|
1
|
Hu Y, Huang Y, Xie X, Li L, Zhang Y, Zhang X. ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling. Cancer Cell Int 2023; 23:205. [PMID: 37716993 PMCID: PMC10505330 DOI: 10.1186/s12935-023-03053-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/03/2023] [Indexed: 09/18/2023] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) possesses the high mortality in cancers worldwide. Nevertheless, the concrete mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is associated with a poor clinical prognosis, which could boost the proliferation of HCC. METHODS Immunohistochemistry and western blotting were used to detect the expression level of ARF6 in HCC tissues. We analyzed the clinical significance of ARF6 in primary HCC patients. We estimated the effect of ARF6 on tumor proliferation with in vitro CCK8, colony formation assay, and in vivo nude mouse xenograft models. Immunofluorescence was conducted to investigate the ARF6 localization. western blotting was used to detect the cell cycle-related proteins with. Additionally, we examined the correlation between ARF6 and STAT3 signaling in HCC with western blotting, immunohistochemistry and xenograft assay. RESULTS ARF6 was upregulated in HCC tissues compared to adjacent normal liver tissues. The increased expression of ARF6 correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 obviously promoted HCC cell proliferation, colony formation, and cell cycle progression. In vivo nude mouse xenograft models showed that ARF6 enhanced tumor growth. Furthermore, ARF6 activated the STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 level in HCC tissues. Furthermore, after intervening of STAT3, the effect of ARF6 on tumor-promoting was weakened, which demonstrated ARF6 functioned through STAT3 signaling in HCC. CONCLUSIONS Our results indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as potential prognostic and therapeutic targets for HCC patients.
Collapse
Affiliation(s)
- Yabing Hu
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Laboratory Medicine, Wuhan No.1 Hospital, Wuhan, China
| | - Yongchu Huang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohang Xie
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longshan Li
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaochao Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
2
|
Zhang HY, Zong RQ, Wu FX, Li YR. Bioinformatics Analysis Identifies ASCL1 as the Key Transcription Factor in Hepatocellular Carcinoma Progression. DISEASE MARKERS 2023; 2023:3560340. [PMID: 36755802 PMCID: PMC9902118 DOI: 10.1155/2023/3560340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/12/2022] [Accepted: 11/25/2022] [Indexed: 01/31/2023]
Abstract
Methods Differentially transcription factors (DETFs) were identified from differentially expressed genes (DEGs) in GSE62232 and transcription factors. Then, they were analyzed by regulatory networks, prognostic risk model, and overall survival analyses to identify the key DETF. Combined with the regulatory networks and binding site analysis, the target mRNA of key DETF was determined, and its prognostic value in HCC was evaluated by survival, clinical characteristics analyses, and experiments. Finally, the expressions and functions of the key DETF on the DEmRNAs were investigated in HCC cells. Results Through multiple bioinformatics analyses, ASCL1 was identified as the key DETF, and SLC6A13 was predicted to be its target mRNA with the common binding site of CCAGCAACTGGCC, both downregulated in HCC. In survival analysis, high SLC6A13 was related to better HCC prognosis, and SLC6A13 was differentially expressed in HCC patients with clinical characteristics. Furthermore, cell experiments showed the mRNA expressions of ASCL1 and SLC6A13 were both reduced in HCC, and their overexpressions suppressed the growth, invasion, and migration of HCC cells. Besides, over-ASCL1 could upregulate SLC6A13 expression in HCC cells. Conclusion This study identifies two suppressor genes in HCC progression, ASCL1 and SLC6A13, and the key transcription factor ASCL1 suppresses HCC progression by targeting SLC6A13 mRNA. They are both potential treatment targets and prognostic biomarkers for HCC patients, which provides new clues for HCC research.
Collapse
Affiliation(s)
- Hong-yan Zhang
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Rui-qing Zong
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fei-xiang Wu
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yi-ran Li
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| |
Collapse
|
|
3
|
Chen Y, Song S, Zhang L, Zhang Y. Circular RNA hsa_circ_0091579 facilitates the Warburg effect and malignancy of hepatocellular carcinoma cells via the miR-624/H3F3B axis. Clin Transl Oncol 2021; 23:2280-2292. [PMID: 33934291 DOI: 10.1007/s12094-021-02627-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/16/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. It has been reported that circular RNA hsa_circ_0091579 (circ_0091579) is involved in HCC progression. Nevertheless, the molecular mechanism by which circ_0091579 modulates HCC advancement is indistinct. METHODS The expression of circ_0091579, microRNA (miR)-624, and H3 histone family member 3B (H3F3B) mRNA was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of HCC cells were analyzed using an extracellular flux analyzer. Adenosine triphosphate (ATP) level was evaluated using a commercial kit. Cell migration, invasion, and apoptosis were assessed by wound-healing, transwell, or flow cytometry assay. The relationship between miR-624 and circ_0091579 or H3F3B was verified using luciferase reporter assay and/or RNA immunoprecipitation (RIP) assay. H3F3B protein level was detected by western blotting. RESULTS Circ_0091579 was upregulated in HCC tissues and cells. Circ_0091579 inhibition decreased xenograft tumor growth in vivo and repressed Warburg effect, migration, invasion, and induced apoptosis of HCC cells in vitro. MiR-624 was downregulated, while H3F3B was upregulated in HCC tissues and cells. Circ_0091579 acted as a miR-624 sponge and regulated H3F3B expression by adsorbing miR-624. MiR-624 inhibitor reversed circ_0091579 downregulation-mediated effects on the Warburg effect and malignant behaviors of HCC cells. H3F3B overexpression reversed the repressive impact of miR-624 mimic on the Warburg effect and malignancy of HCC cells. CONCLUSIONS Circ_0091579 accelerated Warburg effect and tumor growth via upregulating H3F3B via adsorbing miR-624 in HCC, providing evidence to support the involvement of circ_0091579 in the progression of HCC.
Collapse
Affiliation(s)
- Y Chen
- Department of Hepatobiliary Surgery, Tengzhou Central People's Hospital of Shandong Province, Tengzhou, Shandong, China
| | - S Song
- Department of Medical, Yantai Hospital of Traditional Chinese Medicine, Antai, Shandong, China
| | - L Zhang
- Department of Hepatobiliary Vascular Surgery, Qingdao Central Hospital, Qingdao, Shandong, China
| | - Y Zhang
- The Operating Room, Zaozhuang Hospital of Traditional Chinese Medicine, 2666 Taihang Shan Road, Xuecheng District, Zaozhuang, 277000, Shandong, China.
| |
Collapse
|
|
4
|
Jin M, Yu Q, Liu Y, Xu W, Fu X, Ji B. Safety and Efficacy of Physical Thermal Ablation Combined Sorafenib for Hepatocellular Carcinoma: A Meta-analysis. J Clin Transl Hepatol 2021; 9:149-159. [PMID: 34007796 PMCID: PMC8111114 DOI: 10.14218/jcth.2020.00125] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 02/09/2021] [Accepted: 02/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIMS To compare the efficacy and safety of physical thermal ablation (PTA), including radiofrequency ablation (RFA) and microwave ablation (MWA), combined with sorafenib and physical thermal ablation alone for the control and treatment of hepatocellular carcinoma (HCC) according to the available literature. METHODS Comprehensive searches were performed on PubMed, Embase, CNKI, the Cochrane Library, China Biomedical Literature Database (known as CBM), Weipu Journal, and Wanfang Database. Meta-analysis was performed using Revman 5.3 software. RESULTS A total of 15 studies, consisting of 2,227 HCC patients, were selected and included in this meta-analysis. Compared with the RFA-alone group, the patients in the RFA+sorafenib group had longer 1-, 2-, and 3-year overall survival (all p<0.05), better overall efficacy (p<0.0001), longer radiofrequency interval (p<0.001), and lower 2-year recurrence rate (p=0.02). The 1-year overall survival (p=0.003) and overall efficacy (p=0.002) of the MWA+sorafenib group were also higher than those of the MWA-alone group. The incidences of adverse reactions in the RFA+sorafenib group, such as hand-foot skin reactions (p<0.001), diarrhea and constipation (p=0.0001), hypertension (p=0.009), and alopecia (p<0.001), were significantly higher than those in the RFA-alone group. CONCLUSIONS RFA or MWA combined with sorafenib has produced a better therapeutic effect on HCC than physical thermal ablation alone; however, adverse reactions have been obvious. It is necessary to evaluate the safety of combination therapy, and pay close attention to the adverse reactions that develop in patients.
Collapse
Affiliation(s)
- Mengdi Jin
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China
| | - Qiong Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Weiling Xu
- Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Xueqi Fu
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
- Correspondence to: Bai Ji, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, Jilin 130021, China. ORCID: https://orcid.org/0000-0003-1143-1749. Tel: +86-431-81875160, E-mail:
| |
Collapse
|
|
5
|
Constructing the Logical Regression Model to Predict the Target of Jianpi Jiedu Decoction in the Treatment of Hepatocellular Carcinoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:8859558. [PMID: 33424998 PMCID: PMC7781689 DOI: 10.1155/2020/8859558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/23/2020] [Accepted: 12/14/2020] [Indexed: 01/04/2023]
Abstract
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.
