Upregulated LINC01667 Expression Is Correlated With Poor Prognosis in Hepatocellular Carcinoma

The development of hepatocellular carcinoma (HCC) is a complex pathological process. Long intergenic non–protein-coding RNA 1667 (LINC01667, also known as MGC38584) plays an oncogenic role in several human cancers; however, its functional role in HCC tumorigenesis remains unknown. Here, we first evaluated the gene expression levels of LINC01667 in HCC using data from The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then elucidated the association between LINC01667 gene expression levels and the survival rates of patients with HCC. We detected the effect of LINC01667 on the malignant phenotypes (cell proliferation, migration, invasion and apoptosis etc.) and the MAPK and PI3K/AKT/mTOR signaling pathways of HepG2, SMMC-7721 and HUH7 cells. We also analyzed the sensitivity of HepG2, SMMC-7721 and HUH7 with different expression levels of LINC01667 to anti-HCC drugs in vitro. Based on data from the aforementioned databases and our experiments in vitro, we found that LINC01667 was overexpressed in HCC, and that patients with high LINC01667 levels had a remarkably poor overall survival rate. In addition, inhibition of LINC01667 expression suppressed the proliferation, migration and invasion of HepG2 and SMMC-7721 cells and promoted their apoptosis in vitro. In contrast, overexpression of LINC01667 promoted the proliferation, migration and invasion of HUH7 cells and suppressed their apoptosis in vitro. ChIRP-seq (chromatin isolation by RNA purification) showed that LINC01667 bound to MEG3, and downregulated the expression of MEG3. In addition, western blotting showed that LINC01667 could activate the NF-κB pathway to promote cancer progression. In conclusion, we report that LINC01667 is an important oncogene in HCC and may be used as a potential diagnostic and prognostic biomarker of HCC.

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miR-369-3p serves as prognostic factor and regulates cancer progression of hepatocellular carcinoma

Personalized Medicine ◽

10.2217/pme-2020-0012 ◽

2021 ◽

Author(s):

Can Chen ◽

Yi Zong ◽

Jiaojiao Tang ◽

Ruisheng Ke ◽

Lizhi Lv ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cancer Progression ◽

Cell Counting ◽

Migration And Invasion ◽

Pcr Analysis ◽

Reverse Transcription Pcr ◽

Huh7 Cells

Background: The aim of this study was to investigate the role of miR-369-3p in hepatocellular carcinoma (HCC). Materials & methods: The expression levels of miR-369-3p were detected using the quantitative real-time reverse transcription-PCR analysis. The cell counting kit-8 and transwell assays were used to explore the effects of miR-369-3p on cell proliferation, migration and invasion of HCC cells. Results: The miR-369-3p expression was downregulated in HCC tissues and cell lines, in comparison to the normal controls, respectively. In vitro, overexpression of miR-369-3p in Hep 3B and Huh7 cells inhibited cell proliferation, migration and invasion. SOX4 was a direct target of miR-369-3p. Conclusion: Our results suggested that miR-369-3p may be a tumor suppressor in HCC by targeting SOX4.

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Development and validation of a novel ten-gene signature predicting prognosis in Hepatocellular carcinoma

10.21203/rs.3.rs-46933/v1 ◽

2020 ◽

Author(s):

