Search

Background Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. Methods Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. Results Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. Conclusions Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC.

Since angiogenesis has an indispensable effect in the development and progression of tumors, in this study we aimed to identify angiogenic genes closely associated with prognosis of HCC to establish diagnostic, prognostic, and recurrence models. We analyzed 132 angiogenic genes and HCC-related RNA sequence data from the TCGA and ICGC databases by Cox and least absolute shrinkage and selection operator (LASSO) regression, and identified four angiogenic genes (ENFA3, EGF, MMP3 and AURKB) to establish prognosis, recurrence and diagnostic models and corresponding nomograms. The prognostic and recurrence models were determined to be independent predictors of prognosis and recurrence (P < 0.05). And compared with the low-risk group, patients in the high-risk group had worse overall survival (OS) rates in training cohort (P < 0.001) and validation cohort (P < 0.001), and higher recurrence rates in training cohort (P

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization.

OBJECTIVES To construct a precise prediction model of preoperative magnetic resonance imaging (MRI)-based nomogram for aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) patients treated with radiofrequency ablation (RFA). METHODS Among 891 patients with HCC treated by RFA, 22 patients with AIR and 36 patients without AIR (non-AIR) were finally enrolled in our study, and each patient was followed up for more than 6 months to determine the occurrence of AIR. The laboratory indicators and MRI features were compared and assessed. Preoperative contrast-enhanced T1-weighted images (CE-T1WI) were used for radiomics analysis. The selected clinical indicators and texture features were finally screened out to generate the novel prediction nomogram. RESULTS Tumor shape, ADC Value, DWI signal intensity and ΔSI were selected as the independent factors of AIR by univariate and multivariate logistic regression analysis. Meanwhile, two radiomics features were selected from 396 candidate features by LASSO (P

Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients.Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models.Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN.Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC. Video Abstract.

Objectives To develop and validate a pre-transcatheter arterial chemoembolization (TACE) MRI-based radiomics model for predicting tumor response in intermediate-advanced hepatocellular carcinoma (HCC) patients. Materials Ninety-nine intermediate-advanced HCC patients (69 for training, 30 for validation) treated with TACE were enrolled. MRI examinations were performed before TACE, and the efficacy was evaluated according to the mRECIST criterion 3 months after TACE. A total of 396 radiomics features were extracted from T2-weighted pre-TACE images, and least absolute shrinkage and selection operator (LASSO) regression was applied to feature selection and model construction. The performance of the model was evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curves. Results The AFP value, Child-Pugh score, and BCLC stage showed a significant difference between the TACE response (TR) and non-TACE response (nTR) patients. Six radiomics features were selected by LASSO and the radiomics score (Rad-score) was calculated as the sum of each feature multiplied by the non-zero coefficient from LASSO. The AUCs of the ROC curve based on Rad-score were 0.812 and 0.866 in the training and validation cohorts, respectively. To improve the diagnostic efficiency, the Rad-score was further integrated with the above clinical indicators to form a novel predictive nomogram. Results suggested that the AUC increased to 0.861 and 0.884 in the training and validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram was clinically useful. Conclusion The radiomics and clinical indicator-based predictive nomogram can well predict TR in intermediate-advanced HCC and can further be applied for auxiliary diagnosis of clinical prognosis. Key Points • The therapeutic outcome of TACE varies greatly even for patients with the same clinicopathologic features. • Radiomics showed excellent performance in predicting the TACE response. • Decision curves demonstrated that the novel predictive model based on the radiomics signature and clinical indicators has great clinical utility.

The development of magnetic resonance imaging (MRI) contrast agents with high sensitivity and good biocompatibility is of great value for the diagnosis of primary hepatocellular carcinoma (HCC). Here, a novel MRI contrast agent based on calcium phosphate (CaP) nanoparticles modified with a liver cancer cell targeting peptide A54 (A54-CaP) was fabricated. The T1-positive contrast agent Gd-DTPA was encapsulated inside the nanoparticles (A54-CaPNPs), with a mean diameter of 30 nm and a high encapsulation efficiency of 92.73%. The A54-CaPNP solution exhibited higher longitudinal relaxivity (6.07 mM-1 s-1) than that of the clinically used MRI contrast agent Gd-DTPA (3.56 mM-1 s-1). A much higher accumulation of the nanoparticles in the liver cells was observed, which was directed by the A54 targeting peptide. Furthermore, the MRI diagnostic efficiency of A54-CaPNPs was systematically investigated in an orthotopic liver cancer model and primary HCC model. In vivo MRI experiments showed that A54-CaPNPs had higher sensitivity in the BEL-7402 orthotopic liver cancer model with a more remarkable contrast enhancement and a longer imaging time compared to those without A54 modification. Moreover, the experiments on primary HCC models suggested that A54-CaPNPs showed greatly enhanced MR imaging performance in comparison with Gd-DTPA. These results suggest that A54-CaPNPs possess great potential to enable the non-invasive early diagnosis of primary HCC for timely surgical resection.