Collapse
|
|
6
|
Sojoodi M, Wei L, Erstad DJ, Yamada S, Fujii T, Hirschfield H, Kim RS, Lauwers GY, Lanuti M, Hoshida Y, Tanabe KK, Fuchs BC. Epigallocatechin Gallate Induces Hepatic Stellate Cell Senescence and Attenuates Development of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2020; 13:497-508. [PMID: 32253266 DOI: 10.1158/1940-6207.capr-19-0383] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/02/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with diethylnitrosamine at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well-tolerated in diethylnitrosamine-injured rats and was associated with improved serum liver markers including alanine transaminase, aspartate transaminase, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of diethylnitrosamine-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells and induction of the senescence-associated secretory phenotype. In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and antifibrotic effects in a rat diethylnitrosamine liver injury model.
Collapse
Affiliation(s)
- Mozhdeh Sojoodi
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
| | - Lan Wei
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Derek J Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Suguru Yamada
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Tsutomu Fujii
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Hadassa Hirschfield
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Rosa S Kim
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Gregory Y Lauwers
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
7
|
Li H, Wang X, Tang J, Zhao H, Duan M. Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma. Oncol Lett 2019; 18:6214-6220. [PMID: 31788097 DOI: 10.3892/ol.2019.10974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
The present study aimed to investigate the expression of elongation of very long-chain fatty acids family member 6 (ELOVL6) in hepatocellular carcinoma (HCC) tissues, and to determine its role in the development of HCC. A total of 377 HCC specimens were collected for tissue microarray and immunohistochemistry analyses. The ELOVL6 IHC score for HCC tissues was 0.97±0.71, which was significantly lower than that of the matched adjacent normal tissues (1.32±0.68; P<0.001). Patients with low levels of ELOVL6 expression were older (P=0.014) and possessed larger sized tumors (P=0.039) than patients with high expression levels. Additionally, Kaplan-Meier analysis revealed that patients with low ELOVL6 expression levels also had significantly poorer overall (P<0.001) and disease-free (P=0.029) survival times, and a greater probability of recurrence. The tumor size, tumor-node-metastasis (TNM) stage, vascular invasion and ELOVL6 expression were all shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis revealed that vascular invasion (P<0.001), TNM stage (P<0.001) and ELOVL6 expression (P=0.001) were independent prognostic variables for overall survival. In addition, vascular invasion (P=0.032) and ELOVL6 expression (P=0.041) were independent risk factors for disease-free survival, and vascular invasion (P=0.019) and ELOVL6 expression (P=0.045) were independent risk factors associated with HCC recurrence. The present study revealed that in patients with HCC, ELOVL6 expression level was reduced in HCC tissues, and that higher ELOVL6 expression levels correlated with longer survival times. This indicates that ELOVL6 may serves as an independent marker of poor patient outcome.
Collapse
Affiliation(s)
- Hui Li
- Invasive Technology Department, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Xianling Wang
- Invasive Technology Department, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Jun Tang
- Invasive Technology Department, Shandong Medical Imaging Research Institute, Jinan, Shandong 250021, P.R. China
| | - Haibo Zhao
- Invasive Technology Department, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Min Duan
- Department of Physical Examination, Jining First People's Hospital, Jining, Shandong 272000, P.R. China
| |
Collapse
|
|
8
|
Lu JB, Cai SH, Pan YH, Yun JP. Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes. Cancer Manag Res 2018; 10:6275-6284. [PMID: 30538573 PMCID: PMC6260128 DOI: 10.2147/cmar.s181555] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective Hepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear. Subjects and methods A total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed. Results The EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan-Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors. Conclusion Our data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.
Collapse
Affiliation(s)
- Jia-Bin Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China,
| | - Shao-Hang Cai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ying-Hua Pan
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China,
| |
Collapse
|
|
9
|
Retinoblastoma Binding Protein 5 Correlates with the Progression in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1073432. [PMID: 30533424 PMCID: PMC6247687 DOI: 10.1155/2018/1073432] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/16/2018] [Accepted: 09/24/2018] [Indexed: 01/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancy tumors with insidious onset, rapid development and metastasis, and poor prognosis. Therefore, it is necessary to understand molecular mechanisms of HCC and identify clinically useful biomarkers for it. This study aimed to investigate the role of retinoblastoma binding protein 5 (RBBP5) in HCC. The expression level of RBBP5 was examined by immunohistochemistry and western blot. The effect of RBBP5 on cell cycle, proliferation, apoptosis, and drug sensitivity was analyzed. RBBP5 was significantly upregulated in HCC tissues and cells. High RBBP5 expression was significantly associated with elevated level of AFP, advanced TNM stage, high Ki-67 expression, larger tumor size, and poor prognosis. Knockdown of RBBP5 significantly inhibited proliferation of HCC cells through cell cycle arrest. In addition, inhibition of RBBP5 increased the sensitivity of HCC cells to doxorubicin. In conclusion, our findings suggest that RBBP5 plays an important role in the progression of HCC and may serve as a novel biomarker and potential therapeutic target for HCC.
Collapse
|
|
10
|
Xue JY, Huang C, Wang W, Li HB, Sun M, Xie M. HOXA11-AS: a novel regulator in human cancer proliferation and metastasis. Onco Targets Ther 2018; 11:4387-4393. [PMID: 30100744 PMCID: PMC6067783 DOI: 10.2147/ott.s166961] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multiple studies have demonstrated that lncRNAs extensively participate in human cancer proliferation and metastasis. Epigenetic modification, transcriptional and posttranscriptional regulatory mechanisms are involved in lncRNA-led tumorigenesis and transfer. Recently, a novel identified homeobox (HOX) A11 antisense lncRNA, HOXA11-AS, 1,628 bp in length, has been excessively highlighted to be an essential initiator and facilitator in the process of malignant tumor proliferation and metastasis. As found in many reports, HOXA11-AS can not only act as a molecular scaffold of PRC2, LSD1 and DNMT1 to epigenetically modify chromosomes in the nucleus but also occur as ceRNA competitively sponging miRNAs in the cytoplasm. Furthermore, HOXA11-AS may function as a potential biomarker for cancer diagnosis and prognosis. In this review, we summarize the evolvement and mechanisms of HOXA11-AS in proliferation and metastasis of various human cancers.
Collapse
Affiliation(s)
- Jiang-Yang Xue
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Chao Huang
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China,
| | - Wei Wang
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Hai-Bo Li
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Ming Sun
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA,
| | - Min Xie
- Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China,
| |
Collapse
|
|
11
|
Long non-coding RNA FEZF1-AS1 promotes cell invasion and epithelial-mesenchymal transition through JAK2/STAT3 signaling pathway in human hepatocellular carcinoma. Biomed Pharmacother 2018; 106:134-141. [PMID: 29957463 DOI: 10.1016/j.biopha.2018.05.116] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/21/2018] [Accepted: 05/23/2018] [Indexed: 01/05/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as key regulators in the development of hepatocellular carcinoma (HCC). In the present study, we explored the expression profile and biological role of lncRNA FEZF1-AS1 in HCC. We observed remarkable upregulation of FEZF1-AS1 in HCC tissues and cell lines, and high FEZF1-AS1 expression was correlated with aggressive phenotypes and poor prognosis of HCC patients. Furthermore, we found that FEZF1-AS1 knockdown markedly inhibited the proliferation of HCC cells by inducing cell cycle arrest. In addition, FEZF1-AS1 knockdown suppressed HCC tumor growth in vivo. Moreover, FEZF1-AS1 knockdown inhibited the migration and invasion of HCC cells through suppression of JAK2/STAT3 signaling-mediated epithelial-mesenchymal transition (EMT). In conclusion, the present study for the first time demonstrated that FEZF1-AS1 serves as an oncogenic lncRNA in human HCC and implicated FEZF1-AS1 as a valuable therapeutic target for HCC treatment.
