Ago-RIP Sequencing Identifies New MicroRNA-449a-5p Target Genes Increasing Sorafenib Efficacy in Hepatocellular Carcinoma

Objectives. The purpose of this study was to identify the molecular mechanism and prognosis-related genes of Jianpi Jiedu decoction in the treatment of hepatocellular carcinoma. Methods. The gene expression data of hepatocellular carcinoma samples and normal tissue samples were downloaded from TCGA database, and the potential targets of drug composition of Jianpi Jiedu decoction were obtained from TCMSP database. The genes were screened out in order to obtain the expression of these target genes in patients with hepatocellular carcinoma. The differential expression of target genes was analyzed by R software, and the genes related to prognosis were screened by univariate Cox regression analysis. Then, the LASSO model was constructed for risk assessment and survival analysis between different risk groups. At the same time, independent prognostic analysis, GSEA analysis, and prognostic analysis of single gene in patients with hepatocellular carcinoma were performed. Results. 174 compounds of traditional Chinese medicine were screened by TCMSP database, corresponding to 122 potential targets. 39 upregulated genes and 9 downregulated genes were screened out. A total of 20 candidate prognostic related genes were screened out by univariate Cox analysis, of which 12 prognostic genes were involved in the construction of the LASSO regression model. There was a significant difference in survival time between the high-risk group and low-risk group ( p < 0.05 ). Among the genes related to prognosis, the expression levels of CCNB1, NQO1, NUF2, and CHEK1 were high in tumor tissues ( p < 0.05 ). Survival analysis showed that the high expression levels of these four genes were significantly correlated with poor prognosis of HCC ( p < 0.05 ). GSEA analysis showed that the main KEGG enrichment pathways were lysine degradation, folate carbon pool, citrate cycle, and transcription factors. Conclusions. In the study, we found that therapy target genes of Jianpi Jiedu decoction were mainly involved in metabolism and apoptosis in hepatocellular carcinoma, and there was a close relationship between the prognosis of hepatocellular carcinoma and the genes of CCNB1, NQO1, NUF2, and CHEK1.

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Identification of a Potential PPAR-Related Multigene Signature Predicting Prognosis of Patients with Hepatocellular Carcinoma

PPAR Research ◽

10.1155/2021/6642939 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Wenfang Xu ◽

Zhen Chen ◽

Gang Liu ◽

Yuping Dai ◽

Xuanfu Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Target Genes ◽

Prognostic Markers ◽

Cox Regression ◽

Clinical Information ◽

Gene Signature ◽

Peroxisome Proliferator ◽

Clinical Indicators ◽

Ppar Signaling

Peroxisome proliferator-activated receptors (PPARs) and part of their target genes have been reported to be related to the progression of hepatocellular carcinoma (HCC). The prognosis of HCC is not optimistic, and more accurate prognostic markers are needed. This study focused on discovering potential prognostic markers from the PPAR-related gene set. The mRNA data and clinical information of HCC were collected from TCGA and GEO platforms. Univariate Cox and lasso Cox regression analyses were used to screen prognostic genes of HCC. Three genes (MMP1, HMGCS2, and SLC27A5) involved in the PPAR signaling pathway were selected as the prognostic signature of HCC. A formula was established based on the expression values and multivariate Cox regression coefficients of selected genes, that was, risk score = 0.1488 ∗ expression value of M M P 1 + − 0.0393 ∗ expression value of H M G C S 2 + − 0.0479 ∗ expression value of S L C 27 A 5 . The prognostic ability of the three-gene signature was assessed in the TCGA HCC dataset and verified in three GEO sets (GSE14520, GSE36376, and GSE76427). The results showed that the risk score based on our signature was a risk factor with a HR (hazard ratio) of 2.72 ( 95 % CI Confidence Interval = 1.87 ~ 3.95 , p < 0.001 ) for HCC survival. The signature could significantly ( p < 0.0001 ) distinguish high-risk and low-risk patients with poor prognosis for HCC. In addition, we further explored the independence and applicability of the signature with other clinical indicators through multivariate Cox analysis ( p < 0.001 ) and nomogram analysis ( C ‐ index = 0.709 ). The above results indicate that the combination of MMP1, HMGCS2, and SLC27A5 selected from the PPAR signaling pathway could effectively, independently, and applicatively predict the prognosis of HCC. Our research provided new insights to the prognosis of HCC.