Additional file 1 Supplementary Fig. 1 The prognostic value of glycolysis-related genes in HCC. Supplementary Fig. 2 The correlation between glycolysis-related genes and the glycolysis signature. Supplementary Fig. 3 Expression pattern and roles of OPN in HCC cells. Supplementary Fig. 4 Expression pattern and prognostic value of OPN in HCC tissues. Supplementary Table 1: Primers used in this study. Supplementary Table 2: Group information.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths globally. Despite advances in diagnosis and treatment, the incidence and mortality of HCC continue to rise. Piperlongumine (PL), an alkaloid isolated from the fruit of the long pepper, is known to selectively kill tumor tissues while sparing their normal counterparts. However, the killing effects of PL on HCC and the underlying mechanism of PL are not clear. We report that PL may interact with thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, and induce reactive oxygen species (ROS)-mediated apoptosis in HCC cells. Our results suggest that PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells by targeting TrxR1 and increasing intracellular ROS levels. Notably, PL treatment reduces TrxR1 activity and tumor cell burden in vivo. Additionally, TrxR1 is significantly upregulated in existing HCC databases and available HCC clinical specimens. Taken together, these results suggest PL as a novel anticancer candidate for the treatment of HCC. More importantly, this study reveals that TrxR1 might be an effective target in treating HCC.

Background: In the context of the high recurrence rate and poor clinical prognosis of hepatocellular carcinoma (HCC), and considering the indispensable effect of angiogenesis in the development and metastasis of tumors, we analyzed HCC-related RNA sequence data to identify angiogenic genes closely associated with the prognosis of HCC. We used the identified genes to establish diagnostic, prognostic, and recurrence models to help clinicians effectively develop individualized treatment strategies for HCC. Method: We comprehensively analyzed 132 angiogenic genes and HCC-related RNA sequence data from the TCGA and the ICGC databases by Cox regression and least absolute shrinkage and selection operator(LASSO) regression to identify angiogenic genes; the genes were used to establish prognosis, recurrence and diagnostic models and to construct corresponding predictive nomograms. Pharmacological analysis was performed to detect target angiogenic drugs. Subsequently, in vitro cell experiments and western blot experiments were used to explore the anti-tumor effect and possible molecular mechanism of an angiogenesis-targeting target drug. Results: Four angiogenic genes (ENFA3, EGF, MMP3 and AURKB) were used to establish prognostic, relapse and diagnostic models. Through the prognostic model, we found that the overall survival (OS) of the high-risk group in the training cohort (P < 0.001, HR = 0.33) and validation cohort (P < 0.001, HR = 0.33) were significantly worse than those of the low-risk group. The recurrence model also demonstrated that in the training cohort (P

Objectives: To investigate potential diagnostic model for predicting benign or malignant status of subcentimeter pulmonary ground-glass nodules (SPGGNs) (≤1 cm) based on CT texture analysis. Methods: A total of 89 SPGGNs from 89 patients were included; 51 patients were diagnosed with adenocarcinoma, and 38 were diagnosed with inflamed or infected benign SPGGNs. Analysis Kit software was used to manually delineate the volume of interest of lesions and extract a total of 396 quantitative texture parameters. The statistical analysis was performed using R software. The SPGGNs were randomly divided into a training set (n = 59) and a validation set (n = 30). All pre-normalized (Z-score) feature values were subjected to dimension reduction using the LASSO algorithm,and the most useful features in the training set were selected. The selected imaging features were then combined into a Rad-score, which was further assessed by ROC curve analysis in the training and validation sets. Results: Four characteristic parameters (ClusterShade_AllDirection_offset4_SD, ShortRunEmphasis_angle45_offset1, Maximum3DDiameter, SurfaceVolumeRatio) were further selected by LASSO (p < 0.05). As a cluster of imaging biomarkers, the above four parameters were used to form the Rad-score. The AUC for differentiating between benign and malignant SPGGNs in the training set was 0.792 (95% CI: 0.671, 0.913), and the sensitivity and specificity were 86.10 and 65.20%, respectively. The AUC in the validation set was 72.9% (95% CI: 0.545, 0.913), and the sensitivity and specificity were 86.70 and 60%, respectively. Conclusion: The present diagnostic model based on the cluster of imaging biomarkers can preferably distinguish benign and malignant SPGGNs (≤1 cm). Advances in knowledge: Texture analysis based on CT images provide a new and credible technique for accurate identification of subcentimeter pulmonary ground-glass nodules.

Alternative splicing within a gene can create different versions of an mRNA, called isoforms. CFIm, composed of a small subunit CFIm25 and two large subunits CFIm68 and CFIm59 (also known as CPSF7), has been proposed as an enhancer-dependent activator of mRNA 3' processing. In this study, we investigated the role of CPSF7 in hepatocellular carcinoma. Experimental evidence suggests that the expression level of CPSF7 is higher in liver cancer cells and tissues than in non-tumor hepatic cells and tissues. Furthermore, knockdown of CPSF7 effectively suppressed cell proliferation, migration and colony formation in liver cancer cells by inhibiting PTEN/AKT signaling. CPSF7 promoted WWP2-FL due to the presence of PTEN ubiquitination sites in this longer transcript. Taken together, we identified that CPSF7 regulates liver cancer growth by targeting WWP2-FL that in turn regulates AKT activation in a PTEN-dependent manner.

How to evaluate innovation ability objectively and scientifically of high level innovative technical personnel is of great significance for an area to draw up scientific and technical policy and originality innovation strategy. By literature review method, analytic hierarchy process and expert scoring method, throuh the basis on analyzing a variety of factors which impact on innovation ability of local high level technical personnel, after two rounds of expert consultation, three level evaluation index system has been established, which includes sixteen two-level indexes and thirty five three-level indexes. The corresponding weighting coefficients and the main observation point are provided by every index. For example postgraduates graduating in 2013 from an university in Hebei province, output and effect evaluation of index system are investigated from performance appraisal, which proved that this index system is scientific and feasible.