Collapse
|
|
12
|
Zhang W, Qian S, Yang G, Zhu L, Zhou B, Wang J, Liu R, Yan Z, Qu X. MicroRNA-199 suppresses cell proliferation, migration and invasion by downregulating RGS17 in hepatocellular carcinoma. Gene 2018; 659:22-28. [PMID: 29559347 DOI: 10.1016/j.gene.2018.03.053] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/14/2018] [Accepted: 03/16/2018] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis and shows rapid progression. MicroRNAs (miRNAs) play important roles in carcinogenesis and tumor progression. Regulators of G-protein signaling (RGS) are critical for defining G-protein-dependent signal fidelity. RGS17 plays an important role in the regulation of cancer cell proliferation, migration and invasion. Here, we showed that miR-199 was downregulated in a hepatocarcinoma cell line. Overexpression of miR-199 significantly suppressed HCC cell proliferation, migration, and invasion in vitro. RGS17 overexpression promoted HCC cell proliferation, migration, and invasion, and reversed the miR-199 mediated inhibition of proliferation, migration, and invasion. Dual-fluorescence reporter experiments confirmed that miR-199 downregulated RGS17 by direct interaction with the 3'-UTR of RGS17 mRNA. In vivo studies showed that miR-199 overexpression significantly inhibited the growth of tumors. Taken together, the results suggested that miR-199 inhibited tumor growth and metastasis by targeting RGS17.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Sheng Qian
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Guowei Yang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Liang Zhu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Bo Zhou
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Jianhua Wang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Rong Liu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Zhiping Yan
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| | - Xudong Qu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai 20032, China..
| |
Collapse
|
|
13
|
Rastegar M, Marjani HA, Yazdani Y, Shahbazi M, Golalipour M, Farazmandfar T. Investigating Effect of Rapamycin and Metformin on Angiogenesis in Hepatocellular Carcinoma Cell Line. Adv Pharm Bull 2018; 8:63-68. [PMID: 29670840 PMCID: PMC5899784 DOI: 10.15171/apb.2018.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 02/08/2018] [Accepted: 02/10/2018] [Indexed: 12/12/2022] Open
Abstract
Purpose: Human hepatocellular carcinoma is one of the most common causes of death in the world. Metformin and rapamycin may decrease the expression of VEGF protein and subsequently angiogenesis. The purpose of this study was to evaluate the effect of these two drugs on expression of VEGF protein and the cell proliferation in the hepatocellular carcinoma cell line (ATCC HB-8065). Methods: HepG2 was cultured in RPMI-1640 medium at 37°C for 48h as a pre-culture and then treated by different concentrations of metformin (0, 5, 10 and 20 mM) and rapamycin (0, 5, 10 and 20 nM) at different times (12, 24 and 48 h). Cell viability was assessed by the MTT assay. Total RNA was extracted by the Trizol reagent and VEGF gene expression was analyzed by quantitative real-time PCR and was calculated by 2–ΔCt method. The VEGF protein level was determined by Elisa assay. Finally, Apoptosis index was calculated by DAPI staining. Results: Metformin and rapamycin significantly decrease cancer cells viability (p<0.05). Rapamycin but not metformin decreases VEGF gene expression in HepG2 cells. Metformin and rapamycin significantly induce cell apoptosis in hepatocellular carcinoma (HCC) cells. Conclusion: Metformin and rapamycin have an anti-tumor effect on HCC. According to our data rapamycin might have an anti-angiogenesis effect via inhibition of VEGF expression. Our results provide an insight into future clinical strategies to improve chemotherapy outcomes in HCC.
Collapse
Affiliation(s)
- Mandana Rastegar
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Haji-Amin Marjani
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Yaghoub Yazdani
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Masoud Golalipour
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Touraj Farazmandfar
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| |
Collapse
|
|
14
|
Bryce K, Tsochatzis EA. Downstaging for hepatocellular cancer: harm or benefit? Transl Gastroenterol Hepatol 2017; 2:106. [PMID: 29354763 DOI: 10.21037/tgh.2017.11.18] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022] Open
Abstract
Downstaging of hepatocellular carcinoma (HCC) to enable liver transplantation has become an area of intense interest and research. It may allow a curative option in patients outside widely accepted transplantation criteria, with outcomes that, in some studies, are comparable to transplantation for patients within criteria. There have been conflicting opinions on the best downstaging protocols, criteria for downstaging eligibility and for assessment of response. We therefore aimed to review the literature and evidence for downstaging, as well as considering its drawbacks. CONCLUSION Pooled analyses have suggested success in down staging in about half of patients treated, but with higher recurrence rates than patients initially within transplantation criteria. Studies with strict inclusion criteria and mandatory waiting time before transplantation reported survival equivalent to patients who did not require downstaging. In carefully selected patients, there is a role for down staging to provide the chance of transplantation and cure, with acceptable outcomes. Further multi center, well-designed studies are required to clarify who will mostly benefit. Until such data is available, downstaging criteria should be stated within transplantation programs and relevant decisions should be discussed by multidisciplinary teams.
Collapse
Affiliation(s)
- Kathleen Bryce
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| |
Collapse
|
|
15
|
Li J, Sun X, Fang J, Wang C, Han G, Ren W. Analysis of intrahepatic total HBV DNA, cccDNA and serum HBsAg level in Chronic Hepatitis B patients with undetectable serum HBV DNA during oral antiviral therapy. Clin Res Hepatol Gastroenterol 2017; 41:635-643. [PMID: 28438570 DOI: 10.1016/j.clinre.2017.03.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 01/23/2017] [Accepted: 03/15/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to investigate the relationship between intrahepatic cccDNA and serum HBsAg in chronic Hepatitis B (CHB) patients with undetectable serum HBV DNA during antiviral therapy. METHODS We investigated HBsAg serum levels and their relationship to intrahepatic total cccDNA and HBV DNA in CHB patients with undetectable serum HBV DNA during oral antiviral therapy. Intrahepatic cccDNA and HBV DNA quantitation were performed in the same needle biopsy material, while serum HBsAg, HBeAg and HBV DNA levels were measured in samples drawn on the day of the liver biopsy. RESULTS A total of 90 patients who had a liver biopsy were enrolled, including 80 patients with CHB and 10 patients with liver cirrhosis (LC). All the CHB patients were divided into HBeAg-positive and HBeAg-negative group. By using real-time PCR detection, we found that intrahepatic cccDNA and HBV DNA levels were higher in CHB patients than those in LC patients (Intrahepatic cccDNA: 6.15±1.19 vs. 6.12±0.36, HBV DNA: 7.26±0.49 vs. 5.59±0.45, both P<0.05). Intrahepatic cccDNA level was positively correlated with serum HBsAg in HBeAg-negative (r=0.66, P=0.02) and lower serum HBeAg (≤50S/CO) CHB patients (r=0.47, P=0.03), but not in higher serum HBeAg (>50S/CO) CHB patients (both P>0.05). In HBeAg negative patients, serum HBsAg level was correlated with intrahepatic total HBV DNA level (r=0.52, P=0.006). However, no relationship between HBsAg level and intrahepatic total HBV DNA level was found in HBeAg positive patients (both P>0.05). CONCLUSIONS Serum HBsAg can be used to predict intrahepatic cccDNA and HBV DNA level in CHB patients with low serum HBeAg statues, especially in HBeAg negative patients.
Collapse
Affiliation(s)
- Jie Li
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China; Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, United States.
| | - Xizhen Sun
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China.
| | - Jianting Fang
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China.
| | - Chuanxi Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China.
| | - Guoqing Han
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China.
| | - Wanhua Ren
- Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Ji'nan, Shandong 250021, China.
| |
Collapse
|
|
16
|
TNFAIP8 interacts with LATS1 and promotes aggressiveness through regulation of Hippo pathway in hepatocellular carcinoma. Oncotarget 2017; 8:15689-15703. [PMID: 28152516 PMCID: PMC5362516 DOI: 10.18632/oncotarget.14938] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 12/28/2016] [Indexed: 12/11/2022] Open
Abstract
Although TNFAIP8 overexpression has been implicated in several human cancers, its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. Our study demonstrated that TNFAIP8 overexpression in primary HCC samples correlated with TNM stage, recurrence, poor prognosis and served as an independent favorable prognostic factor. We further showed that TNFAIP8 upregulated cell proliferation, migration, invasion and xenograft tumor growth of HCC cells. In addition, TNFAIP8 overexpression inhibited YAP phosphorylation, increased its nuclear localization and stabilization, leading to upregulation of cyclin proteins, CTGF and cell proliferation. We also found that TNFAIP8 could interact with LATS1 and decreased its phosphorylation. Depletion of LATS1 and YAP by siRNA blocked the biological effects of TNFAIP8. Collectively, the present study provides a novel finding that TNFAIP8 promotes HCC progression through LATS1-YAP signaling pathway. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies.
Collapse
|
|
17
|
Zhang SG, Li YF, Zhao NN, Lai CC, Cheng SJ, Yan J, Zhang P, Wang Z, Wang XL, Yang PH. Decreased expression of long non-coding RNA LOC728290 in human hepatocellular carcinoma. Oncol Lett 2017; 14:4551-4556. [PMID: 29085452 PMCID: PMC5649533 DOI: 10.3892/ol.2017.6776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 06/02/2017] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. Despite progress in the diagnosis and treatment of HCC, prognosis remains unfavorable. Long non-coding RNAs (lncRNAs) are emerging as important factors in tumorigenesis and cancer progression; however, the underlying molecular mechanisms and clinical significance of lncRNAs in HCC remain largely unknown. The present study examined the expression pattern and clinical significance of a novel lncRNA, LOC728290, in HCC. Expression of LOC728290 was markedly decreased in HCC tissues compared with adjacent non-tumor liver tissues, as detected using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The area under the receiver operating characteristic curve for LOC728290 was 0.728. The expression of LOC728290 was associated with the level of α-fetoprotein and microvascular invasion. Furthermore, patients with low LOC728290 expression exhibited decreased recurrence-free survival times (P<0.05) compared with those with high LOC728290 expression. The results of the present study indicated that downregulation of LOC728290 in patients with HCC may be a powerful tumor biomarker, with potential clinical applications in prognosis as well as a therapeutic target.
