Diagnostic and Prognostic Potential of AKR1B10 in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although diagnostic measures and surgical interventions have improved in recent years, the five-year survival rate for patients with advanced HCC remains bleak—a reality that is largely attributable to an absence of early stage symptoms, lack of adequate diagnostic and prognostic biomarkers, and the common occurrence of acquired resistance to chemotherapeutic agents during HCC treatment. A limited understanding of the molecular mechanisms underlying HCC pathogenesis also presents a challenge for the development of specific and efficacious pharmacological strategies to treat, halt, or prevent progression to advanced stages. Over the past decade, aldo-keto reductase family 1 member 10 (AKR1B10) has emerged as a potential biomarker for the diagnosis and prognosis of HCC, and experimental studies have demonstrated roles for this enzyme in biological pathways underlying the development and progression of HCC and acquired resistance to chemotherapeutic agents used in the treatment of HCC. Here we provide an overview of studies supporting the diagnostic and prognostic utility of AKR1B10, summarize the experimental evidence linking AKR1B10 with HCC and the induction of chemoresistance, and discuss the clinical value of AKR1B10 as a potential target for HCC-directed drug development. We conclude that AKR1B10-based therapies in the clinical management of specific HCC subtypes warrant further investigation.

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Early alterations of neurovascular unit in the retina in mouse models of tauopathy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01149-y ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Fan Xia ◽

Yonju Ha ◽

Shuizhen Shi ◽

Yi Li ◽

Shengguo Li ◽

...

Keyword(s):

Transgenic Mice ◽

Mouse Models ◽

Molecular Mechanisms ◽

Early Stage ◽

Leukocyte Adhesion ◽

Neurovascular Unit ◽

Integrated Analysis ◽

Therapeutic Effects ◽

Retinal Ganglion ◽

Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

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Discovery and validation of novel protein markers in mucosa of portal hypertensive gastropathy

BMC Gastroenterology ◽

10.1186/s12876-021-01787-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ying Zhu ◽

Wen Xu ◽

Wei Hu ◽

Fang Wang ◽

Yan Zhou ◽

...

Keyword(s):

Portal Hypertension ◽

Gastric Mucosa ◽

Molecular Mechanisms ◽

Early Stage ◽

Trial Registration ◽

Portal Hypertensive Gastropathy ◽

Protein Markers ◽

Decompensated Liver Cirrhosis ◽

Potential Biomarker ◽

Normal Controls

Abstract Background Portal hypertension induced esophageal and gastric variceal bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results LFQ analyses identified 423 significantly differentially expressed proteins. 17 proteins that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment. Trial registration and ethics approval: Trial registration was completed (ChiCTR2000029840) on February 25, 2020. Ethics Approvals were completed on July 17, 2017 (NYSZYYEC20180003) and February 15, 2020 (NYSZYYEC20200005).

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Identification of Key Regulators of Hepatitis C Virus-Induced Hepatocellular Carcinoma by Integrating Whole-Genome and Transcriptome Sequencing Data

Frontiers in Genetics ◽

10.3389/fgene.2021.741608 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guolin Chen ◽

Wei Zhang ◽

Yiran Ben

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Molecular Mechanisms ◽

Sequencing Data ◽

Regulatory Pathways ◽

Regulatory Module ◽

Carcinogenic Potential ◽

Potential Biomarker ◽

New Biomarkers

Background: Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in the understanding of the biological basis of HCC development, the molecular mechanisms underlying HCV-induced HCC (HCC-HCV) remain unclear. The carcinogenic potential of HCV varies according to the genotype and mutation in its viral sequence. Moreover, regulatory pathways play important roles in many pathogenic processes. Therefore, identifying the pathways by which HCV induces HCC may enable improved HCC diagnosis and treatment.Methods: We employed a systematic approach to identify an important regulatory module in the process of HCV-HCC development to find the important regulators. First, an HCV-related HCC subnetwork was constructed based on the gene expression in HCC-HCV patients and HCC patients. A priority algorithm was then used to extract the module from the subnetworks, and all the regulatory relationships of the core genes of the network were extracted. Integrating the significantly highly mutated genes involved in the HCC-HCV patients, core regulatory modules and key regulators related to disease prognosis and progression were identified.Result: The key regulatory genes including EXO1, VCAN, KIT, and hsa-miR-200c-5p were found to play vital roles in HCV-HCC development. Based on the statistics analysis, EXO1, VCAN, and KIT mutations are potential biomarkers for HCV–HCC prognosis at the genomic level, whereas has-miR-200c-5P is a potential biomarker for HCV–HCC prognosis at the expression level.Conclusion: We identified three significantly mutated genes and one differentially expressed miRNA, all related to HCC prognosis. As potential pathogenic factors of HCC, these genes and the miRNA could be new biomarkers for HCV-HCC diagnosis.

