Dataset Information

Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis.

ABSTRACT: Hepatocarcinogenesis is a multistep process involving progression from cirrhosis, to low-grade dysplastic nodule, to high-grade dysplastic nodule (HGDN) and, eventually, to hepatocellular carcinoma (HCC). Early detection of HCC is challenging as the differential diagnosis between HGDN and early HCC (eHCC) is difficult. The aim of the present study was to identify a novel biomarker to specifically differentiate between HGDN and eHCC, which may facilitate early diagnosis of HCC. Immunohistochemistry was performed to determine the expression of heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) in cirrhosis, dysplastic nodules (DNs), well-differentiated HCC and progressed HCC. The staining was evaluated by assigning a staining intensity score of 0-3 and a percentage of positively stained cells score of 0-4. Receiver operator characteristic (ROC) curve analysis was used to assess the ability of HNRNPA3 expression to differentiate between DNs and HCC. HNRNPA3 expression increased in a stepwise trend in non-tumor hepatic tissue, DNs, eHCC and progressed HCC. ROC curves revealed that HNRNPA3 expression could be used to differentiate between HGDN and eHCC, particularly in combination with glypican 3 (GPC3), with a specificity of 100%. Moreover, HNRNPA3 expression was associated with HCC differentiation. In addition, high expression of HNRNPA3 was found to be associated with poor survival rates in patients with HCC. These findings demonstrated that HNRNPA3 combined with GPC3 is a helpful diagnostic biomarker in the differential diagnosis during the multistep process of hepatocarcinogenesis, particularly in the differential diagnosis between HGDN and eHCC. To the best of our knowledge, this is the first study to report the significance of HNRNPA3 in hepatocarcinogenesis and its potential role in carcinogenesis.

SUBMITTER: Ren X

PROVIDER: S-EPMC7709557 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis.

Ren Xinlu X Dong Yi Y Duan Miao M Zhang Hui H Gao Peng P

Oncology letters 20201117 1

Hepatocarcinogenesis is a multistep process involving progression from cirrhosis, to low-grade dysplastic nodule, to high-grade dysplastic nodule (HGDN) and, eventually, to hepatocellular carcinoma (HCC). Early detection of HCC is challenging as the differential diagnosis between HGDN and early HCC (eHCC) is difficult. The aim of the present study was to identify a novel biomarker to specifically differentiate between HGDN and eHCC, which may facilitate early diagnosis of HCC. Immunohistochemist ...[more]

PMID: 33281957

Similar Datasets

Project description:Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)-a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, transforming growth factor (TGF)-β signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.

Project description:Porcine epidemic diarrhea virus (PEDV) requires complete dependence on the metabolic system of the host cell to complete its life cycle. There is a strong link between efficient viral replication and cellular lipid synthesis. However, the mechanism by which PEDV interacts with host cells to hijack cellular lipid metabolism to promote its replication remains unclear. In this study, PEDV infection significantly enhanced the expression of lipid synthesis-related genes and increased cellular lipid accumulation. Furthermore, using liquid chromatography-tandem mass spectrometry, we identified heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) as the interacting molecule of PEDV NSP9. We demonstrated that the expression of HNRNPA3 was downregulated by PEDV-induced miR-218-5p through targeting its 3' untranslated region. Interestingly, knocking down HNRNPA3 facilitated the PEDV replication by promoting cellular lipid synthesis. We next found that the knockdown of HNRNPA3 potentiated the transcriptional activity of sterol regulatory element-binding transcription factor 1 (SREBF1) through zinc finger protein 135 (ZNF135) as well as PI3K/AKT and JNK signaling pathways. In summary, we propose a model in which PEDV downregulates HNRNPA3 expression to promote the expression and activation of SREBF1 and increase cellular lipid accumulation, providing a novel mechanism by which PEDV interacts with the host to utilize cellular lipid metabolism to promote its replication.IMPORTANCEAs the major components and structural basis of the viral replication complexes of positive-stranded RNA viruses, lipids play an essential role in viral replication. However, how PEDV manipulates host cell lipid metabolism to promote viral replication by interacting with cell proteins remains poorly understood. Here, we found that SREBF1 promotes cellular lipid synthesis, which is essential for PEDV replication. Moreover, HNRNPA3 negatively regulates SREBF1 activation and specifically reduces lipid accumulation, ultimately inhibiting PEDV dsRNA synthesis. Our study provides new insight into the mechanisms by which PEDV hijacks cell lipid metabolism to benefit viral replication, which can offer a potential target for therapeutics against PEDV infection.

Dataset Information

Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis.

Publications

Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets