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Yang GY, He ZW, Tang YC, Yuan F, Cao MB, Ren YP, Li YX, Su XR, Yao ZC, Deng MH. Unraveling the efficacy network: A network meta-analysis of adjuvant external beam radiation therapy methods after hepatectomy. World J Gastrointest Surg 2024; 16:205-214. [PMID: 38328333 PMCID: PMC10845281 DOI: 10.4240/wjgs.v16.i1.205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/09/2023] [Accepted: 01/09/2024] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Primary liver cancer is a malignant tumor with a high recurrence rate that significantly affects patient prognosis. Postoperative adjuvant external radiation therapy (RT) has been shown to effectively prevent recurrence after liver cancer resection. However, there are multiple RT techniques available, and the differential effects of these techniques in preventing postoperative liver cancer recurrence require further investigation. AIM To assess the advantages and disadvantages of various adjuvant external RT methods after liver resection based on overall survival (OS) and disease-free survival (DFS) and to determine the optimal strategy. METHODS This study involved network meta-analyses and followed the PRISMA guidelines. The data of qualified studies published before July 10, 2023, were collected from PubMed, Embase, the Web of Science, and the Cochrane Library. We included relevant studies on postoperative external beam RT after liver resection that had OS and DFS as the primary endpoints. The magnitudes of the effects were determined using risk ratios with 95% confidential intervals. The results were analyzed using R software and STATA software. RESULTS A total of 12 studies, including 1265 patients with hepatocellular carcinoma (HCC) after liver resection, were included in this study. There was no significant heterogeneity in the direct paired comparisons, and there were no significant differences in the inclusion or exclusion criteria, intervention measures, or outcome indicators, meeting the assumptions of heterogeneity and transitivity. OS analysis revealed that patients who underwent stereotactic body radiotherapy (SBRT) after resection had longer OS than those who underwent intensity modulated radiotherapy (IMRT) or 3-dimensional conformal RT (3D-CRT). DFS analysis revealed that patients who underwent 3D-CRT after resection had the longest DFS. Patients who underwent IMRT after resection had longer OS than those who underwent 3D-CRT and longer DFS than those who underwent SBRT. CONCLUSION HCC patients who undergo liver cancer resection must consider distinct advantages and disadvantages when choosing between SBRT and 3D-CRT. IMRT, a RT technique that is associated with longer OS than 3D-CRT and longer DFS than SBRT, may be a preferred option.
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Affiliation(s)
- Gao-Yuan Yang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Wei He
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Yong-Chang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Feng Yuan
- Department of General Surgery, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, Guangdong Province, China
| | - Ming-Bo Cao
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Yu-Peng Ren
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Yu-Xuan Li
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Rui Su
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Cheng Yao
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Mei-Hai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
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Li J, Wang WQ, Zhu RH, Lv X, Wang JL, Liang BY, Zhang EL, Huang ZY. Postoperative adjuvant tyrosine kinase inhibitors combined with anti-PD-1 antibodies improves surgical outcomes for hepatocellular carcinoma with high-risk recurrent factors. Front Immunol 2023; 14:1202039. [PMID: 37359534 PMCID: PMC10285103 DOI: 10.3389/fimmu.2023.1202039] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/24/2023] [Indexed: 06/28/2023] Open
Abstract
Background The clinical value of postoperative adjuvant therapy (PAT) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore the effect of PAT with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies on the surgical outcomes of HCC patients with high-risk recurrent factors (HRRFs). Methods HCC patients who underwent radical hepatectomy at Tongji Hospital between January 2019 and December 2021 were retrospectively enrolled, and those with HRRFs were divided into PAT group and non-PAT group. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups after propensity score matching (PSM). Prognostic factors associated with RFS and OS were determined by Cox regression analysis, and subgroup analysis was also conducted. Results A total of 250 HCC patients were enrolled, and 47 pairs of patients with HRRFs in the PAT and non-PAT groups were matched through PSM. After PSM, the 1- and 2-year RFS rates in the two groups were 82.1% vs. 40.0% (P < 0.001) and 54.2% vs. 25.1% (P = 0.012), respectively. The corresponding 1- and 2-year OS rates were 95.4% vs. 69.8% (P = 0.001) and 84.3% vs. 55.5% (P = 0.014), respectively. Multivariable analyses indicated that PAT was an independent factor related to improving RFS and OS. Subgroup analysis demonstrated that HCC patients with tumor diameter > 5 cm, satellite nodules, or vascular invasion could significantly benefit from PAT in RFS and OS. Common grade 1-3 toxicities, such as pruritus (44.7%), hypertension (42.6%), dermatitis (34.0%), and proteinuria (31.9%) were observed, and no grade 4/5 toxicities or serious adverse events occurred in patients receiving PAT. Conclusions PAT with TKIs and anti-PD-1 antibodies could improve surgical outcomes for HCC patients with HRRFs.
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Affiliation(s)
| | | | | | | | | | | | - Er-lei Zhang
- *Correspondence: Zhi-yong Huang, ; Er-lei Zhang,
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Li W, Hong G, Lai X. INKA2-AS1 Is a Potential Promising Prognostic-Related Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma. Mediators Inflamm 2023; 2023:7057236. [PMID: 37181806 PMCID: PMC10169249 DOI: 10.1155/2023/7057236] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 04/12/2023] [Accepted: 04/20/2023] [Indexed: 05/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with one of the worst prognoses. Long noncoding RNAs (lncRNAs) may be important in cancer development and may serve as new biomarkers for the diagnosis and treatment of various tumors, according to mounting research. The purpose of this study was to investigate the expression of INKA2-AS1 and clinical importance in HCC patients. The TCGA database was used to obtain the human tumor samples, while the TCGA and GTEx databases were used to gather the human normal samples. We screened differentially expressed genes (DEGs) between HCC and nontumor tissues. Investigations were made into the statistical significance and clinical significance of INKA2-AS1 expression. A single-sample gene set enrichment analysis (ssGSEA) was used to examine potential relationships between immune cell infiltration and INKA2-AS1 expression. In this investigation, we found that HCC specimens had considerably greater levels of INKA2-AS1 expression than nontumor specimens. When utilizing the TCGA datasets and the GTEx database, high INKA2-AS1 expression showed an AUC value for HCC of 0.817 (95% confidence interval: 0.779 to 0.855). Pan-cancer assays revealed that numerous tumor types had dysregulated levels of INKA2-AS1. Gender, histologic grade, and pathologic stage were all substantially correlated with high INKA2-AS1 expression. A survival study indicated that HCC patients with high INKA2-AS1 expression have shorter OS, DSS, and PFI than those with low INKA2-AS1 expression. Multivariate analysis indicated that INKA2-AS1 expression was an independent prognostic factor for OS of patients with HCC. According to immune analysis, the expression of INKA2-AS1 was favorably correlated with T helper cells, Th2 cells, macrophages, TFH, and NK CD56bright cells and negatively correlated with Th17 cells, pDC, cytotoxic cells, DC, Treg, Tgd, and Tcm. The results of this study collectively suggest that INKA2-AS1 has the potential to be a novel biomarker for predicting the prognosis of HCC patients as well as a significant immune response regulator in HCC.
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Affiliation(s)
- Wenke Li
- Department of Hepatobiliary Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Guoqing Hong
- Department of Hepatobiliary Surgery, Tongnan District People's Hospital, Chongqing, China
| | - Xing Lai
- Department of Hepatobiliary Surgery, Tongnan District People's Hospital, Chongqing, China
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Hu H, Zhang T, Wu Y, Deng M, Deng H, Yang X. Cross-regulation between microRNAs and key proteins of signaling pathways in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2022; 16:753-765. [PMID: 35833844 DOI: 10.1080/17474124.2022.2101994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a subtype of primary liver cancer and a major cause of death. Although miRNA plays an important role in hepatocellular carcinoma, the specific regulatory network remains unclear. Therefore, this paper comprehensively describes the miRNA-related signaling pathways in HCC and the possible interactions among different signaling pathways. The aim is to lay the foundation for the discovery of new molecular targets and multi-target therapy. AREAS COVERED Based on miRNA, HCC, and signaling pathways, the literature was searched on Web of Science and PubMed. Then, common targets between different signaling pathways were found from KEGG database, and possible cross-regulation mechanisms were further studied. In this review, we elaborated from two aspects, respectively, laying a foundation for studying the regulatory mechanism and potential targets of miRNA in HCC. EXPERT OPINION Non-coding RNAs have become notable molecules in cancer research in recent years, and many types of targeted drugs have emerged. From the outset, molecular targets and signal pathways are interlinked, which suggests that signal pathways and regulatory networks should be concerned in basic research, which also provides a strong direction for future mechanism research.
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Affiliation(s)
- Haihong Hu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Taolan Zhang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yiwen Wu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Meina Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Huiling Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, China
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Bai S, Hu L, Liu J, Sun M, Sun Y, Xue F. Prognostic Nomograms Combined Adjuvant Lenvatinib for Hepatitis B Virus–related Hepatocellular Carcinoma With Microvascular Invasion After Radical Resection. Front Oncol 2022; 12:919824. [PMID: 35898866 PMCID: PMC9309730 DOI: 10.3389/fonc.2022.919824] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/08/2022] [Indexed: 11/20/2022] Open
Abstract
Background and Aim Microvascular invasion (MVI) has been established as one of the most important contributors to the prognosis of primary hepatocellular carcinoma (HCC). The objective of this study was to investigate the potential effect of postoperative adjuvant therapy with lenvatinib on the long-term prognosis after radical resection in hepatitis B virus (HBV)-related HCC patients with MVI, as well as to predict the long-term survival based on nomograms. Methods Data from 293 HBV-related hepatocellular carcinoma patients with histologically confirmed MVI who underwent R0 resection at Eastern Hepatobiliary Surgery Hospital (EHBH) was retrospectively analyzed. 57 patients received postoperative adjuvant therapy with lenvatinib, while 236 patients did not. The survival outcome of patients who received postoperative adjuvant lenvatinib versus those who did not was analyzed. Results The 1-year, 2-year recurrence rates and survival rates of the lenvatinib group were improved compared to the non-lenvatinib group (15.9%, 43.2% vs 40.1%, 57.2%, P=0.002; 85.8%, 71.2% vs 69.6%, 53.3%, P=0.009, respectively). Similar findings were also observed after Propensity Score Matching (PSM) compared to non-PSM analyses The 1-year, 2-year recurrence rates and survival rates were more favorable for the lenvatinib group compared to the non-lenvatinib group (15.9%, 43.2% vs 42.1%, 57.4%, P=0.028; 85.8%, 71.2% vs 70.0%, 53.4%, P=0.024, respectively). As shown by univariate and multivariate analyses, absence of adjuvant lenvatinib treatment was identified as an independent risk factor for recurrence and survival. The established nomograms displayed good performance for the prediction of recurrence and survival, with a C-index of 0.658 and 0.682 respectively. Conclusions Postoperative adjuvant therapy with lenvatinib was associated with improved long-term prognosis after R0 Resection in HBV-related HCC patients with MVI, which could be accurately predicted from nomograms.
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Affiliation(s)
- Shilei Bai
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Lei Hu
- Department of Hepatic Surgery I, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jianwei Liu
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Minmin Sun
- Department of Hepatic Surgery I, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yanfu Sun
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- *Correspondence: Mr. Feng Xue, ; Mr. Yanfu Sun,
| | - Feng Xue
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- *Correspondence: Mr. Feng Xue, ; Mr. Yanfu Sun,
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Cheng KC, Ho KM. Pure laparoscopic liver resection versus percutaneous radiofrequency ablation for small hepatocellular carcinoma: a propensity score and multivariate analysis. Transl Cancer Res 2022; 11:43-51. [PMID: 35261883 PMCID: PMC8841462 DOI: 10.21037/tcr-21-1045] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/22/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND In treatment of hepatocellular carcinoma (HCC), both laparoscopic liver resection (LLR) and radiofrequency ablation (RFA) provided similar short-term advantages. However, there was no robust clinical trial comparing the efficacy of LLR and RFA especially for small HCC. This study aimed to compare the short-term and long-term outcomes of LLR and RFA for patients with small HCC using a propensity score matching analysis to minimize potential selection bias. Factors affecting survival were then identified with multivariate analysis. METHODS All patients underwent RFA or LLR for small HCC [defined as Barcelona Clinic Liver Cancer (BCLC) stage 0 or A, size ≤3 cm, ≤3 nodules on contrast CT scan or MRI with no evidence of macrovascular invasion] from April 2005 to August 2020 were included. Propensity score matching was conducted to match patients in the LLR group and RFA group. Prognostic indicators, i.e., age, gender, tumor size, tumor number, Child's grading, albumin, bilirubin, platelet count, international normalized ratio, alpha-fetoprotein level and presence of cirrhosis on imaging were chosen for propensity score calculation. The demographic data, tumor characteristics, operative data, post-operative outcomes and survival data of the two groups were compared. A multivariate analysis based on Cox regression was used to identify factors associated with survival. RESULTS Median follow-up was 34 months. LLR and RFA had similar overall survival (91.8% vs. 79.2% at 5-year, P=0.060); while the LLR had a significantly better disease-free survival (49.0% vs. 30.3% at 5-year, P=0.002) and local recurrence-free survival (96.0% vs. 63.7% at 5-year, P<0.001) when compared with the RFA. Multivariate analysis showed that treatment received by patient (LLR vs. RFA), prothrombin time and platelet counts were significantly associated with disease-free survival. On the other hand, the only factor associated with local recurrence-free survival was the treatment received by patient. CONCLUSIONS Both RFA and LLR are safe and feasible treatment options for patients with small HCC. LLR should be considered for patients with preserved liver function with a better disease-free survival; while RFA offered a comparable overall survival with less surgical trauma and shorter hospital stay.
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Affiliation(s)
| | - Kit-Man Ho
- Department of Surgery, Kwong Wah Hospital, Hong Kong, China
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Fang Z, Wu L, Dai H, Hu P, Wang B, Han Q, Xu Y, Lv S, Zhu Y, Gan M, Zhou W, Zhang W. The role of vesicular overexpressed in cancer pro-survival protein 1 in hepatocellular carcinoma proliferation. Cancer Biomark 2021; 28:9-20. [PMID: 32083568 DOI: 10.3233/cbm-190574] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recently, hepatocellular carcinoma (HCC) has been ranked as the second leading cause of cancer-associated death. However, the underlying molecular mechanisms of HCC progression remain unclear. Vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) could be upregulated in a quantity of human cancers, including squamous cell carcinoma (SCC), gastric cancer, and glioblastoma. However, the precise functional mechanism of VOPP1 in HCC remains poorly understood. The present study aimed to investigate the role of VOPP1 in HCC proliferation. METHODS Immunohistochemistry (IHC), Western blot and Reverse-transcription polymerase chain reaction (RT-PCR) were used to analyze the protein and mRNA expressions of VOPP1, mitogen-activated protein kinase (MAPK) 14, ribosomal protein S6 kinase β1 (RPS6KB1), cylindromatosis (CYLD) and Twist family bHLH transcription factor 1 (TWIST1). The cell proliferation and apoptosis were tested using Celigo cell imaging analyzer and annexin V-APC apoptosis detection kit respectively. Colony formation and tumor xenograft assays were performed to understand their roles in tumorigenicity. RESULTS The expression of VOPP1 in HCC samples was higher than that in adjacent noncancerous tissues by immunohistochemistry. In addition, the down-regulation of VOPP1 using shRNA inhibited cell proliferation and tumour growth, and induced cell apoptosis in vitro and in vivo. Furthermore, VOPP1 silencing increased the expression of MAPK14 and RPS6KB1, indicating that the MAPK and mTOR signalling pathways might be involved in VOPP1-mediated cancer cell proliferation. CONCLUSION The present data indicate that VOPP1 may play an important role in the progression of HCC by targeting the MAPK and mTOR signalling pathways, and that VOPP1 may potentially be a candidate as a novel molecular target for HCC therapy.
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Affiliation(s)
- Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Linjun Wu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Haojiang Dai
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Peng Hu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Binfeng Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Qiuyue Han
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yongfu Xu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shangdong Lv
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu Zhu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Meifu Gan
- Department of Pathology, Enze Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
| | - Weijie Zhou
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenlong Zhang
- Department of Hepatobiliary Surgery, Enze Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
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Jin S, Tan S, Peng W, Jiang Y, Luo C. Radiofrequency ablation versus laparoscopic hepatectomy for treatment of hepatocellular carcinoma: a systematic review and meta-analysis. World J Surg Oncol 2020; 18:199. [PMID: 32787883 PMCID: PMC7425008 DOI: 10.1186/s12957-020-01966-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 07/23/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Several randomized controlled trials (RCTs) compared the effects of laparoscopic hepatectomy (LH) and radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC), but the results have remained inconsistent. Hence, a meta-analysis and a systematic review of these treatment modalities are necessary to evaluate their efficacy and safety for HCC treatment. METHODS From the inception of this meta-analysis and review until August 31, 2019, we searched Medline, PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, and China Biomedical Literature Database for RCTs involving LH and RFA treatments of patients with HCC. The studies were screened and the data from these articles were extracted independently by two authors. Summary odd ratios (OR) or mean differences (MD) with 95% confidence intervals (CI) were calculated for each outcome with a fixed- or random-effect model. The outcomes for effectiveness evaluations included duration of surgery, estimated bleeding volume, incidence of blood transfusion during surgery, duration of hospital stay, and the outcome for safety included the incidence of cancer recurrence. RESULTS Seven RCTs with a total of 615 patients were identified, 312 and 303 of which underwent RFA and LH treatments, respectively. The duration of surgery (MD = -99.04; 95% CI: -131.26--66.82), estimated bleeding volume (MD = -241.97; 95% CI: -386.93--97.02), incidence of blood transfusion during surgery (OR = 0.08; 95% CI: 0.02-0.37), and duration of hospital stay (MD = -3.4; 95% CI: -5.22--1.57) in RFA treatment were significantly lower than those of LH treatment. However, the incidence of cancer recurrence was significantly higher for RFA treatment compared with LH treatment (OR = 2.68; 95% CI: 1.72-4.18). CONCLUSIONS LH treatment is preferred over RFA treatment with a better radical effect, but RFA treatment is more beneficial with smaller trauma, development of less complications, and shorter operating time when compared with HCC treatment.
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Affiliation(s)
- Shan Jin
- Department of oncology, People’s Hospital of Guizhou province, Guiyang City, China
| | - Shisheng Tan
- Department of oncology, People’s Hospital of Guizhou province, Guiyang City, China
| | - Wen Peng
- Department of oncology, People’s Hospital of Guizhou province, Guiyang City, China
| | - Ying Jiang
- Department of oncology, People’s Hospital of Guizhou province, Guiyang City, China
| | - Chunshan Luo
- Department of orthopedic, Guizhou Orthopedic Hospital, No. 184, Zhongshan East Road, Nanming District, Guiyang City, 550000 Guizhou Province China
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Wang J, Huang A, Wang YP, Yin Y, Fu PY, Zhang X, Zhou J. Circulating tumor DNA correlates with microvascular invasion and predicts tumor recurrence of hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:237. [PMID: 32309384 PMCID: PMC7154404 DOI: 10.21037/atm.2019.12.154] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background To evaluate the feasibility of predicting tumor recurrence of hepatocellular carcinoma (HCC) patients after curative hepatectomy by detection of circulating tumor DNA (ctDNA) through droplet digital PCR (ddPCR). Methods HCC patients receiving surgical treatment were enrolled and peripheral blood samples before and after hepatectomy were collected. Four hotspot mutants, TP53-rs28934571 (c.747G>T), TRET-rs1242535815 (c.1-124C>T), CTNNB1-rs121913412 (c.121A>G) and CTNNB1-rs121913407 (c.133T>C) were selected to detect ctDNA and the mutant allele frequency (MAF) was calculated accordingly. The matched peripheral blood mononuclear cells (PBMCs) were used for Sanger sequencing. The clinicopathologic information of the patients was retrospectively analyzed and the predictive abilities for postoperative recurrence of different clinicopathologic parameters and ctDNA were compared. Results Eighty-one patients were enrolled and 70.4% (57/81) of them had detectable ctDNA before hepatectomy. Positive preoperative ctDNA status was related to larger tumor size (P=0.001), multiple tumor lesions (P=0.001), microvascular invasion (MVI) (P<0.001), advanced BCLC stages (P<0.001) and shorter disease free survival (DFS) (P<<0.001) and overall survival (OS) (P<<0.001). Multivariate analysis showed that detectable ctDNA was the independent risk factor for postoperative recurrence. Moreover, receiver operating characteristic (ROC) curves proved that ctDNA possessed the second largest area under the curve (AUC) in foretelling postoperative recurrence right after BCLC stage. For patients after surgery, the alterations of MAF were also correlated to postsurgical recurrence. Patients with increased MAF had more incidences of MVI (P=0.016) and recurrence (P<0.001). At the same time, Kaplan-Meier curves revealed a significant shorter DFS and OS in the patients with increased MAF compared to the patients with decreased MAF (P<0.001 and P=0.0045, respectively) and ROC curves showed MAF to possess the greatest AUC among all the indices for postoperative recurrence. Conclusions Digital droplets PCR assessment of specific gene combination through ctDNA possesses potential prognostic value in HCC patients undergoing surgical treatment.
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Affiliation(s)
- Jian Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Ao Huang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Yu-Peng Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Yue Yin
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Pei-Yao Fu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Xin Zhang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China.,Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.,State Key Laboratory of Genetic Engineering Fudan University, Shanghai 200433, China
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12
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Liu DL, Lu LL, Dong LL, Liu Y, Bian XY, Lian BF, Xie L, Wen D, Gao DM, Ke AW, Fan J, Wu WZ. miR-17-5p and miR-20a-5p suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop. Theranostics 2020; 10:3668-3683. [PMID: 32206115 PMCID: PMC7069088 DOI: 10.7150/thno.41365] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/07/2020] [Indexed: 12/14/2022] Open
Abstract
Dysregulation of microRNA (miRNA) is a frequent event in hepatocellular carcinoma (HCC), but little is known whether it is a bystander or an actual player on residual HCC metastasis during liver microenvironment remodeling initiated by hepatectomy. Methods: The differently expressed miRNAs and mRNAs were identified from RNA-seq data. Western blot, qRT-PCR, fluorescence in situ hybridization, immunofluorescence and immunohistochemical were used to detect the expression of miRNA and mRNA in cell lines and patient tissues. The biological functions were investigated in vitro and in vivo. Chromatin immunoprecipitation, proximity ligation and luciferase reporter assay were used to explore the specific binding of target genes. The expression of HGF/ERBB3 signaling was detected by Western blot. Results: In this study, HGF induced by hepatectomy was shown to promote metastasis of residual HCC cells. miR-17-5p and miR-20a-5p were confirmed to play inhibitory roles on HCC metastasis. And ERBB3 was found to be the common target of miR-17-5p and miR-20a-5p. HCC cells with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 were often more sensitive to response HGF stimuli and to facilitate metastatic colonization both in vitro and in vivo experimental systems. Furthermore, HGF reinforced ERBB3 expression by NF-κB transcriptional activity in a positive feedback loop. Of particular importance, HCC patients with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 had significantly shorter OS and PFS survivals after surgical resection. Conclusion: miR-17-5p and miR-20a-5p could suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop and offer a new probable strategy for metastasis prevention after HCC resection.
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Affiliation(s)
- Dong-Li Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Li-Li Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Li-Li Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yang Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Xin-Yu Bian
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Bao-Feng Lian
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Duo Wen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Wei-Zhong Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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13
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Zhang XP, Chai ZT, Gao YZ, Chen ZH, Wang K, Shi J, Guo WX, Zhou TF, Ding J, Cong WM, Xie D, Lau WY, Cheng SQ. Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis. HPB (Oxford) 2019; 21:1687-1696. [PMID: 31153833 DOI: 10.1016/j.hpb.2019.04.014] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/22/2019] [Accepted: 04/22/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Microvascular invasion (MVI) is a major determinant of survival outcome for hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy of postoperative adjuvant Sorafenib (PA-Sorafenib) in HCC patients with MVI after R0 liver resection (LR). METHODS The data of patients who underwent R0 LR for HCC with histologically confirmed MVI at the Eastern Hepatobiliary Surgery Hospital were retrospectively analyzed. The survival outcomes for patients who underwent PA-Sorafenib were compared with those who underwent R0 LR alone. Propensity score matching (PSM) analysis was performed. RESULTS 728 HCC patients had MVI in the resected specimens after R0 resection, with 581 who underwent LR alone and 147 patients who received in additional adjuvant sorafenib. PSM matched 113 patients in each of these two groups. The overall survival (OS) and recurrence free survival (RFS) were significantly better for patients in the PA-sorafenib group (for OS: before PSM, P = 0.003; after PSM, P = 0.007), (for RFS: before PSM, P = 0.029; after PSM, P = 0.001), respectively. Similar results were obtained in patients with BCLC 0-A, BCLC B and Child-Pugh A stages of disease. CONCLUSIONS PA-Sorafenib was associated with significantly better survival outcomes than LR alone for HCC patients with MVI.
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Affiliation(s)
- Xiu-Ping Zhang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zong-Tao Chai
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu-Zhen Gao
- Department of Molecular Diagnosis, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Zhen-Hua Chen
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wei-Xing Guo
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Teng-Fei Zhou
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, The Second Military Medical University, Shanghai, China
| | - Jin Ding
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, The Second Military Medical University, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Dong Xie
- Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Wan Y Lau
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Shatin, SAR, Hong Kong, China
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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Song W, Li X, Zhao Y, Liu C, Xu J, Wang H, Zhang T. Functional, UV-curable coating for the capture of circulating tumor cells. Biomater Sci 2019; 7:2383-2393. [PMID: 30916683 DOI: 10.1039/c9bm00264b] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The capture of circulating tumor cells (CTCs) plays a crucial role in the early diagnosis, personalized treatment and postoperative evaluation of malignant tumors. In this study, UV-curable coating technology was combined with antibody immobilization to enable CTC captures on poly(methyl methacrylate) (PMMA) substrates. Controlled amounts of carboxyl groups and polyethylene glycol (PEG) segments were introduced into the coating formulation to facilitate immobilization of antibodies and block non-specific protein adsorption, respectively. Then, anti-EpCAM antibodies were immobilized on functionalized, coated PMMA substrates by EDC/NHS chemistry. Multiple physical, chemical and biological properties were investigated, including hydrophilicity, protein adsorption, platelet adhesion and anticoagulant properties. Thereafter, optimized coatings were applied on the inner wall of PMMA tubes, followed by immobilization of anti-EpCAM antibodies. After perfusion of the tubes with whole blood, enriched with SGC7901 gastric cancer cells that overexpress EpCAM antigens, rapid and efficient capture of the tumor cells was observed. These results provide a basis for further development of devices for the selective capture and enrichment of CTCs, using small blood volumes.
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Affiliation(s)
- Wanyun Song
- College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China.
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15
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Hypo-phosphorylated CD147 promotes migration and invasion of hepatocellular carcinoma cells and predicts a poor prognosis. Cell Oncol (Dordr) 2019; 42:537-554. [DOI: 10.1007/s13402-019-00444-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2019] [Indexed: 02/08/2023] Open
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16
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Liu S, Guo C, Wang J, Wang B, Qi H, Sun MZ. ANXA11 regulates the tumorigenesis, lymph node metastasis and 5-fluorouracil sensitivity of murine hepatocarcinoma Hca-P cells by targeting c-Jun. Oncotarget 2017; 7:16297-310. [PMID: 26908448 PMCID: PMC4941315 DOI: 10.18632/oncotarget.7484] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 02/09/2016] [Indexed: 02/05/2023] Open
Abstract
Annexin A11 (Anxa11) is associated with various cancers. Using a pair of syngeneic murine hepatocarcinoma cells, Hca-P with ~25% and Hca-F with ~75% lymph node metastatic (LNM) potentials, we demonstrated Anxa11 involvement in hepatocarcinoma lymphatic metastasis. Here, ANXA11 acted as a suppressor for the tumorigenicity, LNM and 5-FU resistance of Hca-P via c-Jun. We constructed monoclonal Hca-P cell line with stable ANXA11 knockdown. Although Bax and Bcl-2 levels increased in shRNA-Anxa11-transfected Hca-P, ANXA11 downregulation showed no clear effect on Hca-P apoptosis. ANXA11 downregulation promoted in vitro migration and invasion capacities of Hca-P. In situ adhesion potential of Hca-P cells toward LN was significantly enhanced following ANXA11 downregulation. Consistently, ANXA11 downregulation promoted the in vivo tumor growth and LNM capacities of Hca-P cells. ANXA11 knockdown enhanced the chemoresistance of Hca-P cells specifically toward 5-FU instead of cisplatin. Its downregulation increased c-Jun (pSer73) and decreased c-Jun (pSer243) levels in Hca-P. c-Jun (pSer243) downregulation seemed to be only correlated with ANXA11 knockdown without the connection to 5-FU treatment. Interestingly, compared with scramble-Hca-P cells, the levels of c-Jun and c-Jun (pSer73) in shRNA-Anxa11-Hca-P cells were upregulated in the presences of 0.1 and 1.0 mg/L 5-FU. The levels changes from c-Jun and c-Jun (pSer73) in Hca-P cells showed a more obvious tendency with the combination of ANXA11 knockdown and 5-FU treatment. ANXA11 level regulates LNM and 5-FU resistance of Hca-P via c-Jun pathway. It might play an important role in hepatocarcinoma cell malignancy and be a therapeutic target for hepatocarcinoma.
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Affiliation(s)
- Shuqing Liu
- Department of Biochemistry, Dalian Medical University, Dalian 116044, China
| | - Chunmei Guo
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China
| | - Jiasheng Wang
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China
| | - Bo Wang
- Department of Pathology, Dalian Medical University, Dalian 116044, China
| | - Houbao Qi
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China
| | - Ming-Zhong Sun
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China
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17
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Chi X, Yin Z, Jin J, Li H, Zhou J, Zhao Z, Zhang S, Zhao W, Xie C, Li J, Feng M, Lin H, Wang X, Gao J. Arsenite-loaded nanoparticles inhibit the invasion and metastasis of a hepatocellular carcinoma: in vitro and in vivo study. NANOTECHNOLOGY 2017; 28:445101. [PMID: 28829335 DOI: 10.1088/1361-6528/aa8791] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Postoperative recurrence and metastasis are the major problems for the current treatment of hepatocellular carcinomas (HCC) in the clinic, including hepatectomy and liver transplantation. Here, we report that arsentic-loaded nanoparticles (ALNPs) are able to reduce the invasion of HCC cells in vitro, and, more importantly, can strongly suppress the invasion and metastasis of HCC in vivo without adverse side effects. Compared to free drug arsenic trioxide , ALNPs can deliver the drug into cancer cells more efficiently, destroy the structure of microtubules and reduce the aggregation of microfilaments in cell membranes more significantly. Furthermore, our results also reveal that tumor cells in murine blood were reduced remarkably after intravenous injection of ALNPs, indicating that this nano-drug may efficiently kill circulating tumor cells in vivo. In conclusion, our nano-drug ALNPs have great potential for the suppression of metastasis of HCC, which may open up a new avenue for the effective treatment of HCC without metastasis and recurrence.
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Affiliation(s)
- Xiaoqin Chi
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Hepatobiliary and Pancreatic Tumor, Zhongshan Hospital, Xiamen University, Xiamen 361004, People's Republic of China
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18
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Zhao L, Xie C, Liu D, Li T, Zhang Y, Wan C. Early Detection of Hepatocellular Carcinoma in Patients with Hepatocirrhosis by Soluble B7-H3. J Gastrointest Surg 2017; 21:807-812. [PMID: 28243980 DOI: 10.1007/s11605-017-3386-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/05/2017] [Indexed: 01/31/2023]
Abstract
Increasing evidence has demonstrated an association between increased soluble B7-H3 (sB7-H3) levels and unfavorable progression in patients with malignant tumors. In the present study, we detected sB7-H3 levels in serum to investigate the value of sB7-H3 as a tool for differential diagnosis of cirrhotic patients with or without early-stage hepatocellular carcinoma (ESHCC). We also assessed the diagnostic value of sB7-H3regarding the prediction of overall survival (OS) of cirrhotic patients with ESHCC. sB7-H3 expression was measured in 91 healthy volunteers, 149 cirrhotic patients with ESHCC, and 87 cirrhotic patients by ELISA, and correlations between DCP1a level and clinical characteristics were analyzed. SB7-H3 concentrations were significantly higher in patients with ESHCC than in cirrhotic patients (P < 0.001). Using 48.34 ng/mL as a cutoff value, the sensitivity and specificity of sB7-H3 in differentiating between cirrhotic patients and cirrhotic patients with ESHCC were 76.5 and 93.1%, respectively. Moreover, high serum sB7-H3 in cirrhotic patients with ESHCC correlated with tumor size, tumor stage, vascular invasion, and tumor differentiation. The area under the curve (AUC) value for sB7-H3 (0.898) was significantly higher than those for AFP (0.789), CA199 (0.627), and CA125 (0.545) for differentiating between cirrhotic patients with ESHCC and sex- and age-matched cirrhotic patients without ESHCC. Our data indicate that serum sB7-H3 serves as a valuable biomarker for cirrhotic patients with ESHCC and that high levels of sB7-H3 correlate with poor clinical outcomes.
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Affiliation(s)
- Long Zhao
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Chao Xie
- Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Danqing Liu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350000, Fujian Province, People's Republic of China
| | - Tong Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Yu Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China.
| | - Chidan Wan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China.
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19
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Liu YH, Weng YP, Lin HY, Tang SW, Chen CJ, Liang CJ, Ku CY, Lin JY. Aqueous extract of Polygonum bistorta modulates proteostasis by ROS-induced ER stress in human hepatoma cells. Sci Rep 2017; 7:41437. [PMID: 28134285 PMCID: PMC5278379 DOI: 10.1038/srep41437] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 12/16/2016] [Indexed: 01/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains the leading cause of cancer mortality with limited therapeutic targets. The endoplasmic reticulum (ER) plays a pivotal role in maintaining proteostasis in normal cells. However, alterations in proteostasis are often found in cancer cells, making it a potential target for therapy. Polygonum bistorta is used in traditional Chinese medicine owing to its anticancer activities, but the molecular and pharmacological mechanisms remain unclear. Using hepatoma cells as a model system, this study demonstrated that P. bistorta aqueous extract (PB) stimulated ER stress by increasing autophagosomes but by blocking degradation, followed by the accumulation of ubiquitinated proteins and cell apoptosis. In addition, an autophagy inhibitor did not enhance ubiquitinated protein accumulation whereas a reactive oxygen species (ROS) scavenger diminished both ubiquitinated protein accumulation and ligand-stimulated epidermal growth factor receptor (EGFR) expression, suggesting that ROS generation by PB may be upstream of PB-triggered cell death. Nevertheless, PB-exerted proteostasis impairment resulted in cytoskeletal changes, impairment of cell adhesion and motility, and inhibition of cell cycle progression. Oral administration of PB delayed tumour growth in a xenograft model without significant body weight loss. These findings indicate that PB may be a potential new alternative or complementary medicine for HCC.
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Affiliation(s)
- Yu-Huei Liu
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, 404, Taiwan.,Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, 404, Taiwan
| | - Yui-Ping Weng
- Graduate Institute of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan.,Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan
| | - Hsuan-Yuan Lin
- Department of Life Science, National Taiwan Normal University, Taipei, 116, Taiwan
| | - Sai-Wen Tang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Chao-Jung Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, 404, Taiwan
| | - Chi-Jung Liang
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Chung-Yu Ku
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Jung-Yaw Lin
- Department of Life Science, National Taiwan Normal University, Taipei, 116, Taiwan.,Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
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Yang GY, Zhang AQ, Wang J, Li CH, Wang XQ, Pan K, Zhou C, Dong JH. Hepatoma-derived growth factor promotes growth and metastasis of hepatocellular carcinoma cells. Cell Biochem Funct 2017; 34:274-85. [PMID: 27273265 DOI: 10.1002/cbf.3189] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 03/21/2016] [Accepted: 04/05/2016] [Indexed: 12/19/2022]
Abstract
We aimed to elucidate the effects of hepatoma-derived growth factor (HDGF) on growth and metastasis of hepatocellular carcinoma (HCC) cells. Tissue microarrays with 236 HCC specimens and 18 extrahepatic metastases were utilized to detect the HDGF expression by immunohistochemistry. Meanwhile, HDGF expressions in HCC cell lines with different metastatic potentials were examined using immunofluorescence staining, real-time PCR and western blotting. After HDGF silencing, the growth and metastatic potentials of HCC cells were evaluated by soft agar assay, invasion assay, together with tumorigenicity assay in nude mice. The gelatin zymography was performed by detecting MMP-2 and MMP-9 levels. Additionally, western blotting was conducted to determine the levels of total and phosphorylated ERK1/2, JNK, p38 and Akt. The results showed that HDGF was overexpressed in HCC metastasis tumour, and the expression increased with the differentiation degree of tumours (Grade I 44.0%, Grade II 48.4% and Grade III 65.6%). Consistently, HDGF levels were positively associated with the metastatic capability of HCC cells (MHCC97L < MHCC97H < HCCLM3). The growth and metastasis were suppressed by HDGF-siRNA. Gelatinolytic activities were enhanced in the three metastatic HCC cell lines, but had no significant difference among them. The tumourigenicity and metastatic capability of HCCLM3 cells in nude mice were inhibited after silencing HDGF. Meanwhile, HDGF-siRNA specifically suppressed the total and phosphorylated protein levels of ERK1/2, while not JNK, p38 and Akt. In conclusion, HDGF was overexpressed in HCC patients and cells, and HDGF might be closely correlated with HCC metastasis via regulating ERK signalling pathway. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Guang-Yun Yang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Ai-Qun Zhang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Jing Wang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Chong-Hui Li
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Xian-Qiang Wang
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Ke Pan
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Cheng Zhou
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
| | - Jia-Hong Dong
- Department of Hepatobiliary Surgery, PLA General Hospital and Institute of Hepatobiliary of Chinese PLA, Beijing, China
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Fu ZG, Wang L, Cui HY, Peng JL, Wang SJ, Geng JJ, Liu JD, Feng F, Song F, Li L, Zhu P, Jiang JL, Chen ZN. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells. Oncotarget 2017; 7:9429-47. [PMID: 26882566 PMCID: PMC4891050 DOI: 10.18632/oncotarget.6990] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 01/17/2016] [Indexed: 02/07/2023] Open
Abstract
CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.
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Affiliation(s)
- Zhi-guang Fu
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Li Wang
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, P.R. China
| | - Hong-yong Cui
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Jian-long Peng
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Shi-jie Wang
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Jie-jie Geng
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Ji-de Liu
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Fei Feng
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Fei Song
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Ling Li
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Ping Zhu
- Department of Clinical Immunology, PLA Specialized Research Institute of Rheumatology & Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China
| | - Jian-li Jiang
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
| | - Zhi-nan Chen
- Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, P.R. China
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22
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Zhang Z, Xu C, Zhang X, Huang L, Zheng C, Chen H, Wang Y, Ju H, Yao Q. TRIM11 Upregulation Contributes to Proliferation, Invasion, and EMT of Hepatocellular Carcinoma Cells. Oncol Res 2016; 25:691-699. [PMID: 28244856 PMCID: PMC7841231 DOI: 10.3727/096504016x14774897404770] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The tripartite motif-containing protein 11 (TRIM11), a member of the TRIM protein family, has attracted much attention because of its involvement in the development of the central nervous system. It has gained renewed focus because of its newly found function in promoting tumors. However, little is known about its role in hepatocellular carcinoma (HCC). In the present study, we found TRIM11 to be overexpressed in HCC tissues and cell lines. Downregulation of TRIM11 inhibited HCC cell proliferation and invasion in vitro and in vivo as well as suppressed the epithelial–mesenchymal transition (EMT) process. In addition, downregulation of TRIM11 decreased the protein expression levels of p-PI3K and p-Akt in HCC cells and thus inhibited activation of the PI3K/Akt signaling pathway. Based on these results, we suggest the importance of TRIM11 in HCC progression and the potential of TRIM11 as a therapeutic target for HCC.
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23
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Huang A, Zhang X, Zhou SL, Cao Y, Huang XW, Fan J, Yang XR, Zhou J. Detecting Circulating Tumor DNA in Hepatocellular Carcinoma Patients Using Droplet Digital PCR Is Feasible and Reflects Intratumoral Heterogeneity. J Cancer 2016; 7:1907-1914. [PMID: 27698932 PMCID: PMC5039376 DOI: 10.7150/jca.15823] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 07/24/2016] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Circulating tumor DNA (ctDNA) is increasingly recognized as liquid biopsy to profile tumor genome. Droplet digital PCR (ddPCR) is a highly sensitive and easily operable platform for mutant detection. Here, we tried to detect ctDNA in hepatocellular carcinoma (HCC) patients using ddPCR. METHODS Studies sequencing the genome of HCCs and COSMIC (Catalogue of Somatic Mutations in Cancer) database were reviewed to identify hotspot mutations. Circulating cell-free DNAs (cfDNAs) extracted from 1 ml preoperative plasma sample were analyzed to detect circulating mutants using ddPCR. The DNAs from matched tumor and adjacent liver tissues or peripheral blood mononuclear cells (PBMCs) were sequenced to identify the origin of circulating mutants. RESULTS Forty-eight HCC patients were enrolled and four gene loci, TP53 (c.747G>T), CTNNB1 (c.121A>G, c.133T>C), and TERT (c.1-124C>T) were chosen as targets for ddPCR assay. Serial dilution demonstrated the detection limit of ddPCR to be 0.01%. Twenty-seven patients (56.3%, 27/48) were found to have at least one kind of circulating mutants, with the mutant allele frequency ranging from 0.33% to 23.7%. Six patients (22.2%, 6/27) also had matched mutants in tumor tissues while none of the mutants were detected in adjacent liver tissues or PBMCs in all patients, which excluded the nonneoplastic origin of these circulating mutants and qualified them as ctDNA. CONCLUSIONS ctDNA could be readily detected in HCC patients by targeting hotspot mutations using ddPCR and might reflect intratumoral heterogeneity. ctDNA detecting may serve as a promising liquid biopsy in HCC management.
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Affiliation(s)
- Ao Huang
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
| | - Xin Zhang
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
| | - Shao-Lai Zhou
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
| | - Ya Cao
- Cancer Research Institute, Central South University
| | - Xiao-Wu Huang
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
| | - Jia Fan
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
- Institute of Biomedical Sciences, Fudan University, Shanghai, No.130, Dong'an Rd, 200032, China
| | - Xin-Rong Yang
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
| | - Jian Zhou
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University
- State Key Laboratory of Genetic Engineering Fudan University, No.220, Handan Rd, Shanghai, 200433, China
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24
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Zhang L, Wang W, Li X, He S, Yao J, Wang X, Zhang D, Sun X. MicroRNA-155 promotes tumor growth of human hepatocellular carcinoma by targeting ARID2. Int J Oncol 2016; 48:2425-34. [PMID: 27035278 DOI: 10.3892/ijo.2016.3465] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/07/2016] [Indexed: 11/05/2022] Open
Abstract
Aberrant expression of microRNA-155 (miR-155) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR‑155 and its underlying mechanisms involved in hepatocarcinogenesis remain to be determined. In this study, we demonstrated that the expression of miR-155 was elevated in both hepatocellular carcinoma (HCC) tissues and cell lines. Clinical association analysis revealed that high expression of miR-155 was correlated with malignant clinicopathological characteristics including large tumor size, high Edmondson-Steiner grading and TNM tumor stage. Furthermore, its high expression conferred a reduced 5-year overall survival and disease-free survival of HCC patients. Gain- and loss-of function studies revealed that miR‑155 promoted cell cycle progression, cell proliferation and inhibited apoptosis. Mechanistically, we identified AT-rich interactive domain 2 (ARID2) as a direct downstream target and functional mediator of miR‑155 in HCC cells. Notably, alterations of ARID2 expression abrogated the effects of miR‑155 on HCC cell proliferation, cell cycle and apoptosis. Moreover, we demonstrated that Akt phosphorylation is essential for the functional roles of miR‑155 through altering Cyclin D1 and p27, which were key components of cell cycle machinery. Finally, we disclosed that the downregulation of miR‑155 suppressed tumor growth of HCC by inhibiting Akt signaling pathway. In conclusion, our results indicate that miR‑155 promotes tumor growth of HCC by targeting ARID2-mediated Akt phosphorylation pathway, and potentially serves as a novel prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Li Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Wei Wang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaobin Li
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Sai He
- Breast Cancer Program, Shaanxi Provincial Tumor Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Jianfeng Yao
- Department of General Surgery, Shanxi Province People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Xiaolong Wang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Di Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xuejun Sun
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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25
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Lu Y, Zhu M, Li W, Lin B, Dong X, Chen Y, Xie X, Guo J, Li M. Alpha fetoprotein plays a critical role in promoting metastasis of hepatocellular carcinoma cells. J Cell Mol Med 2016; 20:549-558. [PMID: 26756858 PMCID: PMC4759472 DOI: 10.1111/jcmm.12745] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 10/23/2015] [Indexed: 12/29/2022] Open
Abstract
A high level of serum alpha fetoprotein (AFP) is positively associated with human hepatocellular carcinoma (HCC) carcinogenesis and metastasis; however, the function of AFP in HCC metastasis is unknown. This study has explored the effects of AFP on regulating metastatic and invasive capacity of human HCC cells. Forty-seven clinical patients' liver samples were collected and diagnosed; HCC cells line, Bel 7402 cells (AFP-producing) and liver cancer cell line cells (non-AFP-producing) were selected to analyse the role of AFP in the metastasis of HCC cells. The results indicated that high serum concentration of AFP was positively correlated with HCC intrahepatic, lymph nodes and lung metastasis. Repressed expression of AFP significantly inhibited the capability of migration and invasion of Bel 7402 cells, expression of keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), matrix metalloproteinase 2/9 (MMP2/9) and CXC chemokine receptor 4 (CXCR4) were also down-regulated in Bel 7402 cells; migration and invasion, expression of K19, EpCAM, MMP2/9 and CXCR4 were significantly enhanced when HLE cells were transfected with AFP-expressed vector. The results demonstrated that AFP plays a critical role in promoting metastasis of HCC; AFP promoted HCC cell invasion and metastasis via up-regulating expression of metastasis-related proteins. Thus, AFP may be used as a novel therapeutic target for treating HCC patients.
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Affiliation(s)
- Yan Lu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Wei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Xu Dong
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Yi Chen
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Xieju Xie
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Department of Pathophysiology, Hainan Medical College, Haikou, Hainan Province, China
| | - Junli Guo
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan Province, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan Province, China
- Institution of Tumor, Hainan Medical College, Haikou, Hainan Province, China
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26
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Gao JZ, Li J, DU JL, Li XL. Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence. Oncol Lett 2016; 11:1791-1798. [PMID: 26998078 DOI: 10.3892/ol.2016.4130] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 08/25/2015] [Indexed: 12/13/2022] Open
Abstract
The present study aimed to investigate the expression level of HOX transcript antisense RNA (HOTAIR) in hepatocellular carcinoma (HCC) and its association with various clinicopathological characteristics, and to further explore the molecular mechanisms of HOTAIR function in HCC. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression level of HOTAIR in 60 paired fresh HCC samples and adjacent normal liver tissue samples. The association between HOTAIR expression and clinicopathological parameters was analyzed. Lentivirus-mediated HOTAIR-specific small hairpin RNA vectors were transfected into HepG2 cells. Cell proliferation and invasion in vitro were examined by MTT and Transwell assays, respectively. A xenograft model was used to analyze the tumorigenesis of liver cancer cells in vivo. In addition, semi-quantitative RT-PCR was used to detect the expression level of Wnt/β-catenin signaling molecules under the condition of HOTAIR inhibition. The results revealed that the expression level of HOTAIR in HCC tissues was higher than that in adjacent non-cancerous tissues. HOTAIR expression was significantly associated with poor tumor differentiation (P=0.002), metastasis (P=0.002) and early recurrence (P=0.001). In vitro, the inhibition of HOTAIR in liver cancer cells resulted in the suppression of cell proliferation and invasion. HOTAIR depletion significantly inhibited the rate of growth of liver cancer cells in vivo. Furthermore, the expression levels of Wnt and β-catenin were downregulated when HOTAIR expression was suppressed. In conclusion, HOTAIR is important in the progression and recurrence of HCC, partly through the regulation of the Wnt/β-catenin signaling pathway. Targeting HOTAIR may be a novel therapeutic strategy for HCC.
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Affiliation(s)
- Jian-Zhi Gao
- Department of Basic Medical Sciences, Xinxiang Medical College, Xinxiang, Henan 453003, P.R. China; Department of Pathology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Jia Li
- Department of Pathology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China; Department of Pathology, Beijing Tiantan Hospital Affiliated to Capital University of Medical Sciences, Beijing 100050, P.R. China
| | - Jing-Li DU
- Department of Pathology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Xiao-Lei Li
- Department of Molecular Biology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
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Zhang W, Zhao G, Wei K, Zhang Q, Ma W, Song T, Wu Q, Zhang T, Kong D, Li Q. Adjuvant sorafenib reduced mortality and prolonged overall survival and post-recurrence survival in hepatocellular carcinoma patients after curative resection: a single-center experience. Biosci Trends 2015; 8:333-8. [PMID: 25641180 DOI: 10.5582/bst.2014.01120] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Adjuvant therapy after resection of hepatocellular carcinoma (HCC) is limited. Here, we evaluated the effects of postoperative sorafenib on recurrence and survival in HCC patients. Recurrence-free survival and overall survival were analyzed as the main endpoint, recurrence rate, and mortality rate were analyzed as second endpoint. Furthermore, post-recurrence survival was also analyzed. Clinicopathological factors were compared between sorafenib and control groups. Seventy-eight patients were eligible for final data analysis (46 in control group; 32 in sorafenib group). Sorafenib did not significantly prolong recurrence-free survival (11.0 months in the control group vs. 11.7 months in the sorafenib group, p = 0.702), but significantly prolonged overall survival (32.4 vs. 25.0 months, p = 0.046). Sorafenib did not reduce recurrence rate (67.7% vs. 78.3%, p = 0.737), but significantly reduced mortality rate (28.1% vs. 60.9%, p = 0.004). The increased post-recurrence survival (22.2 vs. 4.4 months, p = 0.003) may have contributed to the survival benefit after recurrence in the sorafenib group. Adjuvant sorafenib did not decrease tumor recurrence, but significantly reduced mortality and prolonged overall survival of HCC patients after curative resection, probably by inhibiting tumor growth after tumor recurrence.
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Affiliation(s)
- Wei Zhang
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical ResearchCenter for Cancer and Key Laboratory of Cancer Prevention and Therapy
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28
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Zhou JW, Li Y, Yue LX, Luo CL, Chen Y, Zhang JY. Autoantibody response to Sui1 and its tissue-specific expression in hepatocellular carcinoma. Tumour Biol 2015; 37:2547-53. [DOI: 10.1007/s13277-015-4074-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/13/2015] [Indexed: 01/09/2023] Open
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29
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Zhang C, Li Y, Wang Y. Diagnostic value of serum B7-H4 for hepatocellular carcinoma. J Surg Res 2015; 197:301-6. [DOI: 10.1016/j.jss.2015.04.034] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 03/15/2015] [Accepted: 04/09/2015] [Indexed: 10/23/2022]
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30
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Li W, Liang Y, Yang B, Sun H, Wu W. Downregulation of ARNT2 promotes tumor growth and predicts poor prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol 2015; 30:1085-93. [PMID: 25611915 DOI: 10.1111/jgh.12905] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/02/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) is a transcriptional regulator and member of the basic helix-loop-helix/Per-ARNT-SIM (bHLH/PAS) superfamily. Recently, evidence of that ARNT is involved in carcinogenesis and cancer progression has emerged. The aim of current study was to investigate the role of ARNT2, a homolog of ARNT, in tumor growth, invasion, and prognosis of hepatocellular carcinoma (HCC). METHODS Tissue microarray and immunohistochemical staining were used to examine the expression of ARNT2 in 195 HCC tissues. Factors associated with ARNT2 levels were assessed by univariate and multivariate Cox regression analyses. Cell proliferation, migration, and invasion assays were performed by using ARNT2 silencing and overexpressing HCCLM6 cell line. Orthotopic xenograft HCC model was used to elucidate the effects of ARNT2 on HCC progression in vivo. RESULTS High intratumoral of ARNT2 level was well correlated with longer overall survival (OS) and lower tumor to recurrence (TTR) of HCC patients after resection. Multivariate analysis revealed that intratumoral ARNT2 overexpression was an independent prognostic factor for both OS and TTR. Knockdown of ARNT2 in HCCLM6 cells was significantly enhanced while overexpression of ARNT2 significantly inhibited the ability of cell proliferation, invasion, and migration. In animal studies, downregulation of ARNT2 in HCCLM6 cells promoted, whereas upregulation of ARNT2 in HCCLM6 cells reduced HCCLM6 growth in vivo. CONCLUSIONS Our data demonstrate that ARNT2 plays an inhibitory role in HCC progression and suggest that ARNT2 may be a potential prognostic predictor and therapeutic target for HCC.
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Affiliation(s)
- Weiwei Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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31
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Chai ZT, Zhu XD, Ao JY, Wang WQ, Gao DM, Kong J, Zhang N, Zhang YY, Ye BG, Ma DN, Cai H, Sun HC. microRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3K/Akt pathway in hepatocellular carcinoma. J Hematol Oncol 2015; 8:56. [PMID: 26021873 PMCID: PMC4455972 DOI: 10.1186/s13045-015-0150-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 05/06/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND microRNAs (miRNAs) have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages. The aim of this study was to find whether miR-26a can suppress M-CSF expression and the recruitment of macrophages. METHODS Hepatocellular carcinoma (HCC) cell lines with decreased or increased expression of miR-26a were established in a previous study. M-CSF expression by tumor cells was measured by enzyme-linked immunosorbent assay, and cell migration assays were used to explore the effect of HCC cell lines on macrophage recruitment in vitro. Real-time PCR measured a panel of mRNAs expressed by macrophages. Xenograft models were used to observe tumor growth. Immunohistochemistry was conducted to study the relation between miR-26a expression and M-CSF expression and macrophage recruitment in patients with HCC. RESULTS Ectopic expression of miR-26a reduced expression of M-CSF. The conditioned medium (CM) from HepG2 cells that overexpressed miR-26a reduced the migration ability of THP-1 cells stimulated by phorbol myristate acetate (PMA) increased expression of interleukin (IL)-12b or IL-23 mRNA and decreased expression of chemokine (C-C motif) ligand (CCL)22, CCL17, and IL-10 mRNA, in comparison to the medium from the parental HepG2 cells. These effects could be interrupted by the PI3K/Akt pathway inhibitor LY294002. Ectopic expression of miR-26a in HCC cells suppressed tumor growth, M-CSF expression, and infiltration of macrophages in tumors. Similar results were also found when using HCCLM3 cells. Furthermore, the expression of miR-26a was inversely correlated with M-CSF expression and macrophage infiltration in tumor tissues from patients with HCC. CONCLUSIONS miR-26a expression reduced M-CSF expression and recruitment of macrophages in HCC.
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Affiliation(s)
- Zong-Tao Chai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Xiao-Dong Zhu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Jian-Yang Ao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Wen-Quan Wang
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China.
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Jian Kong
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Ning Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Yuan-Yuan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Bo-Gen Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - De-Ning Ma
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Hao Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
| | - Hui-Chuan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.
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Budker VG, Monahan SD, Subbotin VM. Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) of therapeutic agents as the future direction. Drug Discov Today 2014; 19:1855-70. [PMID: 25173702 DOI: 10.1016/j.drudis.2014.08.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 07/10/2014] [Accepted: 08/21/2014] [Indexed: 01/01/2023]
Abstract
Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities. One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity. Although loco-regional delivery has been most prominent in cancers of the liver, soft tissues and serosal peritoneal malignancies, survival benefits are very far from desirable. This review discusses the evolution of loco-regional treatments, the present approaches and offers rapidly reversible hydrophobization of drugs as the new future direction.
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Dai Z, Zhou SL, Zhou ZJ, Bai DS, Xu XY, Fu XT, Chen Q, Zhao YM, Zhu K, Yu L, Yang GH, Wang Z, Wu WZ, Zhou J, Fan J. Capn4 contributes to tumour growth and metastasis of hepatocellular carcinoma by activation of the FAK-Src signalling pathways. J Pathol 2014; 234:316-28. [PMID: 24962955 DOI: 10.1002/path.4395] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 06/10/2014] [Accepted: 06/17/2014] [Indexed: 01/04/2023]
Abstract
Calpain small subunit 1 (Capn4) has been identified as a major gene that promotes metastasis of hepatocellular carcinoma (HCC). However, the mechanism by which Capn4 promotes progression of HCC is not understood. In this study, we found that Capn4 expression was increased in highly metastatic HCC cell lines and in tumour tissue from HCC patients compared to healthy patient tissue. Over-expression of Capn4 in HCC cells enhanced tumour cell growth in vitro and increased invasiveness, tumourigenicity and lung metastasis in vivo. Protein microarray analyses showed that expression of multiple proteins was regulated by Capn4. Interestingly, Capn4 was found to physically associate with FAK and promoted hyperactivity of the FAK-Src signalling pathway via increased phosphorylation of specific tyrosine residues of FAK, Src and p130Cas. Knock-down of Capn4 expression suppressed the malignant behaviour of HCC cells and inhibited the FAK-Src signalling pathway. Furthermore, Capn4-mediated invasion and metastasis of HCC cells required up-regulation of matrix metalloproteinase-2 (MMP2) through activation of this signalling pathway. Our clinical data revealed that Capn4 expression correlated well with the levels of phospho-FAK, and over-expression of both Capn4 and phospho-FAK correlates with the poorest survival outcomes in HCC. In conclusion, our data showed that Capn4 can contribute to HCC growth and metastasis via activation of the FAK-Src signalling pathway and MMP2.
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Affiliation(s)
- Zhi Dai
- Liver Cancer Institute and Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, People's Republic of China
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Elemene injection induced autophagy protects human hepatoma cancer cells from starvation and undergoing apoptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:637528. [PMID: 25152762 PMCID: PMC4135145 DOI: 10.1155/2014/637528] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 05/23/2014] [Indexed: 11/18/2022]
Abstract
Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anticancer effects against a broad spectrum of tumors. In an in vivo experiment, we found that apatinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR2, combined with elemene injection (Ele) for the treatment of H22 solid tumor in mice resulted in worse effectiveness than apatinib alone. Moreover, Ele could protect HepG2 cells from death induced by serum-free starvation. Further data on the mechanism study revealed that Ele induced protective autophagy and prevented human hepatoma cancer cells from undergoing apoptosis. Proapoptosis effect of Ele was enhanced when proautophagy effect was inhibited by hydroxychloroquine. Above all, Ele has the effect of protecting cancer cells from death either in apatinib induced nutrient deficient environment or in serum-free induced starvation. A combination of elemene injection with autophagy inhibitor might thus be a useful therapeutic option for hepatocellular carcinoma.
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Wang H, Wang X, Li X, Fan Y, Li G, Guo C, Zhu F, Zhang L, Shi Y. CD68(+)HLA-DR(+) M1-like macrophages promote motility of HCC cells via NF-κB/FAK pathway. Cancer Lett 2014; 345:91-99. [PMID: 24333724 DOI: 10.1016/j.canlet.2013.11.013] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 11/17/2013] [Accepted: 11/23/2013] [Indexed: 12/12/2022]
Abstract
TAM is a prominent component of inflammatory microenvironment, presenting M1 and M2 polarized states in HCC. The objective of this study is to investigate the relationship between M1-polarized macrophages and metastasis in HCC. We used immunohistochemical double-staining method to inspect the infiltration of CD68(+)HLA-DR(+) M1-like macrophages in HCC tissues. The M1-polarized macrophage was derived from THP-1 cell treated by LPS and IFN-γ in vitro. Transwell migration assay was used to evaluate whether the M1-polarized macrophage enhanced motility of HCC cells in the presence or absence of NF-κB inhibitor Bay 11-7802. The activation of NF-κB and FAK signaling pathways was examined by Western blot assay. Our results showed that the density of CD68(+)HLA-DR(+) TAM in the HCC with metastasis is significantly higher than that in the HCC without metastasis. Moreover, the conditioned medium from the M1 macrophages promote the migration of HCC cells and induced the activation of NF-κB and FAK signaling. The promoted migration of HCC cells was abrogated by the Bay 11-7802, as well as the activation of NF-κB and FAK pathway. Our findings implied a pro-metastatic role of M1-like TAM in HCC.
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MESH Headings
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Differentiation, Myelomonocytic/metabolism
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Movement/physiology
- Cell Polarity/physiology
- Focal Adhesion Kinase 1/immunology
- Focal Adhesion Kinase 1/metabolism
- HLA-DR Antigens/immunology
- HLA-DR Antigens/metabolism
- Hep G2 Cells
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/pathology
- NF-kappa B/immunology
- NF-kappa B/metabolism
- Neoplasm Metastasis
- Signal Transduction
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Affiliation(s)
- Hao Wang
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China
| | - Xianteng Wang
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China
| | - Xia Li
- Department of Internal Medicine, Jinan No. 1 People's Hospital, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Guosheng Li
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Chun Guo
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China
| | - Faliang Zhu
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China
| | - Lining Zhang
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China
| | - Yongyu Shi
- Institute of Immunology, School of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan 250012, China.
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Tanase AM, Dumitrascu T, Dima S, Grigorie R, Marchio A, Pineau P, Popescu I. Influence of hepatitis viruses on clinicopathological profiles and long-term outcome in patients undergoing surgery for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2014; 13:162-172. [PMID: 24686543 DOI: 10.1016/s1499-3872(14)60026-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The global risk of hepatocellular carcinoma (HCC) is largely due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In recent years, however, an increased prevalence of non-viral HCC has been noted. The clinical impact of the presence/absence of viral infections in HCC remains controversial. The present study aimed to assess the effect of hepatitis viruses on demographics, clinical and pathological features and long-term outcome in a large cohort of Romanian patients who underwent surgery for HCC. METHODS The study included 404 patients with HCC who had undergone resection, transplantation or radiofrequency ablation at a single institution between 2001 and 2010. The patients were divided into four groups: 85 patients with hepatitis B virus infection (HBV group), 164 patients with hepatitis C virus infection (HCV group), 39 patients with hepatitis B and C virus co-infection (HBCV group), and 116 patients without viral infection (non-BC group). RESULTS The patients of both HBV (56.0+/-11.3 years) and HBCV groups (56.0+/-9.9 years) were significantly younger than those of the HCV (61.0+/-8.5 years, P=0.001) and non-BC groups (61.0+/-13.0 years, P=0.002). Interestingly, the prevalence of liver cirrhosis was significantly lower in the non-BC group (47%) than in any other subsets (72%-90%, P<0.002). Furthermore, the non-BC patients were more advanced according to the Barcelona Clinic Liver Cancer stages than the patients of the HCV or HBCV groups (P<0.020); accordingly, they were more frequently assessed beyond the Milan criteria than any other groups (P=0.001). No significant differences in the disease-free or overall survival rates were observed among these groups. CONCLUSIONS Patients with non-viral HCC are diagnosed at advanced ages and stages, a situation plausibly due to the poor effectiveness of cancer surveillance in community practice. The presence of viral infections does not appear to impair the long-term prognosis after surgical treatment in patients with HCC; however, there is a trend for worse disease-free survival rates in HBCV patients, though statistical significance was not reached.
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Affiliation(s)
- Anna-Maria Tanase
- Center of General Surgery and Liver Transplant, Fundeni Clinical Institute, Fundeni Street No. 258, 022328, Bucharest, Romania.
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Zheng YB, Meng QW, Zhao W, Liu B, Huang JW, He X, Li Y, Hu BS, Lu LG. Prognostic value of serum vascular endothelial growth factor receptor 2 response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Med Oncol 2014; 31:843. [PMID: 24442426 DOI: 10.1007/s12032-014-0843-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 01/10/2014] [Indexed: 12/13/2022]
Abstract
We aimed to elucidate whether serum VEGFR2 concentration before and after transarterial chemoembolization (TACE) can predict survival in patients with unresectable hepatocellular carcinoma (HCC). Serum VEGFR2 concentrations were serially measured in 169 patients with advanced HCC before and after TACE. We defined a decrease in the serum VEGFR2 level>10% from the pretreatment level as response. Serum VEGFR2 concentrations decreased in 44 (26.0%) patients at week 4. Patients who had a VEGFR2 response at week 4 had a longer median survival than those who did not have a VEGFR2 decrease (19.0 vs. 9.8 months, p<0.001). Clinical variables associated with OS in addition to VEGFR2 response also included extrahepatic metastases (p=0.005) and vascular invasion (p=0.035). VEGFR2 decrease after TACE (p=0.012) and presence of extrahepatic metastases (p=0.02) were independently associated with OS by multivariate analysis. A serum VEGFR2 concentration decrease at 4 weeks after TACE may predict favorable overall survival in patients with advanced HCC.