Collapse
Affiliation(s)
- Shao-Geng Zhang
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Yu-Feng Li
- Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Na-Na Zhao
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Cheng-Cai Lai
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| | - Si-Jie Cheng
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Jin Yan
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Peirui Zhang
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Zhaohai Wang
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Xi-Liang Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| | - Peng-Hui Yang
- Department of Hepatobiliary, 302 Military Hospital of China, Beijing 100039, P.R. China.,State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| |
Collapse
|
|
18
|
Ying J, Yu X, Ma C, Zhang Y, Dong J. MicroRNA-363-3p is downregulated in hepatocellular carcinoma and inhibits tumorigenesis by directly targeting specificity protein 1. Mol Med Rep 2017; 16:1603-1611. [PMID: 28627662 DOI: 10.3892/mmr.2017.6759] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 03/23/2017] [Indexed: 11/05/2022] Open
Abstract
microRNAs exhibit important regulatory roles in tumorigenesis and tumor development, such as in hepatocellular carcinoma (HCC). The present study aimed to investigate the expression and functional roles of microRNA (miR)‑363‑3p in HCC. miR-363-3p expression levels in a number of HCC tissues and cell lines were measured by reverse transcription-quantitative PCR (RT‑qPCR). The effects of miR‑363‑3p expression on HCC cell proliferation, migration and invasion were exa-mined by MTT assay, Transwell migration and invasion assay, respectively. The effects of miR‑363‑3p on its downstream target gene, specificity protein 1 (SP1), were examined by bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blotting. An SP1 overexpression vector was subsequently transfected into HCC cells to assess any selective effects on miR‑363‑3p in modulating HCC. The results revealed that miR‑363‑3p expression levels were downregulated in both HCC tissues and cell lines, and this low expression level was correlated with tumor size, tumor‑node‑metastasis stage and venous infiltration in patients with HCC. Upregulation of miR‑363‑3p inhibited cell proliferation, migration and invasion in HCC cell cultures. In HCC cells transfected with an SP1 expression vector the miR‑363‑3p‑induced tumor suppressive roles on cell proliferation, migration and invasion were reversed. In conclusion, results from the present study indicated that miR‑363‑3p is a tumor suppressor in HCC and functions through a mechanism involving SP1, suggesting that miR‑363‑3p may be a potential new therapeutic target for the treatment of HCC.
Collapse
Affiliation(s)
- Jie Ying
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Xuechun Yu
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Chaojian Ma
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Yongqi Zhang
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| | - Jingwu Dong
- Department of Gastroenterology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, P.R. China
| |
Collapse
|
|
19
|
Liu X, Yu L, Han C, Lu S, Zhu G, Su H, Qin W, Liao X, Peng T. Polymorphisms of HLA-DQB1 predict survival of hepatitis B virus-related hepatocellular carcinoma patients receiving hepatic resection. Clin Res Hepatol Gastroenterol 2016; 40:739-747. [PMID: 27288300 DOI: 10.1016/j.clinre.2016.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 04/10/2016] [Accepted: 04/13/2016] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Human leukocyte antigen (HLA)-DQB1 genetic polymorphisms are associated with an increased risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). We aimed to evaluate the influence of genetic polymorphisms in HLA-DQB1 exon region and neighboring single nucleotide polymorphisms (SNPs rs9275572 and rs2244546) on survival of HBV-related HCC patients undergoing hepatic resection. METHODOLOGY All SNPs were genotyped by sequencing DNA isolated from tumor samples of 483 patients with HBV-related HCC. RESULTS We identified rs9275572 and HLA-DQB1 haplotype CCCCC (constituted by rs1130375C, rs12722107C, rs12722106C, rs36222416C and rs3189152C) were significantly associated with overall survival (OS) of HBV-related HCC patients (P=0.015 and 0.049, respectively), after adjusting for serum AFP level, the Barcelona Clinic Liver Cancer (BCLC) stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment. In stratified analyses, the AG/GG genotype of rs9275572 significantly decreased risk of death among patients with younger age, serum AFP levels ≥400ng/mL, tumor size ≥10cm, BCLC stage A and radical hepatic resection. HLA-DQB1 haplotype CCCCC was significantly protective for male patients, patients with serum AFP levels <400ng/mL, tumor size ≥10cm, BCLC stage B/C, postoperative adjuvant TACE/TAC/TAE, radical hepatic resection and patients with adjuvant antiviral treatment. Moreover, gene-dosage effects were also observed, patients with SNP rs9275572 AG/GG genotypes and Block2 CCCCC haplotype had a decreased risk of death compared to others after adjusting for serum AFP level, BCLC stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment (adjusted HR=0.38, 95% CI=0.20-0.73, P=0.004). CONCLUSIONS The AG/GG genotype of rs9275572 and HLA-DQB1 Block2 CCCCC haplotype may have protective effects in HBV-related HCC patients receiving hepatic resection.
Collapse
Affiliation(s)
- Xiaoguang Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Long Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Sichong Lu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Hao Su
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China.
| |
Collapse
|
|
20
|
Xiao Q, Fu B, Chen P, Liu ZZ, Wang W, Ye Q. Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2016; 95:e5609. [PMID: 27977601 PMCID: PMC5268047 DOI: 10.1097/md.0000000000005609] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND To assess the association between tumor necrosis factor-alpha (TNF-α) G308A, G238A and C863T polymorphisms and hepatitis B virus related hepatocellular carcinoma (HBV-HCC) susceptibility. METHODS We interrogated the databases of Pubmed, Sciencedirect and Viley online library up to March 8, 2016. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated in a fixed-effects model or a random-effects model when appropriate. RESULTS In total, 12 case-control studies which containing 1580 HBV-HCC cases, 2033 HBV carrier controls, 395 HBV spontaneously recovered (SR) controls and 1116 healthy controls were included. Compared with GG genotype, the genotypes GA/AA of G308A were associated with a significantly increased HBV-HCC risk when the controls were all healthy individuals (AA vs. GG, OR 2.483, 95%CI 1.243 to 4.959; GA vs. GG, OR 1.383, 95%CI 1.028 to 1.860; GA/AA vs. GG, OR 1.381, 95%CI 1.048 to 1.820). Meanwhile, only the AA vs. GG model of G238A and HBV-HCC showed a statistic significance when the controls were healthy individuals (OR 4.776, 95%CI 1.280 to 17.819). CT genotype of TNF-α C863T could increase HBV-HCC risk whenever the controls were healthy individuals, HBV carriers or HBV recovers. CONCLUSION This meta-analysis shows that AA genotype in TNF-α G308A and TNF-α G238A and CT genotype in TNF-α C863T may increase HBV-HCC risk. Therefore, HBV infection seemed to be a more important factor for tumorigenesis of HCC than genetic predisposition in G308A of TNF-α, and interaction between TNF-α C863T polymorphisms and HBV infection might be associated with increased HCC risk.
Collapse
Affiliation(s)
- Qi Xiao
- Department of Transplant Surgery, The Third Xiangya Hospital, Central South University, Changsha
| | - BiQi Fu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang
| | - Ping Chen
- Department of Urinary Surgery, Zhongnan Hospital of Wuhan University
| | - Zhong Zhong Liu
- Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, P.R. China
| | - Wei Wang
- Department of Transplant Surgery, The Third Xiangya Hospital, Central South University, Changsha
| | - QiFa Ye
- Department of Transplant Surgery, The Third Xiangya Hospital, Central South University, Changsha
- Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, P.R. China
| |
Collapse
|
|
21
|
Liu J, Zong G, Zhang C, Li C, Chen X, Zhang Y. Anxiety and serum catecholamines as predictors of survival and recurrence in hepatocellular carcinoma. Psychooncology 2016; 26:1347-1353. [PMID: 27862617 DOI: 10.1002/pon.4305] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 10/23/2016] [Accepted: 10/31/2016] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Increasing evidence suggests that psychological factors are involved in tumor progression. This study investigated the influence of anxiety and serum catecholamines (CAs) on the prognosis of hepatocellular carcinoma (HCC). METHOD We enrolled 110 HCC patients who underwent tumor resection at the Affiliated Hospital of Nantong University, China, in this long-term investigation between 2005 and 2009. We evaluated anxiety using the Hamilton Anxiety Rating Scale (HAMA) and analyzed CA levels using an ELISA kit. We then assessed the association of each of them with overall survival (OS) and time to recurrence (TTR), as well as with other clinical variables. RESULTS The HAMA scores significantly correlated with metastasis (P = 0.015), hepatitis B surface antigens (HBsAg) (P = 0.045), and the tumor-node-metastasis stage (P = 0.032), whereas the CA levels also significantly associated with tumor differentiation (P < 0.001). Univariate and multivariate analyses revealed that HAMA scores and CA levels were significant predictors of OS and TTR in HCC patients, with high levels of each being strongly correlated with poor prognosis. CONCLUSION The HAMA scores and the CA levels were elevated in HCC patients and correlated with OS and TTR, suggesting that they are candidate prognostic markers of HCC.
