Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Abstract Background Several studies have shown that Spindle and Kinetochore-related Complex Subunit 3 (SKA3) is closely related to the diagnosis and prognosis of various cancers. SKA3 plays a vital role in mitosis, but the mechanism underlying its action in tumors has not been fully elucidated. Methods Two separate microarrays of pancreatic adenocarcinoma (PAAD) and hepatocellular carcinoma (HCC) samples were downloaded from the Gene Expression Omnibus (GEO) and analyzed using R software. Tissues from 203 HCC and 321 PAAD patients were used for tissue microarray (TMA) construction and immunohistochemical staining for scoring. Kaplan-Meier estimators were used to determine their clinical relevance. Finally, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) were used for analyzed rich pathways of SKA3 to understand gene function further. Results Contrary to the results obtained from the GEO database, HCC and PAAD tumor tissues exhibited significantly lower expression of SKA3 compared to the adjacent tissues (P < 0.001). The size of HCC tumor and Edmondson grade were statistically correlated with SKA3 expression (P < 0.05). No correlation was observed between the levels of SKA3 expression and vascular invasion, metastasis, or lymphatic infiltration in HCC patients. Moreover, factors related to decreases of SKA3 in PAAD could similarly not be found. Kaplan-Meier survival curves indicated that SKA3 upregulation in HCC was significantly associated with better prognosis (P = 0.016). In contrast, low levels of SKA3 were related to poor prognosis of PAAD patients (P = 0.026). Enrichment analysis of GO and KEGG pathways showed that SKA3 gene was closely related to cell cycle pathways. Conclusions The results of the present study indicate that SKA3 expression can serve as a diagnostic and prognostic biomarker for HCC and PAAD. However, there is a need to conduct further studies to verify these findings, especially the prognostic role of SKA3 in PAAD.

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Identifying Potential Prognostic Biomarkers Associated With Clinicopathologic Characteristics of Hepatocellular Carcinoma by Bioinformatics Analysis

10.21203/rs.3.rs-146400/v1 ◽

2021 ◽

Author(s):

Shaojie Huang ◽

Jia Yao ◽

Xiaofan Lai ◽

Lu Yang ◽

Fang Ye ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Progression Free Survival ◽

Gene Expression Omnibus ◽

Rank Aggregation ◽

Hub Genes ◽

Clinicopathologic Characteristics ◽

Kegg Pathways ◽

Diagnosis And Prognosis

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. However, the molecular mechanisms of HCC remain largely unknown so far. Methods: To unravel the underlying carcinogenic mechanisms, we utilized Robust Rank Aggregation analysis (RRA) to identify a set of overlapping differentially expressed genes (DEGs) from 5 microarray datasets on Gene Expression Omnibus (GEO) database. Enriched Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs were conducted. The protein‐protein interaction (PPI) network was constructed and Cytoscape V3.8.0 was used for selecting hub genes. The expression of hub genes was validated in TCGA datasets and HCC samples in our center by qPCR and immunohistochemistry analysis. Results: Totally 126 DEGs were identified. GO and KEGG pathways of DEGs mostly associated with “organelle fission”, “nuclear division” and “caffeine metabolism. Ten hub genes (BUB1B, CDKN3, CCNB1, CCNB2, CDK1, TOP2A, CDC20, MELK, NUSAP1, AURKA) were selected. Overall survival (OS) and progression-free survival (PFS) analysis suggested the good value of these genes for HCC diagnosis and prognosis. These genes were upregulated in HCC samples from TCGA, which were associated with higher tumor grades and possibly resulted from hypomethylation. Moreover, these hub genes were markedly dysregulated in HCC samples in our center and significantly associated with clinicopathologic characteristics of HCC patients. Conclusions: In conclusion, our study identified several hub genes as novel candidate biomarkers for diagnosis and prognosis of HCC, which may provide new insight into HCC pathogenesis in order to search for better treatments.

