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Zafar S, Bai Y, Muhammad SA, Guo J, Khurram H, Zafar S, Muqaddas I, Shaikh RS, Bai B. Molecular dynamics simulation based prediction of T-cell epitopes for the production of effector molecules for liver cancer immunotherapy. PLoS One 2025; 20:e0309049. [PMID: 39752339 PMCID: PMC11698456 DOI: 10.1371/journal.pone.0309049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/05/2024] [Indexed: 01/06/2025] Open
Abstract
Liver cancer is the sixth most frequent malignancy and the fourth major cause of deaths worldwide. The current treatments are only effective in early stages of cancer. To overcome the therapeutic challenges and exploration of immunotherapeutic options, broad spectral therapeutic vaccines could have significant impact. Based on immunoinformatic and integrated machine learning tools, we predicted the potential therapeutic vaccine candidates of liver cancer. In this study, machine learning and MD simulation-based approach are effectively used to design T-cell epitopes that aid the immune system against liver cancer. Antigenicity, molecular weight, subcellular localization and expression site predictions were used to shortlist liver cancer associated proteins including AMBP, CFB, CDHR5, VTN, APOBR, AFP, SERPINA1 and APOE. We predicted CD8+ T-cell epitopes of these proteins containing LGEGATEAE, LLYIGKDRK, EDIGTEADV, QVDAAMAGR, HLEARKKSK, HLCIRHEMT, LKLSKAVHK, EQGRVRAAT and CD4+ T-cell epitopes of VLGEGATEA, WVTKQLNEI, VEEDTKVNS, FTRINCQGK, WGILGREEA, LQDGEKIMS, VKFNKPFVF, VRAATVGSL. We observed the substantial physicochemical properties of these epitopes with a significant binding affinity with MHC molecules. A polyvalent construct of these epitopes was designed using suitable linkers and adjuvant indicated significant binding energy (>-10.5 kcal/mol) with MHC class-I and II molecule. Based on in silico cloning, we found the considerable compatibility of this polyvalent construct with the E. coli expression system and the efficiency of its translation in host. The system-level and machine learning based cross validations showed the possible effect of these T-cell epitopes as potential vaccine candidates for the treatment of liver cancer.
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Affiliation(s)
- Sidra Zafar
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Multan, Punjab, Pakistan
| | - Yuhe Bai
- Department of Computer Science, Sorbonne University, Paris, France
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Multan, Punjab, Pakistan
| | - Jinlei Guo
- School of Intelligent Medical Engineering, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, China
| | - Haris Khurram
- Department of Mathematics and Computer Science, Faculty of Science and Technology, Prince of Songkla University, Pattani Campus, Pattani, Thailand
- Department of Sciences and Humanities, National University of Computer and Emerging Sciences, Chiniot, Punjab, Pakistan
| | - Saba Zafar
- Department of Biochemistry and Biotechnology, The Women University Multan, Multan, Punjab, Pakistan
| | - Iraj Muqaddas
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Multan, Punjab, Pakistan
| | - Rehan Sadiq Shaikh
- Center for Applied Molecular Biology (CAMB), University of the Punjab, Lahore, Punjab, Pakistan
| | - Baogang Bai
- School of Information and Technology, Wenzhou Business College, Wenzhou, Zhejiang, China
- Zhejiang Province Engineering Research Center of Intelligent Medicine, Wenzhou, China
- The 1 School of Medical, School of Information and Engineering, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Huang J, Shi R, Chen F, Tan HY, Zheng J, Wang N, Li R, Wang Y, Yang T, Feng Y, Zhong Z. Exploring the anti-hepatocellular carcinoma effects of Xianglian Pill: Integrating network pharmacology and RNA sequencing via in silico and in vitro studies. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155905. [PMID: 39128301 DOI: 10.1016/j.phymed.2024.155905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 05/21/2024] [Accepted: 07/20/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND Liver cancer represents a most common and fatal cancer worldwide. Xianglian Pill (XLP) is an herbal formula holding great promise in clearing heat for treating diseases in an integrative and holistic way. However, due to the complex constituents and multiple targets, the exact molecular mechanisms of action of XLP are still unclear. PURPOSE This study is focused on hepatocellular carcinoma (HCC), the most common type of liver cancer. The aim of this study is to develop a fast and efficient model to investigate the anti-HCC effects of XLP, and its underlying mechanisms. MATERIALS AND METHODS HepG2, Hep3B, Mahlavu, HuH-7, or Li-7 cells were employed in the studies. The ingredients were analyzed using liquid chromatography tandem mass spectrometry (LC-MS). RNA sequencing combined with network pharmacology was used to elucidate the therapeutic mechanism of XLP in HCC via in silico and in vitro studies. An approach was constructed to improve the accuracy of prediction in network pharmacology by combining big data and omics. RESULTS First, we identified 13 potential ingredients in the serum of XLP-administered rats using LC-MS. Then the network pharmacology was performed to predict that XLP demonstrates anti-HCC effects via targeting 94 genes involving in 13 components. Modifying the database thresholds might impact the accuracy of network pharmacology analysis based on RNA sequencing data. For instance, when the matching rate peak is 0.43, the correctness rate peak is 0.85. Moreover, 9 components of XLP and 6 relevant genes have been verified with CCK-8 and RT-qPCR assay, respectively. CONCLUSION Based on the crossing studies of RNA sequencing and network pharmacology, XLP was found to improve HCC through multiple targets and pathways. Additionally, the study provides a way to optimize network pharmacology analysis in herbal medicine research.
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Affiliation(s)
- Jihan Huang
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ruipeng Shi
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Feiyu Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Hor Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR 999077, China
| | - Jinbin Zheng
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Ran Li
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yulin Wang
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Yang
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China.
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
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Chen S, Li M, Xue C, Zhou X, Wei J, Zheng L, Duan Y, Deng H, Tang F, Xiong W, Xiang B, Zhou M. Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer. Drug Des Devel Ther 2024; 18:1321-1338. [PMID: 38681206 PMCID: PMC11055549 DOI: 10.2147/dddt.s443305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 04/10/2024] [Indexed: 05/01/2024] Open
Abstract
Purpose Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.
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MESH Headings
- Bufanolides/pharmacology
- Bufanolides/chemistry
- Bufanolides/administration & dosage
- Humans
- Animals
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Cell Proliferation/drug effects
- Mice
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemistry
- Drug Screening Assays, Antitumor
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/metabolism
- Mice, Inbred BALB C
- Cell Cycle/drug effects
- Mice, Nude
- Dose-Response Relationship, Drug
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
- Tumor Cells, Cultured
- Structure-Activity Relationship
- Molecular Structure
- Injections
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Affiliation(s)
- Shipeng Chen
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Mengna Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Changning Xue
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Xiangting Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Jianxia Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Lemei Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Yumei Duan
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Hongyu Deng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
| | - Faqing Tang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China
- Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of China
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Zhang YB, Bao YR, Wang S, Li TJ, Tai H, Leng JP, Yang XX, Wang BC, Meng XS. Possible mechanisms associated with immune escape and apoptosis on anti-hepatocellular carcinoma effect of Mu Ji Fang granules. World J Gastrointest Oncol 2023; 15:504-522. [PMID: 37009316 PMCID: PMC10052660 DOI: 10.4251/wjgo.v15.i3.504] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/19/2023] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers with high mortality rates worldwide. The main ingredients in Mu Ji Fang Granules (MJF) are alkaloids, flavonoids, and polysaccharides. MJF has been used in the clinical treatment of hepatitis, cirrhosis and HCC for more than 30 years. Few previous studies have focused on the mechanism of MJF on tumor immu-nology in the treatment of HCC.
AIM To explore the mechanism of action of MJF on tumor immunology in the treatment of HCC.
METHODS The absorbable ingredients of MJF were identified using Molecule Network related to High Performance Liquid Chromatography-Electron Spray Ionization-Time of Flight- Mass Spectrometry, and hub potential anti-HCC targets were screened using network pharmacology and pathway enrichment analysis. Forty male mice were randomly divided into the Blank, Model, and MJF groups (1.8, 5.4, and 10.8 g/kg/d) following 7 d of oral administration. Average body weight gain, spleen and thymus indices were calculated, tumor tissues were stained with hematoxylin and eosin, and Interferon gamma (IFN-γ), Tumor necrosis factor α (TNF-α), Interleukin-2, aspartate aminotransferase, alanine aminotransferase, alpha-fetoprotein (AFP), Fas, and FasL were measured by Enzyme-linked Immunosorbent Assay. Relevant mRNA expression of Bax and Bcl2 was evaluated by Real Time Quantitative PCR (RT-qPCR) and protein expression of Transforming growth factor β1 (TGF-β1) and Mothers against decapentaplegic homolog (SMAD) 4 was assessed by Western blotting. The HepG2 cell line was treated with 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL of MJF, and another 3 groups were treated with TGF-β1 inhibitor (LY364947) and different doses of MJF. Relevant mRNA expression of TNF-α, IFN-γ, Bax and Bcl2 was evaluated by RT-qPCR and protein expression of TGF-β1, SMAD2, p-SMAD2, SMAD4, and SMAD7 was assessed by Western blotting.
RESULTS It was shown that MJF improved body weight gain and tumor inhibition rate in H22 tumor-bearing mice, protected immune organs and liver function, reduced the HCC indicator AFP, affected immunity and apoptosis, and up-regulated the TGF-β1/SMAD signaling pathway, by increasing the relative expression of TGF-β1, SMAD2, p-SMAD2 and SMAD4 and decreasing SMAD7, reducing immune factors TNF-α and IFN-γ, decreasing apoptosis cytokines Fas, FasL and Bcl2/Bax, and inhibiting the effect of LY364947 in HepG2 cells.
CONCLUSION MJF inhibits HCC by activating the TGF-β1/SMAD signaling pathway, and affecting immune and apoptotic cytokines, which may be due to MJF adjusting immune escape and apoptosis.
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Affiliation(s)
- Yi-Bing Zhang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Department of Clinical Trail Institution Office, Dalian Municipal Central Hospital, Dalian 116033, Liaoning Province, China
| | - Yong-Rui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - Tian-Jiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
| | - He Tai
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Jia-Peng Leng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Xin-Xin Yang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Bo-Cai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Xian-Sheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
- Technical Innovation Center of Multidimensional Analysis of Traditional Chinese Medicine of Liaoning Province, Dalian 116600, Liaoning Province, China
- Engineering Laboratory of Modern Chinese Medicine Research of Liaoning Province, Dalian 116600, Liaoning Province, China
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Yang M, Yan Q, Luo Y, Wang B, Deng S, Luo H, Ye B, Wang X. Molecular mechanism of Ganji Fang in the treatment of hepatocellular carcinoma based on network pharmacology, molecular docking and experimental verification technology. Front Pharmacol 2023; 14:1016967. [PMID: 36744264 PMCID: PMC9892186 DOI: 10.3389/fphar.2023.1016967] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a malignant tumor harmful to human health. Ganji Fang (GJF) has good clinical efficacy in the treatment of HCC, but its mechanism is still unclear. Objective: The aim of this study was to investigate the mechanism of action of GJF in the treatment of HCC through network pharmacology, molecular docking and in vitro experiments. Methods: A series of network pharmacology methods were used to identify the potential targets and key pathways of GJF in the treatment of HCC. Then, molecular docking technology was used to explore the binding ability of key active ingredients and targets in GJF. Multiple external databases were used to validate the key targets. In in vitro experiments, we performed MTT assays, wound-healing assays, cell cycle assays, apoptosis assays and RT‒qPCR to verify the inhibitory effect of GJF on the Human hepatoma G2 (HepG2) cells. Result: A total of 162 bioactive components and 826 protein targets of GJF were screened, and 611 potential targets of HCC were identified. Finally, 63 possible targets of GJF acting on HCC were obtained. KEGG enrichment analyses showed that the top five pathways were the cell cycle, cellular senescence, p53 signaling pathway, PI3K/Akt signaling pathway, and progesterone-mediated oocyte maturation. Among them, we verified the PI3K/Akt signaling pathway. CCNE1, PKN1, CCND2, CDK4, EPHA2, FGFR3, CDK6, CDK2 and HSP90AAI were enriched in the PI3K/Akt pathway. The molecular docking results showed that the docking scores of eight active components of GJF with the two targets were all less than -5.0, indicating that they had certain binding activity. In vitro cell experiments showed that GJF could inhibit the proliferation and migration of HepG2 cells, block the cell cycle and induce apoptosis of HepG2 cells, which may be related to the PI3K/Akt signaling pathway. In summary, EPHA2 may be an important target of GJF in HCC, and pachymic acid may be an important critical active compound of GJF that exerts anticancer activity. Conclusion: In general, we demonstrated, for the first time, that the molecular mechanism of GJF in HCC may involve induction of G0/G1 phase cycle arrest through inhibition of the PI3K/Akt signaling pathway and promote apoptosis of hepatoma cell lines. This study provides a scientific basis for the subsequent clinical application of GJF and the in-depth study of its mechanism.
