Prognostic value of members of the HSP70 family in Hepatocellular Carcinoma

Abstract BACKGROUND: Despite multiple functions in the disease, the prognosis of the heat shock protein (HSP) 70 family in Hepatocellular Carcinoma (HCC) remains unclear. METHODS: The UALCAN database has provided information about the expression level of HSP70 family members in both HCC and in normal tissues. Overall survival (OS) was conducted by Kaplan-Meier plotter (KM plotter). Gene ontology (GO) and KEGG pathway enrichment analyses were accomplished by DAVID database. GeneMANIA and STRING were applied to construct gene-gene and protein-protein interaction (PPI) networks. RESULTS: From the UALCAN database, we found that the expression levels of eight members of the HSP70 family in HCC patients were higher than in normal liver tissues. These eight members were, namely, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA5, HSPA6, HSPA8 and HSPA9. From KM plotter database, high expression of HSPA1A, HSPA1B, HSPA6 and HSPA8 has been observed to be associated with worse OS in patients with HCC (hazard ratio [HR] =1.49, 95% confidence interval [CI]: 1.03-2.15, P=0.031; HR=1.49, 95%CI: 1.05-2.12, P=0.026; HR=1.53, 95%CI: 1.06-2.2, P=0.021 and HR=1.81, 95%CI: 1.21-2.71, P=0.0036, respectively). We also found that the high expressions of HSPA1A, HSPA1B, HSPA6 and HSPA8 were related to unfavorable OS of HCC patients with other factors such as clinical stage, gender, race and hepatitis virus. From GO and KEEG analysis, we detected a close relationship between these eight genes and Biological process, Cellular component, Molecular function and cancer related signaling pathways. The PPI network and GeneMANIA results showed that there was a strong co-expression relationship between the protein homology and the genes. CONCLUSIONS: According to previous studies and analysis, when HSPA1A, HSPA1B, HSPA6 and HSPA8 were highly expressed in HCC patients, they generally demonstrated lower OS. Therefore, the members of HSP70 family are likely to be used as drug targets and prognostic biomarkers when treating HCC patients.

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Expression and Clinical Significance of the Novel Long Noncoding RNA ZNF674-AS1 in Human Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2016/3608914 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Lufei Zhang ◽

Tianyu He ◽

Yingcai Yan ◽

Yuan Zhang ◽

Xiaohu Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Noncoding Rna ◽

Clinical Stage ◽

Normal Liver ◽

Expression Level ◽

The Novel ◽

Normal Liver Cell ◽

Normal Tissues ◽

Cancer Occurrence ◽

Kaplan Meier

Long noncoding RNAs (lncRNAs) play crucial roles in cancer occurrence and progression. However, the relationship between the expression levels of lncRNAs and the hepatocellular carcinoma (HCC) process is unclear. The goal of this study was to determine the expression level of ZNF674-AS1, a newly found lncRNA, in HCC and its clinical association. The expression of ZNF674-AS1 in 137 pairs of tumorous and adjacent normal tissues from patients with HCC was detected by quantitative real-time reverse transcription polymerase chain reaction. Additionally, the potential associations between its level in HCC tissue and clinicopathological features were analyzed. The expression of ZNF674-AS1 in the HCC cell lines HepG2, HCCLM3, SK-Hep1, HuH7, Hep3B, and MHCC97H was significantly downregulated compared with that in the normal liver cell line QSG-7701. The expression of ZNF674-AS1 was downregulated in 72% (99/137) of HCC tissues compared with that in paired adjacent normal tissues (p<0.01). The results showed that the ZNF674-AS1 expression level was significantly correlated with metastasis (p=0.041), clinical stage (p=0.039), and histopathologic grading (p=0.045). In addition, the Kaplan–Meier survival curves revealed that low ZNF674-AS1 expression was associated with poor prognosis in patients with HCC. Our data suggest that ZNF674-AS1 may play some role during cancer occurrence and progression and may be a new biomarker for HCC.