Guanbao Zhou ◽

Genjie Lu ◽

Liang Yang ◽

Yangfang Lu

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Hierarchical Clustering ◽

Risk Score ◽

Cox Regression ◽

Gene Signature ◽

Molecular Biomarkers ◽

The Cancer Genome Atlas ◽

Expression Levels ◽

Gene Expression Levels

Abstract Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer with relatively poor prognosis. Thus, we aimed to identify novel molecular biomarkers to effectively predict the prognosis of HCC patients and eventually guide treatment. Methods: Prognosis-associated genes were determined by Kaplan-Meier and multivariate Cox regression analyses using the expression and clinical data of 373 HCC patients from The Cancer Genome Atlas (TCGA) database and validated in an independent Gene Expression Omnibus (GEO) dataset. The classification of AML was performed by unsupervised hierarchical clustering of ten gene expression levels. A prognostic risk score was established based on a linear combination of ten gene expression levels using the regression coefficients derived from the multivariate Cox regression models. Results: A total of 183 genes were significantly associated with prognosis in HCC. SLC25A15, RAB8A, GOT2, SORBS2, IL18RAP were top five protective genes, while FHL3, AMD1, DCAF13, UBE2E1, PTDSS2 were top five risk genes in HCC. SLC25A15, GOT2, IL18RAP were significantly down-regulated and DCAF13, PTDSS2 and SORBS2 were significantly up-regulated in the HCC samples and these genes exhibited high accuracy in differentiating HCC tissues from normal liver tissues. Hierarchical clustering analysis of the ten genes discovered three clusters of HCC patients. HCC tumors of cluster1 and 2 were significantly associated with more favourable OS than those of cluster3, cluster2 tumors showed higher pathologic stage than cluster3 tumors. The risk score was predictive of increased mortality rate in HCC patients. Conclusions: The ten-gene signature and the risk score may turn out to be novel molecular biomarkers and stratification of HCC patients to considerably ameliorate the prognostic prediction.

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Abnormal Expression of Centromere Protein U Is Associated with Hepatocellular Cancer Progression

BioMed Research International ◽

10.1155/2021/4051192 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Yuanlin Yu ◽

Xiaopeng Chen ◽

Weidong Zhang ◽

Jun Liu

Keyword(s):

Gene Expression ◽

Cancer Progression ◽

Quantitative Polymerase Chain Reaction ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Counting ◽

Migration And Invasion ◽

Abnormal Expression ◽

Centromere Protein

Background. Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, but its molecular mechanism is unclear. Abnormal expression of centromere protein U (CENPU) is closely related to diverse human cancers. The purpose of this article was to evaluate the function and potential mechanisms of CENPU in HCC development. Methods. We performed bioinformatics analysis of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan-Meier plotter databases to investigate the clinical significance and prognostic value of CENPU in HCC. Western blotting and immunohistochemical staining were used to measure protein expression, while reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was used to determine mRNA expression. Cell Counting Kit8 (CCK-8) and colony formation assays were conducted to examine cell proliferation. Transwell and wound healing assays were used to assess cell migration and invasion. Gene set enrichment analysis (GSEA) was used to explore the potential signaling pathways of CENPU involved in HCC. Results. High expression of CENPU in HCC was predicted by public database analysis and indicated a poor prognosis. CENPU expression was significantly higher in HCC tissues and cells than in normal tissues and cell. In vitro, CENPU promoted the proliferation, migration, and invasion of HCC cells. GSEA results indicated that CENPU was linked to the Notch signaling pathway, and our research supported this prediction. Conclusion. CENPU promotes the malignant biological process of HCC and may be a promising target for HCC treatment.

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A Sparse and Low-Rank Regression Model for Identifying the Relationships Between DNA Methylation and Gene Expression Levels in Gastric Cancer and the Prediction of Prognosis

Genes ◽

10.3390/genes12060854 ◽

2021 ◽

Vol 12 (6) ◽

pp. 854

Author(s):

Yishu Wang ◽

Lingyun Xu ◽

Dongmei Ai

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Dna Methylation ◽

Regression Model ◽

The Cancer Genome Atlas ◽

Low Rank ◽

Expression Levels ◽

Rank Regression ◽

Prediction Of Prognosis ◽

Gene Expression Levels

DNA methylation is an important regulator of gene expression that can influence tumor heterogeneity and shows weak and varying expression levels among different genes. Gastric cancer (GC) is a highly heterogeneous cancer of the digestive system with a high mortality rate worldwide. The heterogeneous subtypes of GC lead to different prognoses. In this study, we explored the relationships between DNA methylation and gene expression levels by introducing a sparse low-rank regression model based on a GC dataset with 375 tumor samples and 32 normal samples from The Cancer Genome Atlas database. Differences in the DNA methylation levels and sites were found to be associated with differences in the expressed genes related to GC development. Overall, 29 methylation-driven genes were found to be related to the GC subtypes, and in the prognostic model, we explored five prognoses related to the methylation sites. Finally, based on a low-rank matrix, seven subgroups were identified with different methylation statuses. These specific classifications based on DNA methylation levels may help to account for heterogeneity and aid in personalized treatments.