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Affiliation(s)
- Miaolun Yang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Yan
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuehua Luo
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Boqing Wang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shicong Deng
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huiyan Luo
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Baoqian Ye
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiongwen Wang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China,*Correspondence: Xiongwen Wang,
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Xie Y, Yan F, Wang X, Yu L, Yan H, Pu Q, Li W, Yang Z. Mechanisms and network pharmacological analysis of Yangyin Fuzheng Jiedu prescription in the treatment of hepatocellular carcinoma. Cancer Med 2022; 12:3237-3259. [PMID: 36043445 PMCID: PMC9939140 DOI: 10.1002/cam4.5064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/22/2022] [Accepted: 07/03/2022] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. METHODS The H22 tumor-bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor-infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The proportion of CD8+ T cells and the expression of programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC-related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component-target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein-protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene-gene inner and component-target-pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor-bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. RESULTS Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor-bearing mice. FZP increased the immune organ index and the levels of CD8+ and CD3+ T cells in the spleen and peripheral blood of H22 tumor-bearing mice. FZP also reduced the expression of PD-1, TIGIT, and TIM3 in CD8+ T cells and the production of IL-10, IL-4, IL-6, and IL-1β. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC-related signaling pathways, including the PIK3-Akt signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. CONCLUSION FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC-related targets, pathways, and biological processes.
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Affiliation(s)
- Yuqing Xie
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Qing Pu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Weihong Li
- School of Traditional Chinese MedicineBeijing University of Chinese MedicineBeijingP.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
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Khan SA, Lee TKW. Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidium monnieri in Treating Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:5400. [PMID: 35628212 PMCID: PMC9140548 DOI: 10.3390/ijms23105400] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high mortality rate globally. For thousands of years, Cnidium monnieri has been used to treat human ailments and is regarded as a veritable treasure trove for drug discovery. This study has investigated the key active phytochemicals and molecular mechanisms of Cnidium monnieri implicated in curing HCC. We utilized the TCMSP database to collect data on the phytochemicals of Cnidium monnieri. The SwissTargetPrediction website tool was used to predict the targets of phytochemicals of Cnidium monnieri. HCC-related genes were retrieved from OncoDB.HCC and Liverome, two liver-cancer-related databases. Using the DAVID bioinformatic website tool, Gene Ontology (GO) and KEGG enrichment analysis were performed on the intersecting targets of HCC-related genes and active phytochemicals in Cnidium monnieri. A network of active phytochemicals and anti-HCC targets was constructed and analyzed using Cytoscape software. Molecular docking of key active phytochemicals was performed with anti-HCC targets using AutoDock Vina (version 1.2.0.). We identified 19 active phytochemicals in Cnidium monnieri, 532 potential targets of these phytochemicals, and 566 HCC-related genes. Results of GO enrichment indicated that Cnidium monnieri might be implicated in affecting gene targets involved in multiple biological processes, such as protein phosphorylation, negative regulation of the apoptotic process, which could be attributed to its anti-HCC effects. KEGG pathway analyses indicated that the PI3K-AKT signaling pathway, pathways in cancer, proteoglycans in cancer, the TNF signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance are the main pathways implicated in the anti-HCC effects of Cnidium monnieri. Molecular docking analyses showed that key active phytochemicals of Cnidium monnieri, such as ar-curcumene, diosmetin, and (E)-2,3-bis(2-keto-7-methoxy-chromen-8-yl)acrolein, can bind to core therapeutic targets EGFR, CASP3, ESR1, MAPK3, CCND1, and ERBB2. The results of the present study offer clues for further investigation of the anti-HCC phytochemicals and mechanisms of Cnidium monnieri and provide a basis for developing modern anti-HCC drugs based on phytochemicals in Cnidium monnieri.