Collapse
Affiliation(s)
- Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, People's Republic of China
| | - Guijuan Zong
- Department of Hepatic Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Chengliang Zhang
- Grade 14, Clinical Medicine Medical College, Nantong University, Nantong, Jiangsu Province, People's Republic of China
| | - Chunsun Li
- Department of Hepatic Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Xudong Chen
- Department of Hepatic Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yixin Zhang
- Department of Hepatic Oncology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| |
Collapse
|
|
22
|
Zhang X, Hua L, Yan D, Zhao F, Liu J, Zhou H, Liu J, Wu M, Zhang C, Chen Y, Chen B, Hu B. Overexpression of PCBP2 contributes to poor prognosis and enhanced cell growth in human hepatocellular carcinoma. Oncol Rep 2016; 36:3456-3464. [PMID: 27748915 DOI: 10.3892/or.2016.5167] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/06/2016] [Indexed: 11/06/2022] Open
|
|
23
|
Kuo KK, Lee KT, Chen KK, Yang YH, Lin YC, Tsai MH, Wuputra K, Lee YL, Ku CC, Miyoshi H, Nakamura Y, Saito S, Wu CC, Chai CY, Eckner R, Steve Lin CL, Wang SSW, Wu DC, Lin CS, Yokoyama KK. Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer. Stem Cells 2016; 34:2613-2624. [PMID: 27341307 DOI: 10.1002/stem.2447] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 05/09/2016] [Accepted: 06/06/2016] [Indexed: 12/12/2022]
Abstract
The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.
Collapse
Affiliation(s)
- Kung-Kai Kuo
- Department of Surgery.,Center of Stem Cell Research
| | | | | | - Ya-Han Yang
- Department of Surgery.,Graduate Institute of Medicine.,Center of Stem Cell Research
| | | | | | | | | | | | - Hiroyuki Miyoshi
- Department of Physiology, Keio University School of Medicine, Shinanomachi, Tokyo, 160-8582, Japan
| | | | - Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita, Tochigi, 329-1571, Japan
| | | | | | - Richard Eckner
- Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
| | | | - Sophie S-W Wang
- Department of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.,Center of Stem Cell Research
| | - Deng-Chyang Wu
- Department of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.,Center of Stem Cell Research.,Center of Infectious Diseases and Cancer Research.,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, 807, Taiwan
| | - Chang-Shen Lin
- Graduate Institute of Medicine.,Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine.,Center of Stem Cell Research.,Center of Infectious Diseases and Cancer Research.,Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.,Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, 763-2193, Japan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| |
Collapse
|
|
24
|
Ouyang J, Sun Y, Li W, Zhang W, Wang D, Liu X, Lin Y, Lian B, Xie L. dbPHCC: a database of prognostic biomarkers for hepatocellular carcinoma that provides online prognostic modeling. Biochim Biophys Acta Gen Subj 2016; 1860:2688-95. [PMID: 26940364 DOI: 10.1016/j.bbagen.2016.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/27/2016] [Accepted: 02/26/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a poor prognosis. For decades, more and more biomarkers were found to effect on HCC prognosis, but these studies were scattered and there were no unified identifiers. Therefore, we built the database of prognostic biomarkers and models for hepatocellular carcinoma (dbPHCC). METHODS dbPHCC focuses on biomarkers which were related to HCC prognosis by traditional experiments rather than high-throughput technology. All of the prognostic biomarkers came from literatures issued during 2002 to 2014 in PubMed and were manually selected. dbPHCC collects comprehensive information of candidate biomarkers and HCC prognosis. RESULTS dbPHCC mainly contains 567 biomarkers: 323 proteins, 154 genes, and 90 microRNAs. For each biomarker, the reference information, experimental conditions, and prognostic information are shown. Based on two available patient cohort data sets, an exemplified prognostic model was constructed using 15 phosphotransferases in dbPHCC. The web interface does not only provide a full range of browsing and searching, but also provides online analysis tools. dbPHCC is available at http://lifecenter.sgst.cn/dbphcc/ CONCLUSIONS dbPHCC provides a comprehensive and convenient search and analysis platform for HCC prognosis research. GENERAL SIGNIFICANCE dbPHCC is the first database to focus on experimentally verified individual biomarkers, which are related to HCC prognosis. Prognostic markers in dbPHCC have the potential to be therapeutic drug targets and may help in designing new treatments to improve survival of HCC patients. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
Collapse
Affiliation(s)
- Jian Ouyang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Ying Sun
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
| | - Wei Li
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Wen Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of People Libration Army General Hospital, Beijing 100048, China
| | - Dandan Wang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Xiangqiong Liu
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yong Lin
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Baofeng Lian
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China; Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200240, China.
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China.
| |
Collapse
|
|
25
|
Kim HS, Shen Q, Nam SW. Histone Deacetylases and Their Regulatory MicroRNAs in Hepatocarcinogenesis. J Korean Med Sci 2015; 30:1375-80. [PMID: 26425032 PMCID: PMC4575924 DOI: 10.3346/jkms.2015.30.10.1375] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 06/23/2015] [Indexed: 12/21/2022] Open
Abstract
A growing body of evidence suggests that epigenetic modifications are promising potential mechanisms in cancer research. Among the molecules that mediate epigenetic mechanisms, histone deacetylases (HDACs) are critical regulators of gene expression that promote formation of heterochromatin by deacetylating histone and non-histone proteins. Aberrant regulation of HDACs contributes to malignant transformation and progression in a wide variety of human cancers, including hepatocellular carcinoma (HCC), gastric cancer, lung cancer, and other cancers. Thus, the roles of HDACs have been extensively studied because of their potential as therapeutic targets. However, the underlying mechanism leading to deregulation of individual HDACs remains largely unknown. Some reports have suggested that functional microRNAs (miRNAs) modulate epigenetic effector molecules including HDACs. Here, we describe the oncogenic or tumor suppressive functions of HDAC families and their regulatory miRNAs governing HDAC expression in hepatocarcinogenesis.
Collapse
Affiliation(s)
- Hyung Seok Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Korea
| | - Qingyu Shen
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Functional RNomics Research Center, The Catholic University of Korea, Seoul, Korea
- Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
26
|
Shen S, Sun CY, Du XJ, Li HJ, Liu Y, Xia JX, Zhu YH, Wang J. Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy. Biomaterials 2015; 70:71-83. [PMID: 26302232 DOI: 10.1016/j.biomaterials.2015.08.026] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 08/12/2015] [Accepted: 08/14/2015] [Indexed: 02/07/2023]
Abstract
As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model.
Collapse
Affiliation(s)
- Song Shen
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Chun-Yang Sun
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Xiao-Jiao Du
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Hong-Jun Li
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Yang Liu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Jin-Xing Xia
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China.
| | - Yan-Hua Zhu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China
| | - Jun Wang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China; Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China; High Magnetic Field Laboratory of CAS, University of Science and Technology of China, Hefei, Anhui 230026, PR China.
| |
Collapse
|
|
27
|
Zhang S, Shi W, Chen Y, Xu Z, Zhu J, Zhang T, Huang W, Ni R, Lu C, Zhang X. Overexpression of SYF2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma. Mol Cell Biochem 2015; 410:1-9. [PMID: 26260052 DOI: 10.1007/s11010-015-2533-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 08/06/2015] [Indexed: 01/17/2023]
Abstract
SYF2, also known as p29/NTC31/CBPIN, encodes a nuclear protein that interacts with Cyclin D-type binding-protein 1. SYF2 has been reported to be involved in pre-mRNA splicing and cell cycle regulation. In the present study, we observed that SYF2 was obviously upregulated in HCC tumor tissues and cell lines, and its level was positively correlated with the tumor grade and Ki-67 expression, as well as poor prognosis of HCC. In vitro, using serum starvation-refeeding experiment, our results suggested that SYF2 was upregulated in proliferating HCC cells, and was positive correlated with the expression of PCNA and Cyclin D1. In addition, depletion of SYF2 decreased PCNA and Cyclin D1 levels. Accordingly, interference of SYF2 resulted in cells cycle arrest at G1/S phase in Huh7 HCC cells. Furthermore, we found that SYF2 might interact with Cyclin D1 and could confer doxorubicin resistance in HCC cells. These findings revealed that SYF2 might play a regulatory role in the proliferation of HCC cells. In summary, SYF2 may be a novel prognostic marker and serve as a potential therapeutic target in HCC.