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MiR-486-5p Suppresses Proliferation and Migration of Hepatocellular Carcinoma Cells through Downregulation of the E3 Ubiquitin Ligase CBL

BioMed Research International ◽

10.1155/2019/2732057 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Jia He ◽

Bin Xiao ◽

Xiaoyan Li ◽

Yongyin He ◽

Linhai Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Ubiquitin Ligase ◽

Target Genes ◽

E3 Ubiquitin Ligase ◽

Tumor Stage ◽

Suppressor Gene ◽

Cell Counting ◽

And Migration ◽

Proliferation And Migration

MicroRNAs have been broadly implicated in cancer, but precise functions and mechanisms in carcinogenesis vary among cancer types and in many cases remain poorly understood. Hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. The aim of the present study was to investigate the role of miR-486-5p in HCC and identify its specific target. MiR-486-5p was significantly downregulated in HCC tissues and cell lines compared with noncancerous tissues and, respectively, although expression level was not correlated with the degree of infiltration or tumor stage. However, miR-486-5p overexpression in HCC cells inhibited proliferation and migration as evidenced by CCK-8 cell counting, wound healing, and transwell assays, indicating that miR-486-5p is an HCC suppressor. We employed four miRNA databases to predict the target genes of miR-486-5p and verified retrieved genes using qPCR and western blotting. The E3 ubiquitin ligase CBL was significantly downregulated by miR-486-5p overexpression in HCC cell lines at both mRNA and protein level, and overexpression of CBL counteracted the inhibitory effects of miR-486-5p on HCC cell proliferation and migration. Moreover, CBL expression was negatively correlated with miR-486-5p expression in HCC tissues. Collectively, our results suggest that miR-486-5p may act as a tumor suppressor gene in HCC by downregulating CBL expression.

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Identification of molecular target genes and key pathways in hepatocellular carcinoma by bioinformatics analysis

OncoTargets and Therapy ◽

10.2147/ott.s156737 ◽

2018 ◽

Vol Volume 11 ◽

pp. 1861-1869 ◽

Cited By ~ 24

Author(s):

Lei Zhou ◽

Yanyan Du ◽

Lingqun Kong ◽

Xingyuan Zhang ◽

Qiangpu Chen

Keyword(s):

Hepatocellular Carcinoma ◽

Target Genes ◽

Bioinformatics Analysis ◽

Molecular Target ◽

Key Pathways

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Bioinformatic Analysis of Circular RNA-Associated ceRNA Network Associated with Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2019/8308694 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Jiacheng Wu ◽

Shui Liu ◽

Yien Xiang ◽

Xianzhi Qu ◽

Yingjun Xie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Pathway Analysis ◽

Target Genes ◽

Kegg Pathway ◽

Interaction Network ◽

Bioinformatic Analysis ◽

Differentially Expressed ◽

Qrt Pcr ◽

Cerna Network ◽

Kegg Pathway Analysis

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is associated with a high mortality rate and poor treatment efficacy. In an attempt to investigate the mechanisms involved in the pathogenesis of HCC, bioinformatic analysis and validation by qRT-PCR were performed. Three circRNA GEO datasets and one miRNA GEO dataset were selected for this purpose. Upon combined biological prediction, a total of 11 differentially expressed circRNAs, 15 differentially expressed miRNAs, and 560 target genes were screened to construct a circRNA-related ceRNA network. GO analysis and KEGG pathway analysis were performed for the 560 target genes. To further screen key genes, a protein-protein interaction network of the target genes was constructed using STRING, and the genes and modules with higher degree were identified by MCODE and CytoHubba plugins of Cytoscape. Subsequently, a module was screened out and subjected to GO enrichment analysis and KEGG pathway analysis. This module included eight genes, which were further screened using TCGA. Finally, UBE2L3 was selected as a key gene and the hsa_circ_0009910–miR-1261–UBE2L3 regulatory axis was established. The relative expression of the regulatory axis members was confirmed by qRT-PCR in 30 pairs of samples, including HCC tissues and adjacent nontumor tissues. The results suggested that hsa_circ_0009910, which was upregulated in HCC tissues, participates in the pathogenesis of HCC by acting as a sponge of miR-1261 to regulate the expression of UBE2L3. Overall, this study provides support for the possible mechanisms of progression in HCC.