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Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2019/8964015 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Jie Zhang ◽

Qianqian Song ◽

Jinxia Liu ◽

Lina Lu ◽

Yuqing Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Disease Free Survival ◽

Normal Liver ◽

Regulatory Subunit ◽

Mrna Levels ◽

Cyclin Dependent Kinase ◽

Normal Tissues ◽

Hcc Cells

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P=0.019), poor differentiation (P=0.02), portal vein invasion (P<0.001), TNM stage (P=0.019), tumor metastasis (P=0.008), and recurrence (P=0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR=2.088, P=0.014) and disease-free survival (HR=2.511, P=0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P=0.0003), chemoresistance, migration (P=0.0047), and invasion (P=0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of HCC.

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Long non-coding RNA LINC00641 promotes the growth and invasiveness of hepatocellular carcinoma by antagonizing miR-501-3p

Archives of Medical Science ◽

10.5114/aoms/120789 ◽

2021 ◽

Author(s):

Haitao Xie ◽

Hui Zhou ◽

Yan Jiang ◽

Wenqian Xu ◽

Leping Zeng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Normal Liver ◽

In Vivo Studies ◽

Luciferase Reporter ◽

Normal Tissues ◽

Non Coding Rna ◽

Long Non Coding Rna ◽

Proliferation And Invasion ◽

Hcc Cells

IntroductionLong non-coding RNA LINC00641 has been reported to regulate tumor progression in several cancers. However, the expression and function of LINC00641 in hepatocellular carcinoma (HCC) is still unclear.Material and methodsIn this study, we measured the expression of LINC00641 in 79 pairs of HCC and adjacent normal liver tissues. The clinical significance of LINC00641 in HCC was explored. We also investigated the function of LINC00641 in HCC proliferation and invasion.ResultsWe observed that LINC00641 expression was significantly increased in HCC relative to normal tissues (P < 0.0001). High expression of LINC00641 was significantly associated with vascular invasion, advanced TNM stage, and reduced overall survival in HCC patients. Knockdown of LINC00641 inhibited the proliferation, colony formation, and invasion of HCC cells. In contrast, overexpression of LINC00641 promoted HCC cell growth and invasiveness. In vivo studies confirmed that knockdown of LINC00641 restrained tumorigenesis of HCC cells. Mechanistic studies revealed that LINC00641 inhibited the expression of miR-501-3p, which has been previously reported to act as a tumor suppressor in HCC. Furthermore, luciferase reporter assays validated that LINC00641 harbored a target site for miR-501-3p. Rescue experiments demonstrated that LINC00641-induced proliferation and invasion of HCC cells was reversed by co-expression of miR-501-3p.ConclusionsTaken together, LINC00641 contributes to aggressive phenotype of HCC cells by sponging miR-501-3p and represents a promising therapeutic target for this disease.

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Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma.

Acta Biochimica Polonica ◽

10.18388/abp.2006_3384 ◽

2006 ◽

Vol 53 (1) ◽

pp. 237-241 ◽

Cited By ~ 61

Author(s):

Hanna Czeczot ◽

Dorota Scibior ◽

Michał Skrzycki ◽

Małgorzata Podsiad

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Tissue ◽

Normal Liver ◽

Cancer Tissue ◽

Glutathione Level ◽

Normal Tissues ◽

Control Tissue ◽

Cirrhotic Tissue ◽

Cancer Tissues ◽

Gst Activity

We investigated glutathione level, activities of selenium independent GSH peroxidase, selenium dependent GSH peroxidase, GSH S-transferase, GSH reductase and the rate of lipid peroxidation expressed as the level of malondialdehyde in liver tissues obtained from patients diagnosed with cirrhosis or hepatocellular carcinoma. GSH level was found to be lower in malignant tissues compared to adjacent normal tissues and it was higher in cancer than in cirrhotic tissue. Non-Se-GSH-Px activity was lower in cancer tissue compared with adjacent normal liver or cirrhotic tissue, while Se-GSH-Px activity in cancer was found to be similar to its activity in cirrhotic tissue and lower compared to control tissue. An increase in GST activity was observed in cirrhotic tissue compared with cancer tissue, whereas the GST activity in cancer was lower than in adjacent normal tissue. The activity of GSH-R was similar in cirrhotic and cancer tissues, but higher in cancer tissue compared to control liver tissue. An increased level of MDA was found in cancer tissue in comparison with control tissue, besides its level was higher in cancer tissue than in cirrhotic tissue. Our results show that the antioxidant system of cirrhosis and hepatocellular carcinoma is severely impaired. This is associated with changes of glutathione level and activities of GSH-dependent enzymes in liver tissue. GSH and enzymes cooperating with it are important factors in the process of liver diseases development.