Collapse
Affiliation(s)
- Shusen Zhang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Weidong Shi
- Department of Oncology, The Second People's Hospital of Nantong, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuyan Chen
- Class 5 Grade 13, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Zhiwei Xu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Jia Zhu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Tingting Zhang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Wei Huang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Runzhou Ni
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Cuihua Lu
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Xiubing Zhang
- Department of Oncology, The Second People's Hospital of Nantong, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| |
Collapse
|
|
28
|
Liu Y, Ren F, Luo Y, Rong M, Chen G, Dang Y. Down-Regulation of MiR-193a-3p Dictates Deterioration of HCC: A Clinical Real-Time qRT-PCR Study. Med Sci Monit 2015; 21:2352-60. [PMID: 26263159 PMCID: PMC4538786 DOI: 10.12659/msm.894077] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Although some recent reports have shown that the expression level of miR-193a varied in different cancers, its role in hepatocellular carcinoma (HCC) remains unidentified. The aim of the current study was to validate the relationship between miR-193a-3p and clinicopathological characteristics in HCC patients. Material/Methods Expression of miR-193a-3p in 95 HCC cases and their corresponding peritumoral tissues (PT) was examined by using quantitative reverse transcription polymerase chain reaction (qRT-PCR). miR-193a-3p expression and its correlation with a variety of clinicopathological features and patient recurrence were analyzed. Results The relative level of miR-193a-3p was 3.2028±1.1951 in PT, significantly higher than its expression in HCC tissues (1.5941±0.7079, P<0.001). The area under the curve of underexpression of miR-193a-3p was 0.906 to distinguish HCC from normal liver (95% CI: 0.864–0.948, P<0.001). Expression of miR-193a-3p was negatively correlated to metastasis (r=−0.371, P=0.000), TNM (r=−0.321, P=0.002), respectively. Additionally, the recurrence time was 50.271±2.631 months for the low miR-193a-3p level group and 60.132±3.626 months for the high miR-193a-3p level group. However, no significant difference between them was found (chi-square=0.354, P=0.552). Conclusions MiR-193a-3p may be a tumor-suppressive miRNA which is down-regulated in HCC tissues. It could be regarded as a predictor for the deterioration of HCC patients.
Collapse
Affiliation(s)
- Yongru Liu
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| | - Fanghui Ren
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| | - Yihuan Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| | - Minhua Rong
- Department of Research, Affiliated Cancer Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| | - Yiwu Dang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China (mainland)
| |
Collapse
|
|
29
|
Liu X, Xu J. Body Mass Index and Waistline are Predictors of Survival for Hepatocellular Carcinoma After Hepatectomy. Med Sci Monit 2015. [PMID: 26223028 PMCID: PMC4523070 DOI: 10.12659/msm.894202] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide especially in China. This article aimed to evaluate the influence of body mass index (BMI) and waistline on complications, postoperative death, and long-term survival in patients undergoing surgery for HCC. Material/Methods 136 patients were enrolled and divided into 4 groups: group A, BMI <25; group B, BMI ≥25; group C, waistline <90 cm in males or waistline <80 cm in females; group D, waistline ≥90 cm in males or waistline ≥80 cm in females. Clinical pathological features and surgical outcomes of these patients were analyzed retrospectively. Results There were no significant differences in postoperative complication rate and postoperative death between group A and group B, although pulmonary infection showed a significant difference between 2 groups (P=0.017). Vascular invasion, waistline, and BMI are the independent prognostic factors for long-term survival. The disease-free survival curves after hepatectomy showed no statistically significant difference between group A and group B. Group C had the better overall survival than group D, and group A had the better overall survival than group B. Conclusions BMI and waistline are both independent prognostic factors for long-term survival of HCC after hepatectomy. Waistline is more important than BMI in predicting the disease-free survival of HCC after hepatectomy.
Collapse
Affiliation(s)
- Xiyu Liu
- Department of Internal Medicine, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Jiangfeng Xu
- Department of Surgery, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| |
Collapse
|
|
30
|
Yang X, Ye J, Yan H, Tang Z, Shen J, Zhang J, Yang L. MiR-491 attenuates cancer stem cells-like properties of hepatocellular carcinoma by inhibition of GIT-1/NF-κB-mediated EMT. Tumour Biol 2015; 37:201-9. [DOI: 10.1007/s13277-015-3687-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 06/17/2015] [Indexed: 01/06/2023] Open
|
|
31
|
Upregulated expression of polycomb protein Ring1 contributes to poor prognosis and accelerated proliferation in human hepatocellular carcinoma. Tumour Biol 2015; 36:9579-88. [PMID: 26141041 DOI: 10.1007/s13277-015-3721-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 06/25/2015] [Indexed: 10/23/2022] Open
Abstract
Ring finger protein 1 (Ring1) have recently been reported to be closely related to aggressive tumor features in multiple cancer types, including prostate cancer, non-small-cell lung cancer, and bladder cancer. However, the role of Ring1 in human hepatocarcinogenesis remains unclear. In this study, we aimed at investigating the latent role of Ring1 in hepatocellular carcinoma (HCC) development. The expression of Ring1 was evaluated using Western blot analysis in 8 paired fresh HCC tissues and immunohistochemistry on 98 paraffin-embedded sections from 2005 to 2008. Moreover, RNA interference, CCK-8, colony formation, and flow-cytometry analyses were performed to investigate the role of Ring1 in the regulation of HCC cell proliferation. Compared with adjacent normal tissues, the level of Ring1 was significantly increased in HCC specimens. High expression of Ring1 was associated with histological grade (P = 0.011) and tumor size (P = 0.004), and Ring1 expression was positively related with the proliferation marker Ki-67 (P < 0.001). Moreover, knocking down Ring1 induced growth impairment and G1/S cell cycle arrest in HCC cells. Kaplan-Meier survival curves showed that high expression of Ring1 indicated poor prognosis of HCC (P = 0.03). On the basis of these results, we proposed that the expression of Ring1 protein may be a novel indicator of HCC prognosis.
Collapse
|
|
32
|
Zhang YD, Zhu FP, Xu X, Wang Q, Wu CJ, Liu XS, Shi HB. Classifying CT/MR findings in patients with suspicion of hepatocellular carcinoma: Comparison of liver imaging reporting and data system and criteria-free Likert scale reporting models. J Magn Reson Imaging 2015; 43:373-83. [PMID: 26119393 DOI: 10.1002/jmri.24987] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/15/2015] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To compare the Liver Imaging Reporting and Data System (LI-RADS) and a criteria-free Likert scale (LS) reporting models for classifying computed tomography/magnetic resonance imaging (CT/MR) findings of suspicious hepatocellular carcinoma (HCC). MATERIALS AND METHODS Imaging data of 281 hepatic nodules in 203 patients were retrospectively included. Imaging characteristics including diameter, arterial hyperenhancement, washout, and capsule were reviewed independently by two groups of readers using LI-RADS and LS (range, score 1-5). LS is primarily based on the overall impression of image findings without using fixed criteria. Interreader agreement (IRA), intraclass agreement (ICA), and diagnostic performance were determined by Fleiss, Cohen's kappa (κ), and logistic regression, respectively. RESULTS There were 167 contrast-enhanced CT (CECT) versus 114 MR data. Overall, IRA was moderate (κ = 0.47, 0.52); IRA was moderate-to-good for arterial hyperenhancement, washout, and capsule (κ = 0.56-0.69); excellent for diameter and tumor embolus (κ = 0.99). Overall, ICA between LI-RADS and LS was moderate (κ = 0.44-0.50); ICA was good for scores 1-2 (κ = 0.71-0.90), moderate for scores 3 and 5 (κ = 0.41-0.52), but very poor for score 4 (κ = 0.11-0.19). LI-RADS produced significantly lower accuracy (78.6% vs. 87.2%) and sensitivity (72.1% vs. 92.8%), higher specificity (97.3% vs. 71.2%) and positive likelihood ratio (+LR: 26.32 vs. 3.23) in diagnosis of HCC. CECT produced relatively low IRA, ICA, and diagnostic ability against MR. CONCLUSION There were substantial variations in liver observations between LI-RADS and LS. Further study is needed to investigate ICA between CECT and MR.
Collapse
Affiliation(s)
- Yu-Dong Zhang
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Fei-Peng Zhu
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Xun Xu
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Qing Wang
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Chen-Jiang Wu
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Xi-Sheng Liu
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| | - Hai-Bin Shi
- Department of Radiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| |
Collapse
|
|
33
|
Li G, Yuan L, Liu D, Liu J. Upregulation of Leucine Zipper Protein mRNA in Hepatocellular Carcinoma Associated With Poor Prognosis. Technol Cancer Res Treat 2015; 15:517-22. [PMID: 26031464 DOI: 10.1177/1533034615587432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 04/23/2015] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Leucine zipper protein (LUZP) plays key roles in development. Overexpression of LUZP was documented in several types of solid tumors. In this study, expression of LUZP messenger RNA (LUZP mRNA) in human hepatocellular carcinoma (HCC) was examined, and the correlations of LUZP mRNA level with patients' characteristics and prognosis were also investigated. METHODS Total RNA was extracted from HCC and paired noncancerous liver tissues of 77 patients. Expression of LUZP mRNA in the tissues was determined by real-time quantitative reverse transcriptase polymerase chain reaction. Using average LUZP mRNA level in noncancerous liver tissues as the cutoff, patients with HCC were categorized into high-expression group and low-expression group. Correlations of LUZP mRNA with clinical parameters were analyzed. Overall survival of the patients in the 2 groups was analyzed by Kaplan-Meier method. RESULTS The LUZP mRNA level was significantly higher in HCC samples than in the noncancerous liver tissues (1.87 ± 0.11 vs 0.58 ± 0.05, P < .01). Significant differences were found between the 2 groups in terms of portal vein invasion, Tumor Lymph Node Metastasis (TNM) stage, and recurrence of HCC. The current study failed to find significant differences between the 2 groups in clinical characteristics such as age, gender, lymph node metastasis, hepatitis B virus infection, family HCC history, and alcohol intake. Overall survival in high-expression group was 12 months while that in the low-expression group was 34 months (P = .03). CONCLUSION The LUZP mRNA is a prognostic indicator in HCC, and overexpression is associated with poor prognosis in patients with HCC.