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Affiliation(s)
- Shakeel Ahmad Khan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Rd., Hung Hom, Kowloon 999077, Hong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Rd., Hung Hom, Kowloon 999077, Hong Kong
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8
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Kaur H, Bhalla S, Kaur D, Raghava GP. CancerLivER: a database of liver cancer gene expression resources and biomarkers. DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION 2021; 2020:5798989. [PMID: 32147717 PMCID: PMC7061090 DOI: 10.1093/database/baaa012] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Liver cancer is the fourth major lethal malignancy worldwide. To understand the development and progression of liver cancer, biomedical research generated a tremendous amount of transcriptomics and disease-specific biomarker data. However, dispersed information poses pragmatic hurdles to delineate the significant markers for the disease. Hence, a dedicated resource for liver cancer is required that integrates scattered multiple formatted datasets and information regarding disease-specific biomarkers. Liver Cancer Expression Resource (CancerLivER) is a database that maintains gene expression datasets of liver cancer along with the putative biomarkers defined for the same in the literature. It manages 115 datasets that include gene-expression profiles of 9611 samples. Each of incorporated datasets was manually curated to remove any artefact; subsequently, a standard and uniform pipeline according to the specific technique is employed for their processing. Additionally, it contains comprehensive information on 594 liver cancer biomarkers which include mainly 315 gene biomarkers or signatures and 178 protein- and 46 miRNA-based biomarkers. To explore the full potential of data on liver cancer, a web-based interactive platform was developed to perform search, browsing and analyses. Analysis tools were also integrated to explore and visualize the expression patterns of desired genes among different types of samples based on individual gene, GO ontology and pathways. Furthermore, a dataset matrix download facility was provided to facilitate the users for their extensive analysis to elucidate more robust disease-specific signatures. Eventually, CancerLivER is a comprehensive resource which is highly useful for the scientific community working in the field of liver cancer.Availability: CancerLivER can be accessed on the web at https://webs.iiitd.edu.in/raghava/cancerliver.
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Affiliation(s)
- Harpreet Kaur
- Bioinformatics Centre, CSIR-Institute of Microbial Technology, Sector -39A, Chandigarh-160036, India.,Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi-110020, India
| | - Sherry Bhalla
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi-110020, India.,Centre for Systems Biology and Bioinformatics, Sector-25, Panjab University, Chandigarh-160036, India
| | - Dilraj Kaur
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi-110020, India
| | - Gajendra Ps Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi-110020, India
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9
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Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8897918. [PMID: 33163086 PMCID: PMC7607277 DOI: 10.1155/2020/8897918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 10/04/2020] [Accepted: 10/17/2020] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. Scutellariae Radix (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine systems pharmacology database and the traditional Chinese medicine integrated database. HCC-related targets were acquired from the liver cancer databases OncoDB.HCC and Liverome. The gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. Component-component target and protein-protein interaction networks were set up. A total of 143 components of SR were identified, and 37 of them were considered as candidate active components. Fifty targets corresponding to 29 components of SR were mapped with targets of HCC. Functional enrichment analysis indicated that SR exerted an antihepatocarcinoma effect by regulating pathways in cancer, hepatitis B, viral carcinogenesis, and PI3K-Akt signaling. The holistic approach of network pharmacology can provide novel insights into the mechanistic study and therapeutic drug development of SR for HCC treatment.
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10
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Luo Y, Song L, Wang X, Huang Y, Liu Y, Wang Q, Hong M, Yuan Z. Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma. Front Pharmacol 2020; 11:1264. [PMID: 32903546 PMCID: PMC7438559 DOI: 10.3389/fphar.2020.01264] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/30/2020] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both in vitro and in vivo. We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.