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Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2015-309501 ◽

2015 ◽

Vol 66 (3) ◽

pp. 530-540 ◽

Cited By ~ 73

Author(s):

Victoria Tovar ◽

Helena Cornella ◽

Agrin Moeini ◽

Samuel Vidal ◽

Yujin Hoshida ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Molecular Mechanisms ◽

Acquired Resistance ◽

Gene Signature ◽

Signalling Pathways ◽

Fgf Signalling

ObjectiveSorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.DesignHCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.ResultsSorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).ConclusionsAcquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.

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Autoantibody to GNAS in Early Detection of Hepatocellular Carcinoma: A Large-Scale Sample Study Combined with Verification in Serial Sera from HCC Patients

Biomedicines ◽

10.3390/biomedicines10010097 ◽

2022 ◽

Vol 10 (1) ◽

pp. 97

Author(s):

Xiao Wang ◽

Keyan Wang ◽

Cuipeng Qiu ◽

Bofei Wang ◽

Xiaojun Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Early Detection ◽

Large Scale ◽

Early Stage ◽

Decompensated Cirrhosis ◽

Compensated Cirrhosis ◽

Autoantibody Response ◽

Potential Biomarker ◽

Early Hcc ◽

Normal Controls

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NCs) groups), autoantibody to GNAS was detected with a positive result in 47.8% of HCC patients, which was significantly higher than that in patients with LC (35.1%), CHB (19.7%), and NCs (19.7%). Further analysis showed that the frequency of autoantibody to GNAS started increasing in compensated cirrhosis patients (37.0%) with a jump in decompensated cirrhosis patients (53.2%) and reached a peak in early HCC patients (62.4%). The increasing autoantibody response to GNAS in patients at different stages was closely associated with the progression of chronic liver lesions. The result from 44 human serial sera demonstrated that 5 of 11 (45.5%) HCC patients had elevated autoantibody to GNAS before and/or at diagnosis of HCC. Moreover, 46.1% and 62.4% of high positive rates in alpha-fetoprotein (AFP) negative and early-stage HCC patients can supplement AFP in early detection of HCC. These findings suggest that autoantibody to GNAS could be used as a potential biomarker for the early detection of HCC.

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Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells

Cancers ◽

10.3390/cancers11070918 ◽

2019 ◽

Vol 11 (7) ◽

pp. 918 ◽

Cited By ~ 5

Author(s):

Liu ◽

Yu-Chun ◽

Chang ◽

Kuo ◽

Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Protein Phosphatase ◽

Cell Apoptosis ◽

Histone Deacetylase Inhibitors ◽

Molecular Mechanisms ◽

Chemotherapeutic Agents ◽

Protein Phosphatase 1 ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

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LINC00978 promotes the progression of hepatocellular carcinoma by regulating EZH2-mediated silencing of p21 and E-cadherin expression

Cell Death and Disease ◽

10.1038/s41419-019-1990-6 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 6

Author(s):

Xueying Xu ◽

Jianmei Gu ◽

Xiaoge Ding ◽

Guohong Ge ◽

Xueyan Zang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Serum Levels ◽

Migration And Invasion ◽

Mouse Tumor ◽

Clinical Value ◽

Cycle Arrest ◽

Tumor Tissues ◽

E Cadherin

Abstract Long non-coding RNAs (lncRNAs) have been suggested as important regulators of cancer development and progression in hepatocellular carcinoma (HCC). Nevertheless, the clinical value and biological roles of LINC00978 in HCC remain unclear. In this study, we detected the expression of LINC00978 in tumor tissues and serum of HCC patients, examined the roles of LINC00978 in HCC progression and elucidated the underlying molecular mechanisms. We found that LINC00978 expression was upregulated in tumor tissues and serum of HCC patients. Higher serum levels of LINC00978 could distinguish HCC patients from hepatitis and liver cirrhosis patients and healthy controls. LINC00978 knockdown inhibited HCC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. Overexpression of LINC00978 led to the opposite effects. LINC00978 knockdown also inhibited HCC growth and metastasis in mouse tumor models. Mechanistically, LINC00978 bound to EZH2 and mediated its accumulation at the promoter region of p21 and E-cadherin genes, leading to the trimethylation of H27K3 and the inhibition of p21 and E-cadherin expression. Moreover, the simultaneous depletion of p21 and E-cadherin expression reversed the inhibitory effects of LINC00978 knockdown on HCC cell proliferation, migration, and invasion. Taken together, these findings suggest that LINC00978 promotes HCC progression by inhibiting p21 and E-cadherin expression via EZH2-mediated epigenetic silencing. LINC00978 may represent a novel biomarker for HCC diagnosis, prognosis, and therapy.