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Transcriptomic identification of HBx-associated hub genes in hepatocellular carcinoma

PeerJ ◽

10.7717/peerj.12697 ◽

2021 ◽

Vol 9 ◽

pp. e12697

Author(s):

Zhengzhong Ni ◽

Jun Lu ◽

Weiyi Huang ◽

Hanif Khan ◽

Xuejun Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepg2 Cells ◽

Enrichment Analysis ◽

Gene Expression Omnibus ◽

Pathway Enrichment Analysis ◽

Hub Genes ◽

Protein Protein Interaction ◽

Transcription Profiles ◽

Kaplan Meier ◽

Primary Mouse

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies around the world. Among the risk factors involved in liver carcinogenesis, hepatitis B virus (HBV) X protein (HBx) is considered to be a key regulator in hepatocarcinogenesis. Whether HBx promotes or protects against HCC remains controversial, therefore exploring new HBx-associated genes is still important. Methods HBx was overexpressed in HepG2, HepG2.2.15 and SMMC-7721 cell lines, primary mouse hepatocytes and livers of C57BL/6N mice. High-throughput RNA sequencing profiling of HepG2 cells with HBx overexpression and related differentially-expressed genes (DEGs), pathway enrichment analysis, protein-protein interaction networks (PPIs), overlapping analysis were conducted. In addition, Gene Expression Omnibus (GEO) and proteomic datasets of HBV-positive HCC datasets were used to verify the expression and prognosis of selected DEGs. Finally, we also evaluated the known oncogenic role of HBx by oncogenic array analysis. Results A total of 523 DEGs were obtained from HBx-overexpressing HepG2 cells. Twelve DEGs were identified and validated in cells transiently transfected with HBx and three datasets of HBV-positive HCC transcription profiles. In addition, using the Kaplan-Meier plotter database, the expression levels of the twelve different genes were further analyzed to predict patient outcomes. Conclusion Among the 12 identified HBx-associated hub genes, HBV-positive HCC patients expressing ARG1 and TAT showed a good overall survival (OS) and relapse-free survival (RFS). Thus, ARG1 and TAT expression could be potential prognostic markers.

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Prognostic Values of Stabilin-2 in Hepatocellular Carcinoma

10.21203/rs.3.rs-27280/v1 ◽

2020 ◽

Author(s):

Zhicheng Du ◽

Pengfei Zhu ◽

Long Yu ◽

Kunlun Chen ◽

Janwen Ye ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Survival Time ◽

Cox Regression ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Primary Malignancy ◽

Diagnosis And Prognosis ◽

Kaplan Meier ◽

Potential Biomarker

Abstract Background: Hepatocellular carcinoma (HCC) is the primary malignancy of the liver. However, biomarkers for early HCC diagnosis are not available. Stabilin (STAB) proteins are scavenger receptors involved in apoptosis and clearance of hyaluronic acid .The role of STAB in HCC has not been previously explored; therefore, the aim of this study was to assess whether STAB gene expression can be used as a novel HCC biomarker.Materials and Methods: Data on 370 HCC patients in the Cancer Genome Atlas database and 221 patients in the Gene Expression Comprehensive Database were retrieved and analyzed. Kaplan–Meier analysis and Cox regression model were used to calculate median survival time using hazard ratio (HR) and 95% confidence interval (CI). Results: The Gene Expression Omnibus dataset showed that high Stabilin-2（STAB2） expression implies longer overall survival (HR after correction = 0.541; 95% CI, 0.339–0.865; p = 0.0182, after correction p = 0.010) and longer recurrence-free survival time (adjusted HR = 0.554; 95% CI, 0.376-0.816; p = 0.0085, adjusted p = 0.003). Conclusions: STAB2 is a potential biomarker for the diagnosis and prognosis of HCC.

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NDRG3 overexpression is associated with a poor prognosis in patients with hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20180907 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 1

Author(s):

