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PURPOSE: Hepatocellular carcinoma (HCC) has a poor prognosis, and alpha-fetoprotein (AFP) is widely used to evaluate HCC. However, the proportion of AFP-negative individuals cannot be disregarded. This study aimed to establish a nomogram of risk factors affecting the prognosis of patients with AFP-negative HCC and to evaluate its diagnostic efficiency. PATIENTS AND METHODS: Data from patients with AFP-negative initial diagnosis of HCC (ANHC) between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results database for model establishment and validation. We randomly divided overall cohort into the training or validation cohort (7:3). Univariate and multivariate Cox regression analysis were used to identify the risk factors. We constructed nomograms with overall survival (OS) and cancer-specific survival (CSS) as clinical endpoint events and constructed survival analysis by using Kaplan-Meier curve. Also, we conducted internal validation with Receiver Operating Characteristic (ROC) analysis and Decision curve analysis (DCA) to validate the clinical value of the model. RESULTS: This study included 1811 patients (1409 men; 64.7% were Caucasian; the average age was 64 years; 60.7% were married). In the multivariate analysis, the independent risk factors affecting prognosis were age, ethnicity, year of diagnosis, tumor size, tumor grade, surgery, chemotherapy, and radiotherapy. The nomogram-based model related C-indexes were 0.762 (95% confidence interval (CI): 0.752-0.772) and 0.752 (95% CI: 0.740-0.769) for predicting OS, and 0.785 (95% CI: 0.774-0.795) and 0.779 (95% CI: 0.762-0.795) for predicting CSS. The nomogram model showed that the predicted death was consistent with the actual value. The ROC analysis and DCA showed that the nomogram had good clinical value compared with TNM staging. CONCLUSION: The age(HR:1.012, 95% CI: 1.006-1.018, P-value < 0.001), ethnicity(African-American: HR:0.946, 95% CI: 0.783-1.212, P-value: 0.66; Others: HR:0.737, 95% CI: 0.613-0.887, P-value: 0.001), tumor diameter(HR:1.006, 95% CI: 1.004-1.008, P-value < 0.001), year of diagnosis (HR:0.852, 95% CI: 0.729-0.997, P-value: 0.046), tumor grade(Grade 2: HR:1.124, 95% CI: 0.953-1.326, P-value: 0.164; Grade 3: HR:1.984, 95% CI: 1.574-2.501, P-value < 0.001; Grade 4: HR:2.119, 95% CI: 1.115-4.027, P-value: 0.022), surgery(Liver Resection: HR:0.193, 95% CI: 0.160-0.234, P-value < 0.001; Liver Transplant: HR:0.102, 95% CI: 0.072-0.145, P-value < 0.001), chemotherapy(HR:0.561, 95% CI: 0.471-0.668, P-value < 0.001), and radiotherapy(HR:0.641, 95% CI: 0.463-0.887, P-value:0.007) were independent prognostic factors for patients with ANHC. We developed a nomogram model for predicting the OS and CSS of patients with ANHC, with a good predictive performance.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Male , Humans , Middle Aged , Carcinoma, Hepatocellular/therapy , alpha-Fetoproteins , Prognosis , Liver Neoplasms/therapy , ResearchABSTRACT
This study intends to explore the effect of the PAK1 gene silencing on apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H and HepG2 cells and cells in xenograft tumor. MHCC97-H and HepG2 cells and mice with xenograft tumor in vivo were randomly divided into control, empty vector and PAK1 shRNA groups. Morphology and the expression of green fluorescent protein of MHCC97-H and HepG2 cells and cells in xenograft tumor were observed. MTT assay and flow cytometry were used to detect proliferation, cell cycle and apoptosis of MHCC97-H and HepG2 cells and cells in xenograft tumor. The expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2, p21, p53, Bax and Bcl-2 were measured using the quantitative reverse transcription polymerase chain reaction and western blotting. Compared with the control and empty vector groups, number of adherent cells of MHCC97-H and HepG2 cells and cells in xenograft tumor was reduced, and green fluorescent cells became round and reduced in the PAK1 shRNA group. Cell proliferation, the cells at S phase, the mRNA and protein expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2 and Bcl-2 of MHCC97-H and HepG2 cells and cells in xenograft tumor were decreased, while the cells at G1 phase, apoptosis rate, the mRNA and protein expressions of p21, p53 and Bax of MHCC97-H and HepG2 cells and cells in xenograft tumor were increased in the PAK1 shRNA group. PAK1 gene silencing decreases proliferation of MHCC97-H cells, HepG2 cells and cells in xenograft tumor through the p53/p21 pathway.
Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , p21-Activated Kinases/genetics , Animals , Apoptosis/genetics , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Cell Proliferation/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Gene Silencing , Hep G2 Cells , Humans , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Male , Mice , Mice, Nude , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Random Allocation , Signal Transduction , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays , p21-Activated Kinases/biosynthesis , p21-Activated Kinases/metabolismABSTRACT
Background: Distinguishing pancreatic neuroendocrine tumors (pNETs) from solid pseudopapillary neoplasms (SPNs) is challenging, primarily due to their overlapping pathological characteristics. To address this, our study aims to identify and validate novel biomarkers that effectively differentiate between these two conditions. We focus on the exploration of new immunohistochemical markers to enhance this distinction. Methods: In this study, we analyzed genetic variations in pNETs and SPNs using the GSE43795 dataset from the Gene Expression Omnibus (GEO) database. Our approach was to identify genes with higher expression in pNETs compared to SPNs and normal pancreatic tissues. We conducted enrichment analyses to understand the functions of these genes. Furthermore, protein-protein interaction (PPI) network analysis was utilized to identify key genes associated with pNETs. Our sample consisted of 163 pancreatic tumor specimens, comprising 78 pNETs and 85 SPNs. We also collected clinicopathological data and used immunohistochemistry to measure the expression levels of these key genes. Results: The enrichment analysis revealed that genes overexpressed in pNETs were mainly involved in signal release, vesicle transport, and ion pathway activation, playing significant roles in endocrine processes like insulin secretion, dopamine synapses, and circadian rhythm regulation. The PPI analysis identified secretogranin II (SCG2), carboxypeptidase E (CPE), and chromogranin A (CgA, CHGA) as key markers for differentiating pNETs from SPNs. Immunohistochemical validation of these markers demonstrated high sensitivity (SCG2: 98.7%, CPE: 97.4%) and specificity (100%), indicating their superior discriminative power compared to traditional markers like CgA, ß-catenin, lymphoid enhancer-binding factor 1 (LEF1), and vimentin. Conclusions: Our study indicates that SCG2 and CPE are effective, novel immunohistochemical biomarkers for differentiating pNETs from SPNs.
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This study explored the correlation between semaphorin 4D (SEMA4D) and the prognosis and survival time of patients with melanoma combined with liver cancer. A total of 272 patients were recruited, and clinical and follow-up data were recorded. The expression levels of SEMA4D and SEMA3B were determined. Pearson's χ2 test and Spearman's rank correlation coefficient were used to analyze the relationship between prognosis and the assessed parameters of melanoma patients. Univariate and multivariate Logistic regression and Cox proportional risk regression analyses were used for further analysis. Additionally, receiver operating characteristic curve and survival curves of subjects were plotted. The Pearson's χ2 test showed that the prognosis of melanoma patients was significantly correlated with age, tumor grade, and decreased SEMA4D expression. Additionally, Spearman's correlation coefficient analysis showed that age, tumor grade, and SEMA4D expression were significantly correlated with prognosis. Univariate logistic regression analysis showed that age and tumor grade, and SEMA4D expression, were significantly correlated with prognosis. Older patients, a higher tumor grade, and lower SEMA4D expression were associated with a poorer prognosis. Multivariate logistic regression analysis showed that older patients had a poorer prognosis, and patients with lower SEMA4D expression levels had a significantly worse prognosis than patients with higher SEMA4D expression levels. Kaplan-Meier analysis showed that the survival time of older patients was lower than that of the younger patients. The survival times of patients with lower SEMA4D expression levels were significantly lower than that of patients with higher SEMA4D expression levels. Multivariate Cox regression analysis showed that the survival time of older patients was lower than that of younger patients. The survival time of melanoma patients with low SEMA4D expression was significantly lower than that of patients with higher SEMA4D expression. SEMA4D was significantly associated with melanoma, and lower SEMA4D expression was associated with a poorer survival prognosis in melanoma patients.
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Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 µM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Curcumin/analogs & derivatives , Hydrazines/pharmacology , Liver Neoplasms/drug therapy , MAP Kinase Signaling System/drug effects , Animals , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Curcumin/pharmacology , Curcumin/therapeutic use , Hep G2 Cells , Humans , Hydrazines/therapeutic use , Imidazoles/pharmacology , Liver Neoplasms/pathology , Male , Pyridines/pharmacology , Rats , Toxicity Tests, Subacute , Xenograft Model Antitumor Assays , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is a horrible malignancy derived from liver. Circular RNAs (circRNAs) act important roles in the pathogenesis and progression of human diseases, including HCC. The current assay intended to investigate the function of circRNA low-density lipoprotein receptor (circ_LDLR) in HCC and clarify the underlying mechanism. MATERIALS AND METHODS: Expression of circ_LDLR, microRNA (miR)-7 and ring finger protein 38 (RNF38) was determined by quantitative real-time PCR (qRT-PCR) or Western blot analysis. Flow cytometry was used to detect cell cycle distribution and apoptosis. Cell colony formation ability and viability were examined by colony formation and methyl thiazolyl tetrazolium (MTT) assays, respectively. Levels of cell proliferation and epithelia-mesenchymal transition (EMT) biomarker proteins were analyzed via Western blot assay. Cell migration and invasion were monitored by Transwell assay, and target relationship between miR-7 and circ_LDLR or RNF38 was validated by dual-luciferase reporter assay. Xenograft model was established to explore the role of circ_LDLR in vivo. RESULTS: Expression of circ_LDLR and RNF38 was upregulated, but miR-7 expression was downregulated in HCC tissues and cells. Circ_LDLR knockdown significantly inhibited cell proliferation, migration, invasion and EMT in HCC cells. Circ_LDLR acted as a sponge of miR-7, and interference of miR-7 could attenuate circ_LDLR knockdown-induced inhibitory effects on malignant behaviors of HCC cells. Besides, miR-7 also repressed cell proliferation and metastasis of HCC cells, by targeting RNF38. Depletion of circ_LDLR could suppress tumor growth in vivo. CONCLUSION: Depletion of circ_LDLR restrained HCC cell proliferation, metastasis and tumorigenesis through the regulation on miR-7/RNF38 axis, affording a promising therapeutic target for HCC.