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Affiliation(s)
- You-Bing Zheng
- Department of Interventional Radiology, Cancer Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Chai ZT, Kong J, Zhu XD, Zhang YY, Lu L, Zhou JM, Wang LR, Zhang KZ, Zhang QB, Ao JY, Wang M, Wu WZ, Wang L, Tang ZY, Sun HC. MicroRNA-26a inhibits angiogenesis by down-regulating VEGFA through the PIK3C2α/Akt/HIF-1α pathway in hepatocellular carcinoma. PLoS One 2013; 8:e77957. [PMID: 24194905 PMCID: PMC3806796 DOI: 10.1371/journal.pone.0077957] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 09/06/2013] [Indexed: 12/21/2022] Open
Abstract
Background & Aims microRNAs (miRNAs) have been reported to regulate angiogenesis by down-regulating the expression of pro-angiogenic or anti-angiogenic factors. The aims of this study were to investigate whether miR-26a inhibited angiogenesis by down-regulating vascular endothelial growth factor A (VEGFA) and its clinical relevance in hepatocellular carcinoma (HCC). Methods The expression of miR-26a was modified in HepG2 and HCCLM3 cell lines respectively, and a panel of angiogenic factors was measured by real-time PCR in the cells. A luciferase reporter assay was used to validate the target gene of miR-26a. Specific inhibitors of signal transduction pathway and siRNA approaches were used to explore the regulatory mechanism of miR-26a. Migration and tube forming assays were conducted to show the changes of angiogenesis induced by miR-26a and its target genes. Finally animal studies were used to further validate those findings. Results Ectopic expression of miR-26a exhibited decreased levels of VEGFA in HepG2 cells. Migration and tube forming of human umbilical vein endothelial cells (HUVECs) were decreased in the conditioned medium from ectopic expression of miR-26a in HepG2 cells compared to control HepG2 cells. The pro-angiogenic effects of the conditioned medium of HepG2 cells on HUVECs were specifically decreased by LY294002, YC-1, and bevacizumab. Integrated analysis disclosed PIK3C2α as a downstream target gene of miR-26a. Ectopic expression of miR-26a suppressed ectopic and orthotopic tumor growth and vascularity in nude mice. The results in HCCLM3 were consistent with those in HepG2. miR-26a expression was inversely correlated with VEGFA expression in HCC patients. Conclusions miR-26a modulated angiogenesis of HCC through the PIK3C2α/Akt/HIF-1α/VEGFA pathway. The expression of VEGFA was inversely correlated with miR-26a expression in HCC tumors.
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Affiliation(s)
- Zong-Tao Chai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Jian Kong
- Department of Hepatobiliary Surgery, Capital Medical University, Beijing Chaoyang Hospital, Beijing, P.R. China
| | - Xiao-Dong Zhu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Yuan-Yuan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Lu Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Jia-Min Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Long-Rong Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Ke-Zhi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Qiang-Bo Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Jian-Yang Ao
- Department of Hepatobiliary Surgery, Capital Medical University, Beijing Chaoyang Hospital, Beijing, P.R. China
| | - Miao Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Wei-Zhong Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Lu Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Zhao-You Tang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Hui-Chuan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
- * E-mail:
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Baicalein inhibits the invasion and metastatic capabilities of hepatocellular carcinoma cells via down-regulation of the ERK pathway. PLoS One 2013; 8:e72927. [PMID: 24039823 PMCID: PMC3765161 DOI: 10.1371/journal.pone.0072927] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 07/15/2013] [Indexed: 01/13/2023] Open
Abstract
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
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Zhong Y, Yan J, Deng M, Hu K, Yao Z, Zou Y, Xu R. Impaired phosphate and tension homologue deleted on chromosome 10 expression and its prognostic role in radical surgery for hepatocellular carcinoma with family aggregation resulting from hepatitis B and liver cirrhosis. Exp Biol Med (Maywood) 2013; 238:866-73. [PMID: 23828588 DOI: 10.1177/1535370213494654] [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] [Indexed: 01/17/2023] Open
Abstract
This study aimed to retrospectively investigate the expression of the phosphate and tension homologue deleted on chromosome 10 (PTEN) protein and its prognostic role in hepatocellular carcinoma (HCC) with family aggregation resulting from hepatitis B and liver cirrhosis, which have not been established. Immunohistochemical analysis was performed to evaluate the PTEN protein expression in HCC and paired para-cancerous tissues from 79 patients with HCC caused by hepatitis B and liver cirrhosis. Of these cases, 34 represented HCC with family aggregation (HCCF group), and 45 represented HCC with no family aggregation (HCCN group). Follow-up data were collected for 3 months to 10 years and analysed for HCC recurrence, survival time and prognostic risk factors. The expression of the PTEN protein in the HCC tissue was dramatically lower in the HCCF group than in the HCCN group. The six-month, one-year and two-year overall recurrence (OR) rates of the HCCF group were significantly higher than those of the HCCN group. The one-year, two-year and five-year overall survival (OS) rates of the HCCF group were lower than those of the HCCN group. Impaired PTEN protein expression was an independent prognostic risk factor that was significantly correlated with OR and OS in HCC patients. Dramatically impaired PTEN protein expression in HCC patients with family aggregation resulting from hepatitis B and liver cirrhosis was correlated with OR and OS, and impaired PTEN expression was an independent risk factor for prognosis after radical surgery.
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Affiliation(s)
- Yuesi Zhong
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
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Lu L, Sun HC, Zhang W, Chai ZT, Zhu XD, Kong LQ, Wang WQ, Zhang KZ, Zhang YY, Zhang QB, Ao JY, Li JQ, Wang L, Wu WZ, Tang ZY. Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma. PLoS One 2013; 8:e65023. [PMID: 23741443 PMCID: PMC3669011 DOI: 10.1371/journal.pone.0065023] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 04/19/2013] [Indexed: 12/16/2022] Open
Abstract
Background & Aims We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma (HCC), which is mediated by down-regulation of tumor suppressor HTATIP2. The aim of the present study was to determine whether aspirin minimizes this effect and improves survival. Methods The effects of sorafenib, aspirin, and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice. Tumor growth, intrahepatic metastasis (IHM), lung metastasis, and survival were assessed. Polymerase chain reaction (PCR) array, real-time (RT)-PCR, and Western blotting were used to examine gene expression. The anti-invasion and anti-metastasis effects of aspirin were studied in HTATIP2-knockdown and HTATIP2-overexpressing HCC cell lines. The molecular mechanism of HTATIP2 regulation by aspirin was explored. Results Aspirin suppressed the pro-invasion and pro-metastasis effects of sorafenib in HCC and up-regulated HTATIP2 expression. Aspirin did not inhibit the proliferation of HCC cells, but it decreased the invasiveness of HCC with lower expression of HTATIP2 and increased expression of a set of markers, indicating a mesenchymal-to-epithelial transition in tumor cells. The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase (COX) 2 expression. Conclusions Aspirin minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor HTATIP2; this mechanism is mediated through inhibition of COX2.
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Affiliation(s)
- Lu Lu
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Hui-Chuan Sun
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital (TJCIH); Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, P.R. China
| | - Zong-Tao Chai
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Xiao-Dong Zhu
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Ling-Qun Kong
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Wen-Quan Wang
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital/Cancer Institute, Fudan University, Shanghai, P.R. China
| | - Ke-Zhi Zhang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Yuan-Yuan Zhang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Qiang-Bo Zhang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Jian-Yang Ao
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Jia-Qi Li
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Lu Wang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Wei-Zhong Wu
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University; Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China
- * E-mail:
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Geng YJ, Xie SL, Li Q, Ma J, Wang GY. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res 2012; 39:2119-28. [PMID: 22289527 DOI: 10.1177/147323001103900608] [Citation(s) in RCA: 326] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Increasing evidence suggests that large intervening non-coding RNAs (lincRNAs) regulate key pathways in cancer invasion and metastasis. In this observational retrospective study, the expression of the oncogenic lincRNA HOX transcript antisense RNA (HOTAIR) gene was measured in 63 patients with hepatocellular carcinoma (HCC) following hepatic resection. The HOTAIR gene was significantly overexpressed in HCC tissues compared with adjacent non-tumour tissues. Patients with high HOTAIR gene expression in their tumours had an increased risk of recurrence after hepatectomy. There was also a significant correlation between HOTAIR expression and lymph node metastasis. In vitro assays in the HCC cell line Bel7402 demonstrated that knockdown of HOTAIR lincRNA reduced cell proliferation and was associated with reductions in levels of matrix metalloproteinase-9 and vascular endothelial growth factor protein, which are important for cell motility and metastasis. In conclusion, HOTAIR lincRNA might be a potential biomarker for the existence of lymph node metastasis in HCC.
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Affiliation(s)
- Y J Geng
- Department of General Surgery, The First Clinical Hospital of Jilin University, Changchun, China
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43
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Fan ZC, Yan J, Liu GD, Tan XY, Weng XF, Wu WZ, Zhou J, Wei XB. Real-time monitoring of rare circulating hepatocellular carcinoma cells in an orthotopic model by in vivo flow cytometry assesses resection on metastasis. Cancer Res 2012; 72:2683-91. [PMID: 22454286 DOI: 10.1158/0008-5472.can-11-3733] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The fate of circulating tumor cells (CTC) is an important determinant of metastasis and recurrence, which leads to most deaths in hepatocellular carcinoma (HCC). Therefore, quantification of CTCs proves to be an emerging tool for diagnosing, stratifying, and monitoring patients with metastatic diseases. In vivo flow cytometry has the capability to monitor the dynamics of fluorescently labeled CTCs continuously and noninvasively. Here, we combine in vivo flow cytometry technique and a GFP-transfected HCC orthotopic metastatic tumor model to monitor CTC dynamics. Our in vivo flow cytometry has approximately 1.8-fold higher sensitivity than whole blood analysis by conventional flow cytometry. We found a significant difference in CTC dynamics between orthotopic and subcutaneous tumor models. We also investigated whether liver resection promotes or restricts hematogenous metastasis in advanced HCC. Our results show that the number of CTCs and early metastases decreases significantly after the resection. The resection prominently restricts hematogenous metastasis and distant metastases. CTC dynamics is correlated with tumor growth in our orthotopic tumor model. The number and size of distant metastases correspond to CTC dynamics. The novel in vivo flow cytometry technique combined with orthotopic tumor models might provide insights to tumor hematogenous metastasis and guidance to cancer therapy.