Ji-sheng Jing ◽

Hongbo Li ◽

Shun-cai Wang ◽

Jiu-ming Ma ◽

La-qing Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cox Regression ◽

Survival Curve ◽

Disease Free Survival ◽

Prognostic Indicator ◽

Clinicopathological Characteristics ◽

Pcr Analysis ◽

Kaplan Meier ◽

Tumor Tissues ◽

The Relationship

N-myc downstream-regulated gene 3 (NDRG3), an important member of the NDRG family, is involved in cell proliferation, differentiation, and other biological processes. The present study analyzed NDRG3 expression in hepatocellular carcinoma (HCC) and explored the relationship between expression of NDRG3 in HCC patients and their clinicopathological characteristics. We performed quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry (IHC) analyses on HCC tissues to elucidate NDRG3 expression characteristics in HCC patients. Kaplan–Meier survival curve and Cox regression analyses were used to evaluate the prognoses of 102 patients with HCC. The results revealed that compared with non-tumor tissues, HCC tissues showed significantly higher NDRG3 expression. In addition, our analyses showed that NDRG3 expression was statistically associated with tumor size (P=0.048) and pathological grade (P=0.001). Survival analysis and Kaplan–Meier curves revealed that NDRG3 expression is an independent prognostic indicator for disease-free survival (P=0.002) and overall survival (P=0.005) in HCC patients. The data indicate that NDRG3 expression may be considered as a oncogenic biomarker and a novel predictor for HCC prognosis.

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Identification and Validation of an 6-Metabolism-Related Gene Signature and Its Correlation With Immune Checkpoint in Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.783934 ◽

2021 ◽

Vol 11 ◽

Author(s):

He Ren ◽

Wanjing Li ◽

Xin Liu ◽

Shuliang Li ◽

Hao Guo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Signature ◽

Clinicopathological Characteristics ◽

Gene Set Enrichment Analysis ◽

Operating Characteristics ◽

Kaplan Meier ◽

Characteristics Analysis

Hepatocellular carcinoma (HCC) is a common malignant tumor with relatively high malignancy and rapid disease progression. Metabolism-related genes (MRGs) are involved in the pathogenesis of HCC. This study explored potential key MRGs and their effect on T-cell immune function in the tumor immune microenvironment to provide new insight for the treatment of HCC. Of 456 differentially expressed MRGs identified from TCGA database, 21 were screened by MCODE and cytoHubba algorithms. From the key module, GAD1, SPP1, WFS1, GOT2, EHHADH, and APOA1 were selected for validation. The six MRGs were closely correlated with survival outcomes and clinicopathological characteristics in HCC. Receiver operating characteristics analysis and Kaplan-Meier plots showed that these genes had good prognostic value for HCC. Gene set enrichment analysis of the six MRGs indicated that they were associated with HCC development. TIMER and GEPIA databases revealed that WFS1 was significantly positively correlated and EHHADH was negatively correlated with tumor immune cell infiltration and immune checkpoint expression. Finally, quantificational real-time polymerase chain reaction (qRT-PCR) confirmed the expression of WFS1 and EHHADH mRNA in our own patients’ cohort samples and four HCC cell lines. Collectively, the present study identified six potential MRG biomarkers associated with the prognosis and tumor immune infiltration of HCC, thus providing new insight into the pathogenesis and treatment of HCC.

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Prognostic value of an immune long non-coding RNA signature in liver hepatocellular carcinoma

10.21203/rs.2.19313/v1 ◽

2019 ◽

Author(s):

rui kong ◽

Nan Wang ◽

Wei Han ◽

Yuejuan Zheng ◽

Jie Lu

Keyword(s):

Hepatocellular Carcinoma ◽

Principal Component ◽

Enrichment Analysis ◽

Risk Groups ◽

Gene Set Enrichment Analysis ◽

Kaplan Meier ◽

Non Coding Rna ◽

Liver Hepatocellular Carcinoma ◽

Long Non Coding Rna

Abstract Background: In recent years, long non-coding RNAs (lncRNAs) are emerging as crucial regulators in the immunological process of liver hepatocellular carcinoma (LIHC). Increasing studies have found that some lncRNAs could be used as a diagnostic or therapeutic target for clinical management, but little research has investigated the role of immune-related lncRNA in tumor prognosis. In this study, we aimed to develop an immune lncRNA signature for the precise diagnosis and prognosis of liver hepatocellular carcinoma. Methods: Gene expression profiles of LIHC samples obtained from TCGA were screened for immune-related genes using two reference gene sets. The optimal immune-related lncRNA signature was built via correlational analysis, univariate and multivariate cox analysis. Then the Kaplan-Meier plot, ROC curve, clinical analysis, gene set enrichment analysis, and principal component analysis were carried out to evaluate the capability of immune lncRNA signature as a prognostic indicator. Results: Six long non-coding RNA MSC−AS1, AC009005.1, AL117336.3, AL031985.3, AL365203.2, AC099850.3 were identified via correlation analysis and cox regression analysis considering their interactions with immune genes. Next, tumor samples were separated into two risk groups by the signature with different clinical outcomes. Stratification analysis showed the prognostic ability of this signature acted as an independent factor. The AUC value of ROC curve was 0.779. The Kaplan-Meier method was used in survival analysis and results showed a statistical difference between the two risk groups. The predictive performance of this signature was validated by principal component analysis (PCA). Data from gene set enrichment analysis (GSEA) further unveiled several potential biological processes of these biomarkers may involve in. Conclusion: In summary, the study demonstrated the potential role of the six-lncRNA signature served as an independent prognostic factor for LIHC patients.