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Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000495825 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2065-2072 ◽

Cited By ~ 3

Author(s):

Wei Bian ◽

Hongfei Zhang ◽

Miao Tang ◽

Shaojun Zhang ◽

Lichao Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Metastatic Progression ◽

Mesenchymal Transition ◽

Reporter Assays

Background/Aims: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. Methods: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. Results: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3’-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. Conclusion: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

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High Expression of ANXA2 Pseudogene ANXA2P2 Promotes an Aggressive Phenotype in Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2019/9267046 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Qiu-shuang Wang ◽

Liang-Liang Shi ◽

Fei Sun ◽

Yi-fan Zhang ◽

Ren-Wang Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Disease Free Survival ◽

Annexin A2 ◽

The Cancer Genome Atlas ◽

High Expression ◽

Migration And Invasion ◽

Targeted Drugs ◽

Noncancerous Tissue ◽

Expression Levels ◽

Hcc Cells

Objective. Accumulating evidence suggests that pseudogenes play potential roles in the regulation of their cognate wild-type genes, oncogenes, and tumor suppressor genes. ANXA2P2 (annexin A2 pseudogene 2) is one of three pseudogenes of annexin A2 that have recently been shown to be aberrantly transcribed in hepatocellular carcinoma (HCC) cells. However, its clinical meaning and biological function in HCC have remained unclear. Therefore, the present study was aimed at exploring the prognostic value of a high expression of ANXA2P2 in HCC tissue and at identifying whether it can affect the efficacy of targeted drugs (sorafenib, regorafenib, and lenvatinib). Methods. We obtained ANXA2P2 mRNA expression levels from The Cancer Genome Atlas (TCGA) RNA sequence database. The expression levels of ANXA2P2 in 49 pairs of intratumoral and peritumoral liver tissues were examined by RT-PCR. Wound healing and transwell assays were performed to confirm the tumor-promoting properties of ANXA2P2 in HCC cells. CCK8 assay was conducted to identify whether ANXA2P2 can affect the growth of HCC cells when administered with targeted drugs (sorafenib, regorafenib, and lenvatinib). Results. The expression of ANXA2P2 in HCC tissues was significantly higher than that in adjacent cancerous tissues from TCGA database and validation group. Additionally, patients with high ANXA2P2 expression in HCC tissue had a shorter overall survival, whereas no statistically significant correlation was found between ANXA2P2 expression and disease-free survival (p=0.08) as well as other clinical parameters, such as age, gender, histological grade, T classification, stage, albumin level, alpha-fetoprotein, and vascular invasion (p=0.7323, 0.8807, 0.5762, 0.8515, 0.7113, 0.242, 1.0000, and 0.7685, respectively). Furthermore, in vitro experiments showed that knockdown of ANXA2P2 inhibited migration and invasion of HCC cells but did not have an influence on the HCC cell proliferation when treated with targeted drugs (sorafenib, regorafenib, and lenvatinib). Conclusion. Our study confirmed elevated ANXA2P2 expression levels in HCC tissue compared with adjacent noncancerous tissue and a worse prognosis of patients with high ANXA2P2 levels in the HCC tissue. The newly found properties of promoting migration and invasion of ANXA2P2 in HCC help to explain this phenomenon. ANXA2P2 could be a novel and suitable predicative biomarker for the risk assessment of recurrence or metastasis of HCC patients but may not be effective to predict the efficacy of targeted drugs.

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Exploration and validation of a novel prognostic signature based on comprehensive bioinformatics analysis in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20203263 ◽

2020 ◽

Vol 40 (11) ◽

Author(s):

Xiaofei Wang ◽

Jie Qiao ◽

Rongqi Wang

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Overall Survival ◽

Risk Score ◽

Expression Profiles ◽

Univariate Analysis ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Good Prediction ◽