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Affiliation(s)
- Zhi-Chao Fan
- Department of Chemistry, Zhongshan Hospital, Shanghai, China
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Zhao YM, Zhou JM, Wang LR, He HW, Wang XL, Tao ZH, Sun HC, Wu WZ, Fan J, Tang ZY, Wang L. HIWI is associated with prognosis in patients with hepatocellular carcinoma after curative resection. Cancer 2011; 118:2708-17. [PMID: 21989785 DOI: 10.1002/cncr.26524] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Revised: 07/20/2011] [Accepted: 07/22/2011] [Indexed: 01/05/2023]
Abstract
BACKGROUND PIWI protein family was found to play an important role in stem cell self-renewal. Overexpression of HIWI, the human homolog of PIWI family proteins, was found in several solid tumors, although the role of HIWI in hepatocellular carcinoma (HCC) and its prognostic value remain unclear. METHODS HIWI expression was measured in stepwise metastatic HCC cell lines (HCCLM3, MHCC97H, MHCC97L, SMMC7721, and HepG2), the normal liver cell line (L02), and HCC tissue samples (n = 20). Proliferation and invasion were investigated in HCC cell lines undergoing HIWI target small interfering RNA transfection. Also explored was HIWI expression in HCC tissue microarrays (n = 168) for survival analysis. RESULTS Levels of HIWI protein and mRNA were up-regulated in highly metastatic HCC cell lines (HCCLM3, MHCC97H, and MHCC97L), whereas their proliferation and invasion significantly decreased after depletion of HIWI. Intratumoral HIWI expression was higher than that of peritumoral tissue (P < .001) and positively associated with proliferating cell nuclear antigen expression (P < .001). Positive expression of intratumoral HIWI was associated with larger tumor size (P = .047) and intrahepatic metastasis (P = .027) and was an independent risk factor for overall survival (P = .007) and recurrence-free survival (P = .036), particularly in patients with low serum α-fetoprotein and low Edmondson-Steiner grade. CONCLUSIONS HIWI may play a key role in HCC proliferation and metastasis and can be a potential prognostic factor for HCC after curative resection, particularly with well-differentiated HCC.
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Affiliation(s)
- Yi-Ming Zhao
- Fudan University, Shanghai, People's Republic of China
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45
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Liang Y, Li WW, Yang BW, Tao ZH, Sun HC, Wang L, Xia JL, Qin LX, Tang ZY, Fan J, Wu WZ. Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma. Int J Cancer 2011; 130:1745-54. [PMID: 21544813 DOI: 10.1002/ijc.26166] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Accepted: 04/21/2011] [Indexed: 11/06/2022]
Abstract
bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single-minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S-phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S-phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients.
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Affiliation(s)
- Ying Liang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China
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46
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Cheng B, Ling C, Dai Y, Lu Y, Glushakova LG, Gee SWY, McGoogan KE, Aslanidi GV, Park M, Stacpoole PW, Siemann D, Liu C, Srivastava A, Ling C. Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells. Gene Ther 2011; 19:375-84. [PMID: 21776025 PMCID: PMC3519243 DOI: 10.1038/gt.2011.105] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Our recent studies have revealed that among the 10 different commonly used adeno-associated virus (AAV) serotypes, AAV3 vectors transduce human liver cancer cells extremely efficiently because these cells express high levels of human hepatocyte growth factor receptor (hHGFR), and AAV3 utilizes hHGFR as a cellular co-receptor for viral entry. In this report, we provide further evidence that both extracellular as well as intracellular kinase domains of hHGFR are involved in AAV3 vector entry and AAV3-mediated transgene expression. We also document that AAV3 vectors are targeted for degradation by the host cell proteasome machinery, and that site-directed mutagenesis of surface-exposed tyrosine (Y) to phenylalanine (F) residues on AAV3 capsids significantly improves the transduction efficiency of Y701F, Y705F and Y731F mutant AAV3 vectors. The transduction efficiency of the Y705+731F double-mutant vector is significantly higher than each of the single mutants in liver cancer cells in vitro. In immunodeficient mouse xenograft models, direct intratumoral injection of AAV3 vectors also led to high-efficiency transduction of human liver tumor cells in vivo. We also document here that the optimized tyrosine-mutant AAV3 vectors lead to increased transduction efficiency following both intratumoral and tail-vein injections in vivo. The optimized tyrosine-mutant AAV3 serotype vectors containing proapoptotic genes should prove useful for the potential gene therapy of human liver cancers.
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Affiliation(s)
- B Cheng
- Division of Cellular and Molecular Therapy, Departments of Pediatics and Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-3633, USA
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Tang N, Xie Q, Wang X, Li X, Chen Y, Lin X, Lin J. Inhibition of invasion and metastasis of MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity and epithelial-mesenchymal transition. Arch Pharm Res 2011; 34:781-9. [PMID: 21656364 DOI: 10.1007/s12272-011-0512-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 09/27/2010] [Accepted: 10/04/2010] [Indexed: 12/18/2022]
Abstract
Snake venom cystatin (sv-cystatin) is a member of the cystatin family of cysteine protease inhibitors. To further evaluate the possibility of sv-cystatin in cancer therapy, this study examined the effects of sv-cystatin on the invasion and metastasis of liver cancer cells (MHCC97H) in vitro and in vivo as well as the underlying mechanism. sv-cystatin cDNA was transfected into MHCC97H cells and the anti-invasion and antimetastasis effects of sv-cystatin were determined using migration and matrigel invasion assays and a lung-metastasis mice model. The results suggest that sv-cyst clone (sv-cystatin expression in MHCC97H cells) delayed the invasion and metastasis in vitro and in vivo compared to the parental, mock and si-sv-cyst clone cells (inhibited sv-cystatin expression by siRNA). The decreased activities of cathepsin B, MMP-2 and MMP-9 and EMT change index including higher E-cadherin, lower N-cadherin and decreased Twist activity were observed in the sv-cyst clone, which contributes to the change in invasion and metastasis ability of MHCC97H cells. This study provides evidence that expression of the sv-cystatin gene in MHCC97H cells inhibits tumor cell invasion and metastasis through the reduction of the proteinases activity and Epithelial-Mesenchymal Transition (EMT), which might contribute to the anticancer research of the sv-cystatin protein.
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Affiliation(s)
- Nanhong Tang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center for Molecular Medicine, Fujian Medical University, Fuzhou 350004, China
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Zhao YM, Wang L, Dai Z, Wang DD, Hei ZY, Zhang N, Fu XT, Wang XL, Zhang SC, Qin LX, Tang ZY, Zhou J, Fan J. Validity of plasma macrophage migration inhibitory factor for diagnosis and prognosis of hepatocellular carcinoma. Int J Cancer 2011; 129:2463-72. [PMID: 21213214 DOI: 10.1002/ijc.25918] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2010] [Accepted: 12/22/2010] [Indexed: 11/05/2022]
Abstract
We performed our study to determine whether plasma macrophage migration inhibitory factor (MIF) levels have diagnostic and prognostic value in hepatocellular carcinoma (HCC) patients. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the expression of MIF in plasma and tissues, respectively. Plasma MIF levels were compared to HCC occurrence, clinicopathological features and outcomes. Cutpoints of plasma MIF levels for diagnosis and prognosis were, respectively, determined by receiver operating characteristic analysis and X-tile in corresponding training cohort, and then were confirmed in the validation cohort. The postoperative plasma MIF levels of HCC patients were detected in an independent cohort (80 HCC patients). As a result, MIF expression in situ was mainly observed in the cytoplasm of HCC cells. Intratumoral MIF expression was positively correlated with plasma MIF levels (r = 0.759, p < 0.001). Compared to serum α-fetoprotein (AFP), plasma MIF had a higher diagnostic value for discrimination of HCC from controls at 35.3 ng/ml. With determined cutpoints, plasma MIF levels demonstrated a significant association with overall survival (OS) and disease-free survival (DFS) of HCC patients even in patients with normal serum AFP levels and Tumor Node Metastasis (TNM) stage I. In addition, the plasma MIF levels were identified as an independent factor for OS [hazard ratio (HR) = 1.754; p = 0.012] and DFS (HR = 2.121; p < 0.001). Plasma MIF levels decreased markedly within 30 days after tumor resection (p < 0.001). Therefore, plasma MIF levels have potential as a diagnostic and prognostic factor for HCC.
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Affiliation(s)
- Yi-Ming Zhao
- Liver Cancer Institute, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
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Wang DD, Zhao YM, Wang L, Ren G, Wang F, Xia ZG, Wang XL, Zhang T, Pan Q, Dai Z, Chen JP, Dai HY, Zhang W, He HW, Zhou JM, Tang GY, Zhou J, Fan J, Tang ZY. Preoperative serum retinol-binding protein 4 is associated with the prognosis of patients with hepatocellular carcinoma after curative resection. J Cancer Res Clin Oncol 2011; 137:651-8. [PMID: 20549233 DOI: 10.1007/s00432-010-0927-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Accepted: 05/27/2010] [Indexed: 01/05/2023]
Abstract
PURPOSE Metabolic syndrome and insulin resistance have been linked to increased risk of occurrence and mortality of hepatocellular carcinoma (HCC). Recently, retinol-binding protein 4 (RBP4) was clarified as a specific serological marker of insulin resistance. The aim of this study was to determine whether serum RBP4 could be used as a potential marker for predicting prognosis in patients with HCC after curative resection. METHODS Western immunoblotting and Enzyme-linked immunosorbent assay were used to measure the RBP4 expression in cell lines, supernatant, and serum. Serum RBP4 levels were compared with clinicopathological features and outcomes of patients with HCC. Furthermore, we investigated the impact of serum RBP4 level, serum C-peptide level, and HOMA-IR on overall survival (OS) and disease-free survival (DFS) of patients with HCC in the training cohort (156 patients with HCC), and then were validated in the validation cohort (105 patients with HCC). RESULTS RBP4 protein overexpressed in HCC cell lines compared with normal liver cell line (P < 0.001) and correlated with metastatic potential. Serum RBP4 levels were associated with OS [hazard ratio (HR) = 2.208, P < 0.001] and DFS (HR = 1.878, P = 0.029) of patients with HCC. By multivariate analysis, the serum RBP4 level was identified as an independent factor for OS (HR = 2.170, P = 0.004) and DFS (HR = 1.769, P = 0.037) of patients with HCC. The prognostic value of serum RBP4 level was confirmed in the validation cohort. CONCLUSIONS The serum RBP4 level is potential to be a useful prognostic factor for HCC after curative resection.
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Affiliation(s)
- Dan-Dan Wang
- Department of Endocrinology, Punan Hospital, Shanghai 200125, China
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Xu GL, Jia WD. Perioperative liver function in hepatectomy: evaluation and influencing factors. Shijie Huaren Xiaohua Zazhi 2010; 18:3721-3723. [DOI: 10.11569/wcjd.v18.i35.3721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatectomy is currently still the major treatment for hepatocellular carcinoma. Although hepatectomy has become safer because of progress made in surgical techniques, it is still frequently associated with the development of postoperative liver insufficiency. Therefore, investigation of factors influencing perioperative liver function in hepatectomy and intraoperative evaluation of residual liver function can help surgeons predict post-hepatectomy outcome and select appropriate postoperative rehabilitation treatment.
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