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High Squalene Epoxidase in Tumors Predicts Worse Survival in Patients With Hepatocellular Carcinoma: Integrated Bioinformatic Analysis on NAFLD and HCC

Cancer Control ◽

10.1177/1073274820914663 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482091466

Author(s):

Tingting Shen ◽

Yunfei Lu ◽

Qin Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Messenger Rna ◽

Disease Free Survival ◽

Bioinformatic Analysis ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Squalene Epoxidase ◽

Nonalcoholic Fatty Liver ◽

Kaplan Meier ◽

High Level

This study aimed to identify candidate biomarkers for predicting outcomes in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Using Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) databases, we identified common upregulated differential expressed genes (DEGs) in patients with NAFLD/nonalcoholic steatohepatitis (NASH) and HCC and conducted survival analysis of these upregulated DEGs with HCC outcomes. Two common upregulated DEGs including squalene epoxidase (SQLE) and EPPK1 messenger RNA (mRNA) were significantly upregulated in NAFLD, NASH, and HCC tissues, both in GSE45436 ( P < .001) and TCGA profile ( P < .001). Both SQLE and EPPK1 mRNA were upregulated in 15.56% and 8.06% patients with HCC in TCGA profile. Overexpression of SQLE in tumors was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in patients with HCC (log-rank P = .027 and log-rank P = .048, respectively), while no statistical significances of OS and DFS were found in EPPK1 groups (both log-rank P > .05). For validation, SQLE upregulation contributed to significantly worse OS in patients wih HCC using Kaplan-Meier plotter analysis (hazard ratio = 1.43, 95% confidence interval: 1.01-2.02, log-rank P = .043). In addition, high level of SQLE significantly associated with advanced neoplasm histologic grade, advanced AJCC stage, and α-fetoprotein elevation ( P = .036, .045, and .029, respectively). Squalene epoxidase is associated with OS and DFS and serves as a novel prognostic biomarker for patients with HCC.

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Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

BioMed Research International ◽

10.1155/2019/1742341 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 1

Author(s):

Linxin Teng ◽

Kaiyuan Wang ◽

Yu Liu ◽

Yanxia Ma ◽

Weiping Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Predictive Biomarkers ◽

Principal Component ◽

Roc Curves ◽

Core Gene ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Protein Protein Interaction ◽

The Core ◽

Kaplan Meier

Accumulating statistics have shown that liver cancer causes the second highest mortality rate of cancer-related deaths worldwide, of which 80% is hepatocellular carcinoma (HCC). Given the underlying molecular mechanism of HCC pathology is not fully understood yet, identification of reliable predictive biomarkers is more applicable to improve patients’ outcomes. The results of principal component analysis (PCA) showed that the grouped data from 1557 samples in Gene Expression Omnibus (GEO) came from different populations, and the mean tumor purity of tumor tissues was 0.765 through the estimate package in R software. After integrating the differentially expressed genes (DEGs), we finally got 266 genes. Then, the protein-protein interaction (PPI) network was established based on these DEGs, which contained 240 nodes and 1747 edges. FOXM1 was the core gene in module 1 and highly associated with FOXM1 transcription factor network pathway, while FTCD was the core gene in module 2 and was enriched in the metabolism of amino acids and derivatives. The expression levels of hub genes were in line with The Cancer Genome Atlas (TCGA) database. Meanwhile, there were certain correlations among the top ten genes in the up- and downregulated DEGs. Finally, Kaplan–Meier curves and receiver operating characteristic (ROC) curves were plotted for the top five genes in PPI. Apart from CDKN3, the others were closely concerned with overall survival. In this study, we detected the potential biomarkers and their involved biological processes, which would provide a new train of thought for clinical diagnosis and treatment.