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Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00269.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G401-G409

Author(s):

Asahiro Morishita ◽

Koji Fujita ◽

Hisakazu Iwama ◽

Taiga Chiyo ◽

Shintaro Fujihara ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Target Genes ◽

Aberrant Expression ◽

Tissue Samples ◽

Nontumor Tissue ◽

B Virus ◽

Enhanced Expression ◽

Hcc Cells

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002–2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC. NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

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Single Nucleotide Polymorphisms inmiR-122Are Associated with the Risk of Hepatocellular Carcinoma in a Southern Chinese Population

BioMed Research International ◽

10.1155/2018/1540201 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Chunhua Bei ◽

Shun Liu ◽

Xiangyuan Yu ◽

Moqin Qiu ◽

Bo Tang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Single Nucleotide Polymorphisms ◽

Chinese Population ◽

Target Genes ◽

Risk Group ◽

High Risk Group ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Southern Chinese ◽

Increased Risk

Single nucleotide polymorphisms (SNPs) in microRNA may affect its expression and regulation of target genes, which may consequently alter individual susceptibility to cancer. In this study we aimed to investigate associations betweenmiR-122polymorphisms and hepatocellular carcinoma (HCC) in a southern Chinese population. Three selected SNPs inmiR-122(rs9966765, rs1135519, and rs17669) were genotyped in 1050 HCC patients and 1079 cancer-free controls using Sequenom MassARRAY platform and the associations of the three SNPs and HCC risk were evaluated. We found that individuals with the rs1135519 CC genotypes had a significant increased risk of HCC than those with TT genotypes (adjusted OR=2.71, 95% CI=1.15-6.36, andP=0.022), while the rs9966765 CC genotypes showed a borderline significant association with increased risk of HCC when compared with the GG genotypes (adjusted OR=2.38, 95% CI=0.99-5.75, andP=0.052). There was also a significant increased risk of HCC when combining risk genotypes of these loci, i.e., rs1135519 CC and rs9966765 CC. Compared with the low-risk group (0 risk genotype), the high risk group (1-2 risk genotypes) had significantly increased risk of HCC (OR=1.61, 95% CI=1.05-2.44, andP=0.028). Further genotype-expression analysis revealed that cases carrying the CC genotype of rs1135519 had lower levels ofmiR-122expression than those with the TT genotype. Our results suggest that SNP of rs1135519 modulatesmiR-122expression and contributes to the genetic susceptibility of HCC, either independently or together with rs9966765 inmiR-122.Further well-designed studies with lager sample sizes are needed to confirm our findings.

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Identification of the Sixth Complement Component as Potential Key Genes in Hepatocellular Carcinoma via Bioinformatics Analysis

BioMed Research International ◽

10.1155/2020/7042124 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Di Mu ◽

Feng Qin ◽

Baoshan Li ◽

Qian Zhou

Keyword(s):

Hepatocellular Carcinoma ◽

Target Genes ◽

Significant Negative Correlation ◽

Complement Component ◽

Molecular Characteristics ◽

Poor Overall Survival ◽

Protein Protein Interaction ◽

Key Genes ◽

Underlying Mechanisms ◽

Low Expression

The present study is designed to determine potential target genes involved in hepatocellular carcinoma (HCC) and provide possible underlying mechanisms of action. Several studies (GSE112790, GSE87630, and GSE56140) from the GEO database looking at molecular characteristics in HCC were screened and analyzed by GEO2R, which led to the identification of a total of 93 differentially expressed genes (DEGs). From the protein–protein interaction (PPI) network, we selected 13 key genes with high degree of variability in expression in HCC. Expression of three key genes (NQO1, CYP2C9, and C6) presented with poor overall survival (OS) in HCC patients by UALCAN. C6, which is a complement component, was found by ONCOMINE and TIMER to have low expression in many solid cancers including HCC. Besides, Kaplan-Meier plotter and UALCAN database analysis to access diseases prognosis suggested that low expression of C6 is significantly related to worse OS in LIHC patients, especially in advanced HCC patients. Finally, the TIMER analysis suggested that the C6 expression showed significant negative correlation with infiltrating levels of six immune cells. The somatic copy number alterations (SCNAs) of C6 were associated with CD4+ T cell infiltration in HCC. Taken together, these results together identified C6 as a potential key gene in the diagnosis and prognosis of HCC.

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Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21155378 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5378 ◽

Cited By ~ 2

Author(s):

Effi Haque ◽

M. Rezaul Karim ◽

Aamir Salam Teeli ◽

Magdalena Śmiech ◽

Paweł Leszczynski ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Leucine Zipper ◽

Molecular Mechanisms ◽

Target Genes ◽

Precancerous Lesions ◽

Redox Homeostasis ◽

Detoxification Enzymes ◽

Related Factor ◽

Basic Leucine Zipper ◽

Nrf2 Activation

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

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