamics statistics showed that the pre- and postoperative blood vessel diameters in the two cohorts did not differ statistically. Although the postoperative blood velocity and flow volume reduced significantly when compared with the preoperative values, there were no significant inter-group differences. CONCLUSION: TLS contributes to comparable clinical efficacy, safety, hepatic hemodynamics, and liver function as those of OS in treating PH, with a longer OT but lesser intraoperative blood loss.
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BACKGROUND: Due to the poor prognosis of gastric cancer (GC), early detection methods are urgently needed. Plasma exosomal circular RNAs (circRNAs) have been suggested as novel biomarkers for GC. AIM: To identify a novel biomarker for early detection of GC. METHODS: Healthy donors (HDs) and GC patients diagnosed by pathology were recruited. Nine GC patients and three HDs were selected for exosomal whole-transcriptome RNA sequencing. The expression profiles of circRNAs were analyzed by bioinformatics methods and validated by droplet digital polymerase chain reaction. The expression levels and area under receiver operating characteristic curve values of plasma exosomal circRNAs and standard serum biomarkers were used to compare their diagnostic efficiency. RESULTS: There were 303 participants, including 240 GC patients and 63 HDs, involved in the study. The expression levels of exosomal hsa_circ_0079439 were significantly higher in GC patients than in HDs (P < 0.0001). However, the levels of standard serum biomarkers were similar between the two groups. The area under the curve value of exosomal hsa_circ_0079439 was higher than those of standard biomarkers, including carcinoembryonic antigen, carbohydrate antigen (CA)19-9, CA72-4, alpha-fetoprotein, and CA125 (0.8595 vs 0.5862, 0.5660, 0.5360, 0.5082, and 0.5018, respectively). The expression levels of exosomal hsa_circ_0079439 were significantly decreased after treatment (P < 0.05). Moreover, the expression levels of exosomal hsa_circ_0079439 were obviously higher in early GC (EGC) patients than in HDs (P < 0.0001). CONCLUSION: Our results suggest that plasma exosomal hsa_circ_0079439 is upregulated in GC patients. Moreover, the levels of exosomal hsa_circ_0079439 could distinguish EGC and advanced GC patients from HDs. Therefore, plasma exosomal hsa_circ_0079439 might be a potential biomarker for the diagnosis of GC during both the early and late stages.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Detección Precoz del Cáncer , ARN Circular , Antígeno CA-19-9 , Biología ComputacionalRESUMEN
Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer death worldwide. Hepatitis B x-interacting protein (HBXIP), a cofactor of survivin, was originally identified by binding with the C-terminus of the HBx and negatively regulated the activity of HBx. In this study, the effect of HBXIP on the hepatoma cells-induced angiogenesis was investigated. Proliferation and migration of human umbilical vein endothelial cells (HUVECs) were detected by MTT and transwell assay, respectively. Tube formation and chick chorioallantoic membrane model were used to observe the angiogenesis. Vascular endothelial growth factor activity was assayed using ELISA kits. Western blotting was performed to examine the protein expression. Our results indicated that overexpression of HBXIP increased HepG2 cell-induced endothelial cells migration, proliferation, and angiogenesis, which may be related to increasing phosphorylation of endothelial NO synthase in HUVECs. These results suggest that HBXIP may play an important role in tumorigenesis by enhancing angiogenesis in HCC.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/genética , Neovascularización Patológica/genética , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Comunicación Celular , Movimiento Celular/genética , Proliferación Celular , Medios de Cultivo Condicionados , Células Hep G2 , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Neovascularización Patológica/patología , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Fosforilación , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Salvia miltiorrhiza Bge. f. alba is a traditional Chinese herbal drug with special pharmacological effect on thromboangiitis obliterans. However, the nature source of S.miltiorrhiza Bge.f.alba is now in short supply because of the over-collection of the wild plant. To better utilize this resource, the diversity and antioxidant activity of endophytic fungi isolated from S. miltiorrhiza Bge. f. alba were investigated. RESULTS: A total of 14 endophytic fungi were isolated from different parts of S. miltiorrhiza Bge.f.alba. Based on morphological and molecular identification, the endophytic fungi isolated were classified into four genera (Alternaria sp., Fusarium sp., Schizophyllum sp. and Trametes sp.). These fungal extracts were prepared using ethanol and evaluated for their phytochemical compounds and antioxidant activity. Alternaria alternata SaF-2 and Fusarium proliferatum SaR-2 are of particular interest because they yielded all of nine phytochemicals including saponins, phenol, flavonoids, cardiac glycosides, steroids, tannins, alkaloids, anthroquinone and terpenoids. F. proliferatum SaR-2 and A. alternata SaF-2 also exhibited stronger antioxidant activities by FRAP and DPPH method, having the higher levels of phenol and flavonoid than those of plant root. The total amount of phenol and flavonoid quantified were of 21.75, 20.53 gallic acid equivalent per gram and 8.27 and 7.36 µg/mg of quercetin equivalent respectively. These two endophytic fungi (SaR-2 and SaF-2) were found to have comparable scavenging abilities on both FRAP (1682.21 and 1659.05 µmol/mg, respectively) and DPPH-free radicals (90.14% and 83.25%, respectively, at 0.1 mg/mL). This is the first report about isolation of endophytic fungi from S. miltiorrhiza Bge.f.alba and their antioxidant activities. CONCLUSIONS: These results indicate that the endophytic fungi associated with S. miltiorrhiza Bge.f. alba can be a potential source of novel natural antioxidants.
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PI3K/Akt/mTOR pathway plays an important role in tumor progression and anti-cancer drug resistance. The aim of the present study is to determine the antitumor effect of CCT128930, a novel small molecule inhibitor of Akt, in the HepG2 hepatoma cancer cells. Our results showed that at low concentrations, CCT128930 increased, but not inhibited, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 inhibited cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. A higher dose (20 µM) of CCT128930 triggered cell apoptosis with activation of caspase-3, caspase-9, and PARP. Treatment with CCT128930 increased phosphorylation of ERK and JNK in HepG2 cells. CCT128930 activated DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2. Upon exposure to CCT128930 at a higher concentration, HepG2 cells exhibited autophagy was accompanied by an increase the levels of LC3-II and Beclin-1. Blocking autophagy using chloroquine magnified CCT128930-induced apoptotic cell death and the phosphorylation of H2AX. The results in this study have advanced our current understandings of the anti-cancer mechanisms of CCT128930 in cancer cells.