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Affiliation(s)
- Yi Luo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Song
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinyu Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yujie Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongqiang Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ming Hong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongyu Yuan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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11
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dBMHCC: A comprehensive hepatocellular carcinoma (HCC) biomarker database provides a reliable prediction system for novel HCC phosphorylated biomarkers. PLoS One 2020; 15:e0234084. [PMID: 32497121 PMCID: PMC7272086 DOI: 10.1371/journal.pone.0234084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 05/18/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC), which is associated with an absence of obvious symptoms and poor prognosis, is the second leading cause of cancer death worldwide. Genome-wide molecular biology studies should provide biological insights into HCC development. Based on the importance of phosphorylation for signal transduction, several protein kinase inhibitors have been developed that improve the survival of cancer patients. However, a comprehensive database of HCC-related phosphorylated biomarkers (HCCPMs) and novel HCCPMs prediction platform has been lacking. We have thus constructed the dBMHCC databases to provide expression profiles, phosphorylation and drug information, and evidence type; gathered information on HCC-related pathways and their involved genes as candidate HCC biomarkers; and established a system for evaluating protein phosphorylation and HCC-related biomarkers to improve the reliability of biomarker prediction. The resulting dBMHCC contains 611 notable HCC-related genes, 234 HCC-related pathways, 17 phosphorylation-related motifs and their 255 corresponding protein kinases, 5955 HCC biomarkers, and 1077 predicted HCCPMs. Methionine adenosyltransferase 2B (MAT2B) and acireductone dioxygenase 1 (ADI1), which regulate HCC development and hepatitis C virus infection, respectively, were among the top 10 HCCPMs predicted by dBMHCC. Platelet-derived growth factor receptor alpha (PDGFRA), which had the highest evaluation score, was identified as the target of one HCC drug (Regorafenib), five cancer drugs, and four non-cancer drugs. dBMHCC is an open resource for HCC phosphorylated biomarkers, which supports researchers investigating the development of HCC and designing novel diagnosis methods and drug treatments. Database URL:http://predictor.nchu.edu.tw/dBMHCC.
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12
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Huang J, Chen F, Zhong Z, Tan HY, Wang N, Liu Y, Fang X, Yang T, Feng Y. Interpreting the Pharmacological Mechanisms of Huachansu Capsules on Hepatocellular Carcinoma Through Combining Network Pharmacology and Experimental Evaluation. Front Pharmacol 2020; 11:414. [PMID: 32308626 PMCID: PMC7145978 DOI: 10.3389/fphar.2020.00414] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 03/18/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal cancers across the world. Chinese medicine has been used as adjunctive or complementary therapy for the management of HCC. Huachansu belongs to a class of toxic steroids isolated from toad venom that has important anti-cancer property. This study was aimed to identify the bioactive constituents and molecular targets of Huachansu capsules (HCSCs) for treating HCC using network pharmacology analysis and experimental assays. The major bioactive components of HCSCs were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A series of network pharmacology methods including target prediction, pathway identification, and network establishment were applied to identify the modes of action of HCSCs against HCC. Furthermore, a series of experiments, including MTT, clonogenic assay, 3-D transwell, wound healing assay, as well as flow cytometry, were conducted to verify the inhibitory ability of HCSCs on HCC in vitro. The results showed that 11 chemical components were identified from HCSCs. The network pharmacological analysis showed that there were 82 related anti-HCC targets and 14 potential pathways for these 11 components. Moreover, experimental assays confirmed the inhibitory effects of HCSCs against HCC in vitro. Taken together, our study revealed the synergistic effects of HCSCs on a systematic level, and suggested that HCSCs exhibited anti-HCC effects in a multi-component, multi-target, and multi-pathway manner.