Collapse
Affiliation(s)
- Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Li Yuan
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Dejie Liu
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| |
Collapse
|
|
34
|
Yang L, Hu B, Zhang Y, Qiang S, Cai J, Huang W, Gong C, Zhang T, Zhang S, Xu P, Wu X, Liu J. Suppression of the nuclear transporter-KPNβ1 expression inhibits tumor proliferation in hepatocellular carcinoma. Med Oncol 2015; 32:128. [PMID: 25794490 DOI: 10.1007/s12032-015-0559-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 02/28/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the malignant tumors and leads to the highly death in the solid tumors, but its mechanism remains unclear. KPNβ1 is one of the soluble nuclear transport receptors, has been reported to act as an important role in the occurrence and development of tumor, such as cervical cancer, head and neck and lung cancer. However, the expression mechanisms and physiological significance of KPNβ1 in HCC is still unclear. AIM The expression of KPNβ1 and its involvement in HCC was studied. METHODS The expression of KPNβ1 protein was measured by Western blot and immunohistochemistry in HCC. We analyzed the effects of growth and interference of KPNβ1 in the cell cycle process by CCK8 and flow cytometrical analysis. RESULTS KPNβ1 protein level was up-regulated in HCC tissue samples. The KPNβ1 expression was significantly associated with histological differentiation. The levels of KPNβ1 were significantly correlated with histological grade (P = 0.03), metastasis (P = 0.01), vein invasion (P = 0.04) and tumor size (P = 0.01) in HCC samples. Serum starvation assay proved that KPNβ1 was arrested in G1 phase and was gradually reduced by refeeding serum. Moreover, the knockdown of KPNβ1 induced cell proliferation arrest in HepG2 cell. Western blot analyses showed that KPNβ1 was correlated with NF-кB signaling pathway. CONCLUSIONS Our datum showed that KPNβ1 expression was up-regulated in HCC tissue samples and increasing HCC cells growth and the KPNβ1 expression was associated with poor survival. KPNβ1 may take part in the pathogenesis of hepatocellular carcinoma via NF-кB signaling pathway and serve as an independent prognostic indicator and a novel therapeutic target for HCC.
Collapse
Affiliation(s)
- Linlin Yang
- Department of Hepatic Oncology, Nantong Tumor Hospital, Nantong, 226361, Jiangsu Province, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Fatourou EM, Tsochatzis EA. ART and science in using transarterial chemoembolization for retreating patients with hepatocellular carcinoma. Hepatobiliary Surg Nutr 2015; 3:415-8. [PMID: 25568865 DOI: 10.3978/j.issn.2304-3881.2014.07.01] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 07/02/2014] [Indexed: 12/21/2022]
Abstract
Intermediate stage hepatocellular carcinoma (HCC) comprises of a highly heterogeneous patient population, both in terms of liver function and tumour burden. Transarterial chemoembolization (TACE) is the treatment of choice for this subgroup of patients, provided that liver function is relatively preserved. Not all patients respond to an initial session of TACE, and further session might impair liver function. The ART score consists of an increase of AST >25%, increase of Child-Pugh of one or two points and absence of radiological tumour response and helps identify patients that would not benefit from further TACE sessions. We critically appraise the use of this score, particularly in terms of patient selection and timing of calculation of its variables. Once sufficiently validated, it can become a safe, objective and accurate clinical tool in everyday practice.
Collapse
Affiliation(s)
- Evangelia M Fatourou
- 1 Liver Unit, St. Mary's Hospital, London, UK ; 2 Sheila Sherlock Liver Unit and UCL Institute of Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Emmanuel A Tsochatzis
- 1 Liver Unit, St. Mary's Hospital, London, UK ; 2 Sheila Sherlock Liver Unit and UCL Institute of Liver and Digestive Health, Royal Free Hospital, London, UK
| |
Collapse
|
|
36
|
miR-141 suppresses the growth and metastasis of HCC cells by targeting E2F3. Tumour Biol 2014; 35:12103-7. [PMID: 25142234 DOI: 10.1007/s13277-014-2513-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 08/14/2014] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) function as essential post-transcriptional modulators of gene expression involved in a wide range of physiologic and pathologic states, including cancer. Numerous miRNAs have been deregulated in hepatocellular carcinoma (HCC). Here, we investigated the role of miR-141 in HCC. Decreased expression of miR-141 was observed in both HCC tissues and cell lines. Ectopic overexpression of miR-141 reduced proliferation, migration, and invasion of HCC cells. E2F transcription factor 3 (E2F3) was confirmed to be a target of miR-141 in HCC cells. Moreover, restoration of E2F3 significantly reversed the tumor suppressive effects of miR-141. Our results suggest a critical role of miR-141 in suppressing metastasis of HCC cells by targeting E2F3.
Collapse
|
|
37
|
Hu B, Xiong Y, Ni R, Wei L, Jiang D, Wang G, Wu D, Xu T, Zhao F, Zhu M, Wan C. The downregulation of ErbB3 binding protein 1 (EBP1) is associated with poor prognosis and enhanced cell proliferation in hepatocellular carcinoma. Mol Cell Biochem 2014; 396:175-85. [PMID: 25081333 DOI: 10.1007/s11010-014-2153-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023]
Abstract
ErbB3 binding protein 1 (EBP1) has been recently reported to function as a tumor suppressor in the progression of multiple cancers, including breast cancer, prostate cancer, salivary adenoid cystic carcinoma (ACC), and oral squamous cell carcinoma (OSCC). However, the expression and physiological significance of EBP1 in hepatocellular carcinoma (HCC) remain unclear. In the study, we showed that EBP1 was significantly downregulated in clinical HCC specimens, and that decreased expression of EBP1 was associated with enhanced proliferation in HCC cells. Western blot and immunohistochemical analyses revealed that EBP1 was remarkably downregulated in HCC tissues compared with the adjacent normal ones. The levels of EBP1 were significantly associated with histological grade (P = 0.034), tumor size (P = 0.001), and Ki67 expression (P < 0.001) in HCC specimens. Univariate and multivariate analyses showed that EBP1 could serve as an independent prognostic indicator of patients' survival. Serum starvation and refeeding assay indicated that EBP1 was accumulated in growth-arrested HCC cells, and was progressively decreased when cells entered into S phase. Moreover, the depletion of EBP1 induced growth acceleration and cell cycle progression in L02 hepatocytes. On the basis of these findings, we conclude that EBP1 may be a valuable prognostic marker and promising therapeutic target of HCC.
Collapse
Affiliation(s)
- Baoying Hu
- Basic Medical Research Centre, Medical College, Nantong University, Nantong, 226001, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Jiang F, Mu J, Wang X, Ye X, Si L, Ning S, Li Z, Li Y. The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. PLoS One 2014; 9:e96698. [PMID: 24806207 PMCID: PMC4013140 DOI: 10.1371/journal.pone.0096698] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/10/2014] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of cancer stem cells (CSCs)-mediated post-surgical recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become a new approach for the treatment of HCC. GLA exhibits anti-tumor effects in that it attenuates the proliferation, migration, invasion, and angiogenesis of human cancer cells. However, the functions of GLA in the regulation of CSCs-like properties in HCC cells, and the molecular mechanisms underlying in remain obscure. Here we found that GLA attenuated the CSCs-like properties by the microRNA-148a (miR-148a)-mediated inhibition of transforming growth factor beta (TGF-β)/SMAD2 signal pathway in HCC cell lines (HepG2, Huh-7, and MHCC97H). Indeed, GLA inhibited the activations/expressions of both TGFβ-induced and the endogenous SMAD2. Further, GLA improved the expression of miR-148a in a dose/time-dependent manner. MiR-148a, which targeted the SMAD2-3'UTR, decreased the expression and function of SMAD2. Knockdown of miR-148a abolished the GLA-induced inhibition of TGF-β/SMAD2 signal pathway and the CSCs-like properties in HCC cells. Our study found a novel mechanism that GLA inhibits the CSCs-like properties of HCC cells by miR-148a-mediated inhibition of TGF-β/SMAD2 signal pathway, which may help to identify potential targets for the therapies of HCC.
Collapse
Affiliation(s)
- Fei Jiang
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Juan Mu
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xingxing Wang
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xianqing Ye
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Lu Si
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Shilong Ning
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Zhong Li
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Yuan Li
- Department of Nutrition and Food Hygiene, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| |
Collapse
|
|
39
|
Tsochatzis EA, Fatourou E, O’Beirne J, Meyer T, Burroughs AK. Transarterial chemoembolization and bland embolization for hepatocellular carcinoma. World J Gastroenterol 2014; 20:3069-3077. [PMID: 24695579 PMCID: PMC3964379 DOI: 10.3748/wjg.v20.i12.3069] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Transarterial chemoembolization (TACE) is the first line treatment for patients with intermediate stage hepatocellular carcinoma but is also increasingly being used for patients on the transplant waiting list to prevent further tumor growth. Despite its widespread use, TACE remains an unstandardized procedure, with variation in type and size of embolizing particles, type and dose of chemotherapy and interval between therapies. Existing evidence from randomized controlled trials suggest that bland transarterial embolization (TAE) has the same efficacy with TACE. In the current article, we review the use of TACE and TAE for hepatocellular carcinoma and we focus on the evidence for their use.