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Long noncoding RNA CASC2c inhibited cell proliferation in hepatocellular carcinoma by inactivated ERK1/2 and Wnt/β-catenin signaling pathway

Clinical & Translational Oncology ◽

10.1007/s12094-019-02223-7 ◽

2019 ◽

Vol 22 (3) ◽

pp. 302-310 ◽

Cited By ~ 5

Author(s):

Q. Y. Li ◽

K. Yang ◽

F. G. Liu ◽

X. G. Sun ◽

L. Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Cancer Susceptibility ◽

Vital Role ◽

Migration And Invasion ◽

Tumor Tissues ◽

Hcc Cells

Abstract Purpose Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumorigenesis, but their biological functions and the underlying molecular mechanisms remain unclear. Alternative splicing of five exons results in three transcript variants of cancer susceptibility 2 (CASC2): the lncRNAs CASC2a, CASC2b, and CASC2c. CASC2a/b have been found to have crucial regulatory functions in a number of malignancies, but few studies have examined the effects of CASC2c in cancers. The objective of the study was to investigate the role of CASC2c in the proliferation and apoptosis of hepatocellular carcinoma (HCC) cells. Methods This study first investigated the expression levels of CASC2c in tumor tissues, corresponding non-tumor tissues and cells using quantitative real-time polymerase chain reaction. The function and underlying molecular mechanism of CASC2c in human HCC were investigated in QGY-7703 cell line, as well as in gastric cancer (GC) cell and colorectal cancer (CRC) cell. Results In the present work, we observed that CASC2c was significantly down-regulated in HCC tissues and cells. Moreover, its overexpression remarkably inhibited the growth, migration, and invasion of HCC cells in vitro and promoted their apoptosis. Furthermore, we demonstrated that CASC2c overexpression decreased p-ERK1/2 levels in HCC, GC, and CRC cells. Interestingly, while overexpression of CASC2c decreased β-catenin expression in HCC and GC cells, it increased that in CRC cells. Conclusion The lncRNA–CASC2c has a vital role in tumorigenesis and cancer progression, and may serve as a biomarker or therapeutic target in cancer treatment via down-regulation of the ERK1/2 and Wnt/β-catenin signaling pathways.

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Elevated FOXC2 Expression Promotes Invasion of HCC Cell Lines and is Associated with Poor Prognosis in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000484586 ◽

2017 ◽

Vol 44 (1) ◽

pp. 99-109 ◽

Cited By ~ 7

Author(s):

Fang Yang ◽

Lizhi Lv ◽

Kun Zhang ◽

Qiucheng Cai ◽

Jianyong Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Flow Cytometric Analysis ◽

Vital Role ◽

Migration And Invasion ◽

Flow Cytometric ◽

Kaplan Meier ◽

Proliferation Assays ◽

The Relationship

Background/Aims: Increasing evidence has indicated that Forkhead box protein C2 (FOXC2) plays an important role in carcinogenesis. However, the expression and the role of FOXC2 in hepatocellular carcinoma (HCC) have not been extensively studied. Methods: FOXC2 expression was analyzed by quantitative real-time polymerase chain reaction, Western blot analysis and immunohistochemistry in HCC tissue and cells. The relationship between FOXC2 expression and patient clinical significance and survival were assessed by Pearson’s correlation and Kaplan-Meier analysis, respectively. Cell proliferation assays, colony formation assays, flow cytometric analysis and Transwell assays were employed to measure the effects of FOXC2 on HCC cells in vitro. Results: The expression of FOXC2 was increased in HCC tissue, and high FOXC2 expression was associated with worse patient survival. Knockdown of FOXC2 inhibited HCC cell growth, migration, and invasion in vitro, as well as tumor growth. Furthermore, we found that activation of AKT-mediated MMP-2 and MMP-9 was involved in FOXC2 promoting an aggressive phenotype. Conclusions: Taken together, these findings demonstrate that FOXC2 is upregulated in HCC tissue and is associated with tumor size, vascular invasion and advanced TNM stage. Further investigation suggested that FOXC2 may play a vital role in promoting proliferation and invasion in HCC and serves as a novel therapeutic target in HCC.

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