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Affiliation(s)
- Jihan Huang
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Cardiology, Cardiovascular Research Institute, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feiyu Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Zhangfeng Zhong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Yuting Liu
- Department of Cardiology, Cardiovascular Research Institute, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinyuan Fang
- Marine College, Shandong University (Weihai), Weihai, China
| | - Tao Yang
- Center for Drug Clinical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Cardiology, Cardiovascular Research Institute, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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13
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Guo W, Huang J, Wang N, Tan HY, Cheung F, Chen F, Feng Y. Integrating Network Pharmacology and Pharmacological Evaluation for Deciphering the Action Mechanism of Herbal Formula Zuojin Pill in Suppressing Hepatocellular Carcinoma. Front Pharmacol 2019; 10:1185. [PMID: 31649545 PMCID: PMC6795061 DOI: 10.3389/fphar.2019.01185] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/13/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a kind of complicated disease with an increasing incidence all over the world. A classic Chinese medicine formula, Zuojin pill (ZJP), was shown to exert therapeutic effects on HCC. However, its chemical and pharmacological profiles remain to be elucidated. In the current study, network pharmacology approach was applied to characterize the action mechanism of ZJP on HCC. All compounds were obtained from the corresponding databases, and active compounds were selected according to their oral bioavailability and drug-likeness index. The potential proteins of ZJP were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the traditional Chinese medicine integrated database (TCMID), whereas the potential genes of HCC were obtained from OncoDB.HCC and Liverome databases. The potential pathways related to genes were determined by gene ontology (GO) and pathway enrichment analyses. The compound-target and target-pathway networks were constructed. Subsequently, the potential underlying action mechanisms of ZJP on HCC predicted by the network pharmacology analyses were experimentally validated in HCC cellular and orthotopic HCC implantation murine models. A total of 224 components in ZJP were obtained, among which, 42 were chosen as bioactive components. The compound-target network included 32 compounds and 86 targets, whereas the target-pathway network included 70 proteins and 75 pathways. The in vitro and in vivo experiments validated that ZJP exhibited its prominent therapeutic effects on HCC mainly via the regulation of cell proliferation and survival though the EGFR/MAPK, PI3K/NF-κB, and CCND1 signaling pathways. In conclusion, our study suggested combination of network pharmacology prediction with experimental validation may offer a useful tool to characterize the molecular mechanism of traditional Chinese medicine (TCM) ZJP on HCC.
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Affiliation(s)
- Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jihan Huang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Fan Cheung
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Feiyu Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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14
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Jie M, Hai-Xia L, Fei-Fei T, Shu-Ling L, Tian-Yi F, Xue-Qian W, Qing-Guo W, Fa-Feng C. Systematic Investigation of Berberine for Treating Hepatocellular Carcinoma Based on Network Pharmacology. DIGITAL CHINESE MEDICINE 2019. [DOI: 10.1016/j.dcmed.2019.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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15
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The Korea Cancer Big Data Platform (K-CBP) for Cancer Research. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16132290. [PMID: 31261630 PMCID: PMC6651426 DOI: 10.3390/ijerph16132290] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/31/2019] [Accepted: 06/24/2019] [Indexed: 12/23/2022]
Abstract
Data warehousing is the most important technology to address recent advances in precision medicine. However, a generic clinical data warehouse does not address unstructured and insufficient data. In precision medicine, it is essential to develop a platform that can collect and utilize data. Data were collected from electronic medical records, genomic sequences, tumor biopsy specimens, and national cancer control initiative databases in the National Cancer Center (NCC), Korea. Data were de-identified and stored in a safe and independent space. Unstructured clinical data were standardized and incorporated into cancer registries and linked to cancer genome sequences and tumor biopsy specimens. Finally, national cancer control initiative data from the public domain were independently organized and linked to cancer registries. We constructed a system for integrating and providing various cancer data called the Korea Cancer Big Data Platform (K-CBP). Although the K-CBP could be used for cancer research, the legal and regulatory aspects of data distribution and usage need to be addressed first. Nonetheless, the system will continue collecting data from cancer-related resources that will hopefully facilitate precision-based research.