Collapse
|
|
40
|
Liu J, Li G, Liu D, Liu J. FH535 inhibits the proliferation of HepG2 cells via downregulation of the Wnt/β-catenin signaling pathway. Mol Med Rep 2014; 9:1289-92. [PMID: 24482011 DOI: 10.3892/mmr.2014.1928] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 01/23/2014] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary cancer of the liver. Target therapy may improve prognosis of HCC. In the present study, we evaluated the inhibition of the Wnt/β-catenin pathway as a potential therapeutic approach. HepG2 cells were treated with the β-catenin inhibitor FH535. β-catenin protein expression was semi-quantitatively assessed using western blot analysis. Cell proliferation was examined with a 3‑(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. The mRNA expression of nitric oxide synthase (iNOS) was detected by reverse transcription polymerase chain reaction. The Griess assay was used to determine nitric oxide (NO) concentration. FH535 inhibited the proliferation of HepG2 cells and decreased β-catenin protein expression. mRNA expression of iNOS, a target gene of the Wnt/β-catenin pathway, was decreased in FH535‑treated HepG2 cells compared to the control group. NO production was also reduced by FH535. In conclusion, the β-catenin inhibitor FH535 may inhibit HCC cell proliferation via downregulation of the Wnt/β-catenin pathway. Thus, targeting this pathway may be useful in HCC therapy.
Collapse
Affiliation(s)
- Jing Liu
- Department of Ophthalmology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Dejie Liu
- Department of Anesthesiology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| |
Collapse
|
|
41
|
Zhou Y, Li Y, Ye J, Jiang R, Yan H, Yang X, Liu Q, Zhang J. MicroRNA-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. Liver Int 2013; 33:1271-80. [PMID: 23725476 DOI: 10.1111/liv.12190] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 04/14/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; the prognosis of HCC patient remains poor owing to intrahepatic and extrahepatic metastasis and postsurgical recurrence. The aim of the present study is to determine the molecular mechanisms underlying the metastasis of HCC. METHODS HCC patients and treated HCC cells were molecularly characterized by miRNA microarray analysis, qRT-PCR, Western blots, transwell assay, and immunohistochemistry. RESULTS Here, by employing a miRNAs microarray analysis, we found that miR-491 level was the most significant down-regulation in poorly differentiated HCC tissue compared with well-differentiated HCC tissue. We then selected HepG2 (very low migratory capacity), MHCC97L (low migratory capacity) and MHCC97H (high migratory capacity), as well as HCC tissues with different status to further investigate the effects of miR-491 on the metastasis of HCC. Our data showed that miR-491 levels were inversely correlated with different status of differentiation in HCC tissues and with migratory potential in HCC cell lines. In HepG2 cells, inhibition of miR-491 increased the expression of matrix metalloproteinase 2/9 (MMP-2/9) and the migratory potential; however, in MHCC97H cells, overexpression of miR-491 level decreased the expression of MMP-2/9 and the migratory capacity. Moreover, miR-491 had a positive relationship with E-cadherin level; however, it had a negative relationship with vimentin level both in cell lines and tissue samples of HCC. MiR-491 levels of non-metastasis HCC tissue are higher than that of metastasis HCC tissue. CONCLUSION Our results suggest that miR-491 is involved in metastasis of HCC by blocking EMT and decreasing MMP-9 levels, which may provide a new clue for preventing tumour metastasis of HCC.
Collapse
Affiliation(s)
- Yun Zhou
- Department of General Surgery, The Second Affiliated Hospital, School of Public Health, Nanjing Medical University, Nanjing, China
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Yan H, Dong X, Zhong X, Ye J, Zhou Y, Yang X, Shen J, Zhang J. Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog 2013; 53:960-9. [PMID: 23861222 DOI: 10.1002/mc.22064] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 05/21/2013] [Accepted: 05/31/2013] [Indexed: 12/13/2022]
Abstract
The epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cells (CSCs)-like properties are essential steps in the metastasis and postsurgical recurrence of hepatocellular carcinomas (HCCs). The molecular mechanisms involved, however, remain obscure. As determined by an miRNA microarray analysis, there was lower expression of miR-148a in poorly differentiated HCC tissues relative to well-differentiated HCC tissues. MHCC97H and MHCC97L (HCC cells with migratory capacity) and HCC tissues with various differentiation status were selected for further investigation. The results showed that miR-148a levels inversely correlated with the differentiation status of HCC tissues. In MHCC97H and MHCC97L cells, over-expression of miR-148a blocked the EMT process, attenuated the expression of CD90 and CD44 (biomarkers for liver cancer stem cells), and inhibited their migratory capacity. Via TargetScan and microRNA.org algorithms, miR-148a was predicted to bind to the Wnt1 mRNA 3'-UTR. Wnt1 was confirmed as a target gene of miR-148a in HCC cells, and the Wnt signal pathway was determined to be involved in the miR-148a-mediated inhibition of EMT and CSCs-like properties of MHCC97H cells. Moreover, the expression of miR-148a in nonmetastatic HCC tissues was higher than that in metastatic HCC tissues. The results suggest that miR-148a inhibits the metastasis of HCCs by blocking EMT and CSCs-like properties through effects on the Wnt signaling pathway.
Collapse
Affiliation(s)
- Han Yan
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Tsochatzis E, Garcovich M, Marelli L, Papastergiou V, Fatourou E, Rodriguez-Peralvarez ML, Germani G, Davies N, Yu D, Luong TV, Dhillon AP, Thorburn D, Patch D, O'Beirne J, Meyer T, Burroughs AK. Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma. Liver Int 2013; 33:944-9. [PMID: 23530918 DOI: 10.1111/liv.12144] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 02/14/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Neo-adjuvant transarterial therapies are commonly used for patients with HCC in the waiting list for liver transplantation (LT) to delay tumour progression, however, their effectiveness is not well-established. We studied the effect of pre-LT transarterial therapies on post-LT HCC recurrence, using the explanted liver histology to assess therapeutic efficacy and the predictors of response to these therapies. METHODS We included 150 consecutive patients from our prospectively compiled database, listed for liver transplantation using the Milan criteria. Transarterial embolization without chemotherapeutic agents was the transarterial therapy used as standard of care. PVA particles were the embolizing agent of choice. RESULTS Sixty-seven (45%) patients had TAE as bridging therapy to liver transplantation, of which 60 were transplanted after 2001. The majority of patients (36, 54%) had partial tumour necrosis after transarterial therapy, whereas 22 (33%) had complete tumour necrosis and 9 (13%) had no necrosis. HCC post-transplant recurrence was independently associated with no neo-adjuvant transarterial therapy (OR 5.395, 95% CI 1.289-22.577; P = 0.021) and the total radiological size of HCC nodules (OR 1.037, 95% CI 1.006-1.069; P = 0.020). CONCLUSIONS Pre-transplant TAE with the more permanently occluding PVA particles significantly reduces post-transplant HCC recurrence in patients within the Milan criteria.
Collapse
Affiliation(s)
- Emmanuel Tsochatzis
- The Royal Free Sheila Sherlock Liver Centre and UCL Institute of Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Molecular functions of thyroid hormones and their clinical significance in liver-related diseases. BIOMED RESEARCH INTERNATIONAL 2013; 2013:601361. [PMID: 23878812 PMCID: PMC3708403 DOI: 10.1155/2013/601361] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/14/2013] [Accepted: 05/28/2013] [Indexed: 02/06/2023]
Abstract
Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine (T3) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3 via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3 stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3 analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms.
Collapse
|
|
45
|
Tsochatzis E, Meyer T, O’Beirne J, Burroughs AK. Transarterial chemoembolisation is not superior to embolisation alone: The recent European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC) guidelines. Eur J Cancer 2013; 49:1509-10. [DOI: 10.1016/j.ejca.2012.11.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 11/12/2012] [Indexed: 12/30/2022]
|
|
46
|
Transarterial therapies for hepatocellular carcinoma (HCC): a long way towards standardization. J Hepatol 2013; 58:194. [PMID: 23046673 DOI: 10.1016/j.jhep.2012.08.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 08/30/2012] [Indexed: 01/13/2023]
|
|
47
|
Tinkle CL, Haas-Kogan D. Hepatocellular carcinoma: natural history, current management, and emerging tools. Biologics 2012; 6:207-19. [PMID: 22904613 PMCID: PMC3421475 DOI: 10.2147/btt.s23907] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer.
Collapse
Affiliation(s)
- Christopher L Tinkle
- Department of Radiation Oncology, University of California, San Francisco, CA, USA
| | | |
Collapse
|