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Role of MicroRNA in the Diagnosis and Management of Hepatocellular Carcinoma

MicroRNA ◽

10.2174/2211536608666190619155406 ◽

2019 ◽

Vol 9 (1) ◽

pp. 25-40 ◽

Cited By ~ 4

Author(s):

Ioannis A. Ziogas ◽

Georgios Sioutas ◽

Konstantinos S. Mylonas ◽

Georgios Tsoulfas

Keyword(s):

Hepatocellular Carcinoma ◽

Malignant Tumors ◽

Early Stage ◽

Survival Rates ◽

Chemotherapeutic Agents ◽

Diagnostic Methods ◽

Early Stage Disease ◽

Stage Disease ◽

Underlying Mechanisms

Introduction: Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world and comes third in cancer-induced mortality. The need for improved and more specific diagnostic methods that can detect early-stage disease is immense, as it is amenable to curative modalities, while advanced HCC is associated with low survival rates. microRNA (miRNA) expression is deregulated in HCC and this can be implemented both diagnostically and therapeutically. Objective: To provide a concise review on the role of miRNA in diagnosis, prognosis, and treatment of HCC. Method: We conducted a comprehensive review of the PubMed bibliographic database. Results: Multiple miRNAs are involved in the pathogenesis of HCC. Measurement of the levels of these miRNAs either in tumor tissue or in the blood constitutes a promising diagnostic, as well as prognostic tool. OncomiRs are miRNAs that promote tumorigenesis, thus inhibiting them by administering antagomiRs is a promising treatment option. Moreover, replacement of the depleted miRNAs is another potential therapeutic approach for HCC. Modification of miRNA levels may also regulate sensitivity to chemotherapeutic agents. Conclusion: miRNA play a pivotal role in HCC pathogenesis and once the underlying mechanisms are elucidated, they will become part of everyday clinical practice against HCC.

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Role of FBXL19-AS1 in hepatocellular carcinoma by lncRNA–miRNA–mRNA network analysis and its diagnostic and prognostic value

10.21203/rs.3.rs-44069/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Dingdong He ◽

Xiaokang Zhang ◽

Xinyu Zhu ◽

Narayani Maharjan ◽

Yingchao Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Value ◽

Clinical Value ◽

Cerna Network ◽

Diagnosis And Prognosis ◽

Potential Biomarker ◽

Viral Carcinogenesis ◽

New Biomarkers ◽

Diagnostic And Prognostic Value

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common neoplastic diseases worldwide. Available biomarkers are not sensitive enough for the diagnosis of HCC, seeking new biomarkers of HCC is urgent and challenging. The purpose of this study was to investigate the role of F-box and leucine-rich repeat protein 19-antisense RNA 1 (FBXL19-AS1) through competing endogenous RNA (ceRNA) network and its diagnostic and prognostic value in HCC.Methods: A comprehensive strategy of genomic data mining, bioinformatics and experimental validation was used to evaluate the clinical value of FBXL19-AS1 in the diagnosis and prognosis of HCC and to identify the pathways that FBXL19-AS1 may be involved in.Results: FBXL19-AS1 was up-regulated in HCC, and its high expression was associated with TNM stage and poor prognosis of HCC patients. The combined use of plasma FBXL19-AS1 and alpha-fetoprotein (AFP) could prominently improve the diagnostic validity for HCC. FBXL19-AS1 might participate in regulating HCC related pathways, including hepatitis C, hepatitis B, microRNAs in cancer, cell cycle, viral carcinogenesis, and proteoglycans in cancer through ceRNA network.Conclusions: Our findings indicated that FBXL19-AS1 not only serves as a potential biomarker for HCC diagnosis and prognosis, but it may be functionally carcinogenic.

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