Expression Levels

Abstract The present study aimed to construct a novel signature for indicating the prognostic outcomes of hepatocellular carcinoma (HCC). Gene expression profiles were downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. The prognosis-related genes with differential expression were identified with weighted gene co-expression network analysis (WGCNA), univariate analysis, the least absolute shrinkage and selection operator (LASSO). With the stepwise regression analysis, a risk score was constructed based on the expression levels of five genes: Risk score = (−0.7736* CCNB2) + (1.0083* DYNC1LI1) + (−0.6755* KIF11) + (0.9588* SPC25) + (1.5237* KIF18A), which can be applied as a signature for predicting the prognosis of HCC patients. The prediction capacity of the risk score for overall survival was validated with both TCGA and ICGC cohorts. The 1-, 3- and 5-year ROC curves were plotted, in which the AUC was 0.842, 0.726 and 0.699 in TCGA cohort and 0.734, 0.691 and 0.700 in ICGC cohort, respectively. Moreover, the expression levels of the five genes were determined in clinical tumor and normal specimens with immunohistochemistry. The novel signature has exhibited good prediction efficacy for the overall survival of HCC patients.

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Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis

Cancer Cell International ◽

10.1186/s12935-019-1093-6 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 9

Author(s):

Qun Dai ◽

Jingyi Deng ◽

Jinrong Zhou ◽

Zhuhong Wang ◽

Xiao-feng Yuan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Noncoding Rna ◽

Critical Role ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Marked Rise ◽

Hcc Cells

Abstract Background Accumulating evidence indicates that the long noncoding RNA taurine upregulated gene 1(TUG1) plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of TUG1 in hepatocellular carcinoma (HCC) remain largely unknown. Methods The expressions of TUG1, microRNA-216b-5p and distal-less homeobox 2 (DLX2) were detected by Quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships were predicted by StarBase v.2.0 or TargetScan and confirmed by dual-luciferase reporter assay. The cell growth, apoptosis, migration and invasion were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow cytometry and Transwell assays, respectively. All protein expression levels were detected by western blot. Tumor xenografts were implemented to explore the role of TUG1 in vivo. Results We found that there was a marked rise in TUG1 expression in HCC tissues and cells, and knockdown of TUG1 repressed the growth and metastasis and promoted apoptosis of HCC cells. In particular, TUG1 could act as a ceRNA, effectively becoming a sink for miR-216b-5p to fortify the expression of DLX2. Additionally, repression of TUG1 impared the progression of HCC cells by inhibiting DLX2 expression via sponging miR-216b-5p in vitro. More importantly, TUG1 knockdown inhibited HCC tumor growth in vivo through upregulating miR-216b-5p via inactivation of the DLX2. Conclusion TUG1 interacting with miR-216b-5p contributed to proliferation, metastasis, tumorigenesis and retarded apoptosis by activation of DLX2 in HCC.

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Primary Cilia Blockage Promotes the Malignant Behaviors of Hepatocellular Carcinoma via Induction of Autophagy

BioMed Research International ◽

10.1155/2019/5202750 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Lian Liu ◽

Jia-Qi Sheng ◽

Mu-Ru Wang ◽

Yun Gan ◽

Xiao-Li Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Primary Cilia ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Serum Starvation ◽

Autophagic Flux ◽

And Function ◽

Hcc Cells

Primary cilia are organelles protruding from cell surface into environment that function in regulating cell cycle and modulating cilia-related signal. Primary ciliogenesis and autophagy play important roles in tumorigenesis. However, the functions and interactions between primary cilia and autophagy in hepatocellular carcinoma (HCC) have not been reported yet. Here, we aimed to investigate the relationship and function of primary cilia and autophagy in HCC. In vitro, we showed that serum starvation stimuli could trigger primary ciliogenesis in HCC cells. Blockage of primary ciliogenesis by IFT88 silencing enhanced the proliferation, migration, and invasion ability of HCC cells. In addition, inhibition of primary cilia could positively regulate autophagy. However, the proliferation, migration, and invasion ability which were promoted by IFT88 silencing could be partly reversed by inhibition of autophagy. In vivo, interference of primary cilia led to acceleration of tumor growth and increase of autophagic flux in xenograft HCC mouse models. Moreover, IFT88 high expression or ATG7 low expression in HCC tissues was correlated with longer survival time indicated by the Cancer Genome Atlas (TCGA) analysis. In conclusion, our study demonstrated that blockage of primary ciliogenesis by IFT88 silencing had protumor effects through induction of autophagy in HCC. These findings define a newly recognized role of primary cilia and autophagy in HCC.

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