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Low Expression of KAT6B May Affect Prognosis in Hepatocellular Carcinoma

Technology in Cancer Research & Treatment ◽

10.1177/15330338211033063 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110330

Author(s):

Junjie Jiang ◽

Hui-Ju Wang ◽

Xiao-Zhou Mou ◽

Huanqing Zhang ◽

YiZhen Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Normal Liver ◽

Clinicopathological Parameters ◽

Expression Array ◽

Chi Square ◽

Normal Tissues ◽

Kaplan Meier ◽

Chi Square Test ◽

The Relationship ◽

Liver Tissues

Aims: Lysine acetyltransferase 6B (KAT6B), is a histone acetyltransferase implicated to have a role in tumor suppression. However, the relationship between KAT6B and hepatocellular carcinoma (HCC) is unclear. The purpose of this study was to detect the expression of KAT6B in HCC tissues and analyze its connection with the clinicopathological features of HCC. Methods: First, we performed immunohistochemical staining on 250 HCC tissues and 222 non-tumor liver tissues to examine the expression of KAT6B.Then the relation between KAT6B expression and clinicopathological parameters was analyzed by chi-square test, and the overall survival analysis was conducted by Kaplan-Meier survival method. In addition, based on the Oncomine expression array online and the UALCAN database, we compared KAT6B expression differences between normal liver tissues and HCC tissues more broadly. Results: Compared with normal tissues, KAT6B expression was significantly lower in HCC tissues. Low KAT6B expression was found to be related to gender, AFP level, and tumor size. According to the online database, KAT6B expression was found to be decreased in HCC tissues and high in normal tissues. Conclusions: Lower expression of KAT6B is associated with poor prognosis of HCC, and KAT6B may be a potential tumor suppressor in liver cancer.

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Overexpression of PSF1 is correlated with poor prognosis in hepatocellular carcinoma patients

The International Journal of Biological Markers ◽

10.5301/jbm.5000105 ◽

2015 ◽

Vol 30 (1) ◽

pp. 56-64 ◽

Cited By ~ 9

Author(s):

Lei Zhou ◽

Xue-jun Sun ◽

Chang Liu ◽

Qi-fei Wu ◽

Ming-hui Tai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Normal Liver ◽

Down Regulation ◽

New Therapeutic Approaches ◽

Nontumor Tissue ◽

Close Relationship ◽

Cell Invasiveness ◽

Interfering Rna

Background PSF1 is a subunit of the GINS complex which is essential for establishment of DNA replication forks, and the progression of the replisome. Previous studies have shown a close relationship between PSF1 and cell cycle in the proliferation of immature cells as well as tumors. The purpose of this study was to measure PSF1 expression in hepatocellular carcinoma (HCC) tissues, and determine the effects of down-regulation of PSF1 expression on growth of cancer cells, the cell cycle, apoptosis and cell invasiveness. Methods Samples from 137 HCC tissues, 67 from adjacent nontumor tissue and 15 from normal liver were studied using immunochemistry. The HepG2 cell line was used for knockdown experiments studied by RT-PCR, real-time PCR, apoptosis and invasiveness assays. Results PSF1 was overexpressed in HCC tissues compared with normal liver tissues. High PSF1 expression correlated with a more aggressive phenotype as well as worse prognosis in HCC patients. Knockdown of PSF1 expression using small interfering RNA (siRNA) slowed the growth of cancer cell by suppressing the cell cycle progression as well as increasing apoptosis, especially early apoptosis. In addition, the invasiveness of HepG2 cells was also reduced by down-regulation of PSF1. Conclusions These results suggest that the inhibition of PSF1 might provide new therapeutic approaches for HCC.

