Zhijiao Duan’s research while affiliated with Nanfang Hospital and other places

Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Lipid metabolism is essential for cancer development. Nicotinamide nucleotide transhydrogenase (NNT) is abnormally expressed in multiple cancers; however, its role in HCC is unclear. We assessed the NNT expression level in The Cancer Genome Atlas (TCGA) cohort and Gene Expression Omnibus (GEO) datasets and found that the expression level of NNT was lower in HCC patients than non-cancer control subjects in the public databases. Survival analysis was conducted according to high and low NNT expression. Low NNT expression was significantly associated with a poor prognosis. For confirmation, the gene and protein expression of NNT in cancer and adjacent non-cancer tissues from HCC patients at our institute cohort indicated the lower expression level of NNT in cancer compared to adjacent non-cancer tissues using quantitative polymerase chain reaction and western blot, respectively. Bioinformatics was used to analyze the underlying mechanisms and establish the protein-protein interaction network of NNT. It showed that NNT is associated with functions of bile acid and fatty acid metabolism and their related genes. To conclude, our results supported that NNT expression is downregulated in HCC, and can serve as a novel prognostic biomarker.

Hepatocellular carcinoma (HCC) is ranked the sixth most common cancer and the fourth leading cause of cancer-related death worldwide, and its incidence is expected to increase in the future. Cisplatin has been widely used in chemotherapy and transarterial chemoembolization in treatment for HCC. However, the main obstacle to the clinical use of cisplatin is the development of resistance, the mechanisms of which are poorly defined. Therefore, it is imperative to investigate the cellular mechanisms mediating cisplatin resistance in HCC. Here, we demonstrated that high mobility group box 1 (HMGB1) is upregulated in patients with cancer, and implicated in a tumor-supportive role. Further, we showed that HMGB1 has an important role in mediating cisplatin resistance via an HMGB1/ nuclear factor kappa-B (NF-κB)/ hypoxia inducible factor-1α (HIF-1α) feedback loop. The study findings reveal an unappreciated molecular mechanism of HMGB1-mediated cisplatin resistance and may provide a new clue in cancer therapy.

Hepatocellular carcinoma (HCC)is a prevalent malignancy with increasing incidence and extremely poor prognosis worldwide. The multi-kinase inhibitor sorafenib is widely used as a first-line systematic treatment agent of advanced hepatocellular carcinoma. However, the benefit of sorafenib in clinical treatment is often impeded by drug resistance. Therefore, it is of critical importance to investigate the molecular mechanisms underlying sorafenib resistance in HCC. The present study shows that expression of the key glycolytic enzyme PFKFB3 is significantly up-regulated in both HCC cell lines and tissues. Thereafter, the expression of PFKFB3 was elevated in hepatocellular carcinoma cell after sorafenib treatment, which was confirmed in Gene Expression Omnibus (GEO)datasets. As predicted, the overexpression of PFKFB3 significantly enhanced HCC cells resistance to sorafenib by decreasing expression of the apoptosis-related molecules as well as apoptotic cells. Additionally, blockage of hypoxia-inducible factor-1α (HIF-1α)restricted the enhancement of PFKFB3. More interestingly, we initially found that exogenous expression of PFKFB3 significantly up-regulated the protein levels of HIF-1α in both SK-Hep-1 and SMMC-7721 cells. Further mechanistic study uncovered that HIF-1α deficiency impaired sorafenib resistance induced by PFKFB3 overexpression in HCC cells. To conclude, here we reveal a previously unrecognised positive feedback loop exists between PFKFB3 and HIF-1α and a novel HIF-1α-dependent role of PFKFB3 in regulating sorafenib resistance in HCC cells, suggesting new potential therapeutic targets for HCC treatment.

Background: Increasing studies have indicated that biomarkers based on quantitative radiomics features are related to clinical prognosis across a range of cancer types, but the association between radiomics and prognosis in hepatocellular carcinoma (HCC) is unclear. We aimed to develop and validate a radiomics nomogram for the preoperative prediction of prognosis for patients with HCC undergoing partial hepatectomy. Methods: In total, 177 patients were randomly divided into training (n=113) and validation (n=64) cohorts. A total number of 980 radiomics features were extracted from computed tomography images. And the least absolute shrinkage and selection operator algorithm was used to select the optimal features and build a radiomics signature in the training set. Besides, a radiomics nomogram was developed using multivariate regression analysis. The performance of the radiomics nomogram was estimated regarding its discrimination and calibration abilities, and clinical usefulness. Results: The radiomics signature was significantly associated with disease-free survival (DFS) (P < 0.001 and P=0.00013, respectively) and overall survival (OS) (both P < 0.0001) in two cohorts. Additionally, the radiomics nomogram showed good discrimination calibration, and clinical usefulness both in the training and validation cohorts. Conclusions: The proposed radiomics nomogram showed excellent performance for the individualized and non-invasive estimation of DFS, which may help clinicians better identify patients with HBV-related HCC who can benefit from the surgery.