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Association of Low Zinc Finger Antiviral Protein Expression with Progression and Poor Survival of Patients with Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000493285 ◽

2018 ◽

Vol 49 (3) ◽

pp. 1048-1059

Author(s):

Ying Liu ◽

Cheng Hu ◽

Wen-Bo Zhu ◽

Wen-Xiong Xu ◽

Zhan-Yi Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Expression ◽

Cell Lines ◽

Zinc Finger ◽

Clinical Stage ◽

Human Hepatocytes ◽

Antiviral Protein ◽

Normal Tissues ◽

Normal Human ◽

Hcc Cells

Background/Aims: Zinc finger antiviral protein (ZAP) has been reported to be expressed in hepatocellular carcinoma (HCC), and ZAP expression is associated with apoptotic signaling in cancer cells. This study aimed at investigating the expression of ZAP in HCC cells and its significance in clinical pathology. Methods: Real-time quantitative PCR and western blot assays were employed to detect ZAP RNA and protein expression in normal human hepatocytes, HCC cells, and five primary HCC cell lines. Immunohistochemistry was performed to detect ZAP expression in 147 paraffin-embedded HCC tissues and adjacent normal tissues. The clinical significance of ZAP expression was analyzed in tissue samples from patients with or without infection by hepatitis B virus (HBV). Results: ZAP expression in HCC cells and human primary HCC cell lines was significantly lower than that of normal human hepatocytes. Among 147 HCC samples, ZAP expression was lower in HCC tissues than in adjacent normal tissues for 107 (77.0%) samples. In patients with HCC and HBV infection, ZAP expression was related to pathological grade (P < 0.05); in HBV-negative patients with HCC, ZAP expression was associated with tumor size (P < 0.05) and clinical stage (P < 0.05). The overall survival time in patients with low ZAP expression was significantly shorter than survival times of those with high ZAP expression (P < 0.05), especially for patients with moderately to well-differentiated HCC (Grade 1–2) and HCC at stage T1 and T2 (P < 0.05). Cox multivariate analysis showed that ZAP expression was an independent predictor of survival of patients with HCC (P < 0.01). Conclusion: Low ZAP expression is closely associated with disease progression and poor prognosis for patients with HCC.

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Ultrasonography in the study of hepatocellular carcinoma in woodchucks chronically infected with WHV

Laboratory Animals ◽

10.1258/002367703766453083 ◽

2003 ◽

Vol 37 (3) ◽

pp. 233-240 ◽

Cited By ~ 8

Author(s):

D. Lisi ◽

L. A. Kondili ◽

M. T. Ramieri ◽

R. Giuseppetti ◽

R. Bruni ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis Virus ◽

Early Stage ◽

False Negative ◽

Normal Liver ◽

Liver Parenchyma ◽

Microscopical Examination ◽

Negative Results ◽

Chronic Hepatitis B Virus ◽

Us Findings

The woodchuck hepatitis virus (WHV)/woodchuck system is studied as animal model of human hepatocellular carcinoma (HCC) induced by chronic hepatitis B virus infection. The aim of the present study was the evaluation of ultrasound (US) liver examination in woodchuck as a routine method to detect HCC nodules and to follow their growth. Sixteen woodchucks were included in the study. US liver examination was carried out in all animals using a 5 MHz convex scanner. Macroscopic and microscopic examinations were performed to evaluate the US findings. The lower limit of nodule detection by US examination was a diameter of 5 mm. Macroscopic and microscopic examinations confirmed US findings in 14 of 16 animals (86.6%). No false negative results were obtained. Increase of nodule size was faster in the early phase of tumour growth. Small nodules (16 ± 5 mm) appeared as hypoechoic lesions with well-defined margins and homogeneous structure. Large nodules (42 ± 19 mm) appeared as hyperechoic lesions with irregular margins, heterogeneous or of mixed pattern; microscopical examination showed different degrees of necrosis, inflammation and fibrosis inside these latter neoplasms. The hepatitis reaction was conspicuously more severe around HCC nodules. No fibrosis and/or cirrhosis were found in normal liver parenchyma surrounding tumour nodules. On the whole, US appears to be helpful in the diagnosis of woodchuck HCC even at an early stage. Serial US evaluation can be used to study the growth rate of tumour nodules during natural history or experimental HCC treatments in woodchuck.

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High mRNA Expression of CENPL and Its Significance in Prognosis of Hepatocellular Carcinoma Patients

Disease Markers ◽

10.1155/2021/9971799 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Zhongyuan Cui ◽

Lijia Xiao ◽

Fengsui Chen ◽

Jielong Wang ◽

Haiyan Lin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Mrna Expression ◽

Hepatitis Virus ◽

Progression Free Survival ◽

Normal Liver ◽

Mrna Levels ◽

Free Survival ◽

Centromere Proteins ◽

Tumor Stages

Centromere proteins (CENPs) are the main constituent proteins of kinetochore, which are essential for cell division. In recent years, several studies have revealed that several CENPs were aberrantly expressed in hepatocellular carcinoma (HCC). However, numerous centromere proteins have not been studied in HCC. In this study, we used databases of Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Kaplan-Meier Plotter, cBioPortal, the Human Protein Atlas (HPA), and TIMER (Tumor Immune Estimation Resource) and immunohistochemical staining of clinical specimens to investigate the expression of 15 major centromere proteins in HCC to evaluate their potential prognostic value. We found that the mRNA levels of 4 out of 15 centromere proteins (CENPL, CENPQ, CENPR, and CENPU) were significantly higher in HCC than in normal tissues, and their mRNA levels were associated with the tumor stages ( p values < 0.01). Patients with higher mRNA levels of CENPL had poorer overall survival, progression-free survival, relapse-free survival, and disease-specific survival ( p values < 0.05). Furthermore, the higher levels of CENPL mRNA were associated with worse overall survival in males without hepatitis virus infection ( p values < 0.05). The protein expression level of CENPL in human HCC tissue was higher than that in normal liver tissue. In addition, the expression of CENPL was positively correlated with the levels of the tumor-infiltrating lymphocytes. The results suggest that the high mRNA expression of CENPL may be a potential predictor of prognosis in HCC patients.

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miR-139-5p Loss-Mediated WTAP Activation Contributes to Hepatocellular Carcinoma Progression by Promoting the Epithelial to Mesenchymal Transition

Frontiers in Oncology ◽

10.3389/fonc.2021.611544 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wenli Liu ◽

Xuewei Gao ◽

Xiaolong Chen ◽

Na Zhao ◽

Ying Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial To Mesenchymal Transition ◽

Wilms Tumor ◽

Clinical Stage ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Expression Levels ◽

Normal Tissues ◽

Proliferation And Invasion

Background: Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms' tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. However, the potential role of WTAP in HCC remains largely unknown.Methods: The expression levels of WTAP in human HCC tissues were determined by the western blotting and immunohistochemical (IHC) staining. A correlation between the WTAP expression, clinicopathological features, and the HCC prognosis was analyzed. The WTAP expression was silenced by short hairpin RNA (shRNA), and effects of the knockdown of WTAP on the proliferation and invasion of HCC cells were assessed. The microRNAs (miRNAs) involved in the regulation of the WTAP expression were identified by a bioinformatics analysis and further confirmed by in vitro assays.Results: The expression levels of WTAP in liver cancer tissues were significantly elevated and compared with those in the adjacent normal tissues and significantly correlated with the clinical stage and prognosis in patients with HCC. Further investigation revealed that the knockdown of WTAP drastically suppressed HCC cell proliferation and invasion abilities. Luciferase reporter assay and validation experiments confirmed that WTAP was a direct target of miR-139-5p. Moreover, the overexpression of WTAP could partly abolish the inhibitory effects of miR-139-5p on the HCC cell growth and invasion. Mechanistically, we revealed that the miR-139-5p/WTAP axis regulated the HCC progression by controlling the epithelial to mesenchymal transition (EMT).Conclusions: In summary, the results indicate that WTAP is a potential oncogene in HCC and miR-139-5p negatively regulates the WTAP expression. MiR-139-5p/WTAP can be utilized as a potential therapeutic target for HCC.

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