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16
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Wang Y, Wang Y, Wang S, Tong Y, Jin L, Zong H, Zheng R, Yang J, Zhang Z, Ouyang E, Zhou M, Zhang X. GIDB: a knowledge database for the automated curation and multidimensional analysis of molecular signatures in gastrointestinal cancer. DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION 2019; 2019:5487627. [PMID: 31089686 PMCID: PMC6517830 DOI: 10.1093/database/baz051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 01/08/2019] [Accepted: 03/29/2019] [Indexed: 01/12/2023]
Abstract
Gastrointestinal (GI) cancer is common, characterized by high mortality, and includes oesophagus, gastric, liver, bile duct, pancreas, rectal and colon cancers. The insufficient specificity and sensitivity of biomarkers is still a key clinical hindrance for GI cancer diagnosis and successful treatment. The emergence of `precision medicine', `basket trial' and `field cancerization' concepts calls for an urgent need and importance for the understanding of how organ system cancers occur at the molecular levels. Knowledge from both the literature and data available in public databases is informative in elucidating the molecular alterations underlying GI cancer. Currently, most available cancer databases have not offered a comprehensive discovery of gene-disease associations, molecular alterations and clinical information by integrated text mining and data mining in GI cancer. We develop GIDB, a panoptic knowledge database that attempts to automate the curation of molecular signatures using natural language processing approaches and multidimensional analyses. GIDB covers information on 8730 genes with both literature and data supporting evidence, 248 miRNAs, 58 lncRNAs, 320 copy number variations, 49 fusion genes and 2381 semantic networks. It presents a comprehensive database, not only in parallelizing supporting evidence and data integration for signatures associated with GI cancer but also in providing the timeline feature of major molecular discoveries. It highlights the most comprehensive overview, research hotspots and the development of historical knowledge of genes in GI cancer. Furthermore, GIDB characterizes genomic abnormalities in multilevel analysis, including simple somatic mutations, gene expression, DNA methylation and prognosis. GIDB offers a user-friendly interface and two customizable online tools (Heatmap and Network) for experimental researchers and clinicians to explore data and help them shorten the learning curve and broaden the scope of knowledge. More importantly, GIDB is an ongoing research project that will continue to be updated and improve the automated method for reducing manual work.
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Affiliation(s)
- Ying Wang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yueqian Wang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Shuangkuai Wang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yuantao Tong
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ling Jin
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Hui Zong
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Rongbin Zheng
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jinxuan Yang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zeyu Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - En Ouyang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Mengyan Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiaoyan Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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17
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Interpretation of Euphorbia Kansui Stir-Fried with Vinegar Treating Malignant Ascites by a UPLC-Q-TOF/MS Based Rat Serum and Urine Metabolomics Strategy Coupled with Network Pharmacology. Molecules 2018; 23:molecules23123246. [PMID: 30544627 PMCID: PMC6322356 DOI: 10.3390/molecules23123246] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 12/12/2022] Open
Abstract
Euphorbia kansui stir-fried with vinegar (V-kansui) has promising biological activities toward treating malignant ascites with reduced toxicity compared to crude kansui. But the mechanism concerning promoting the excretion of ascites has not been systematically studied. The purpose of this paper was to investigate the possible mechanism of V-kansui in treating malignant ascites, including metabolic pathways and molecular mechanism using an integrated serum and urine metabolomics coupled with network pharmacology. Serum and urine samples of rats were collected and analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A comparison with crude kansui was also made to demonstrate the feasibility of processing. Principle component analysis (PCA) and orthogonal partial least square discriminate analysis (OPLS-DA) were conducted to discriminate the groups, search important variables and reveal the possible pathways. A compound-target-metabolite network was finally constructed to identify the crucial targets to further understand the molecular mechanism. Sixteen significant metabolites contributing to the discrimination of model and control groups were tentatively screened out. They were mainly involved in the arachidonic acid metabolism, steroid hormone biosynthesis and primary bile acid to possibly reduce inflammatory and modulate the renin-angiotensin-aldosterone system to achieve treating malignant ascites. A bio-network starting from the compounds and ending in the metabolites was constructed to elucidate the molecular mechanism. HSP90AA1, ANXA2, PRDX6, PCNA, SOD2 and ALB were identified as the potential key targets that were responsible for the treatment of malignant ascites by the parameter combining the average shortest path length and betweenness centrality. The correlated 17 compounds were considered as the potential active ingredients in V-kansui. In addition, the metabolomics showed that the effect of V-kansui was almost in accordance with crude kansui. These results systematically revealed the mechanism of V-kansui against malignant ascites for the first time using metabolomics coupled with network pharmacology. V-kansui could be a promising safe and therapeutic medicine for the excretion of ascites.
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18
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Systematic Investigation of Scutellariae Barbatae Herba for Treating Hepatocellular Carcinoma Based on Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:4365739. [PMID: 30584453 PMCID: PMC6280310 DOI: 10.1155/2018/4365739] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/30/2018] [Accepted: 11/08/2018] [Indexed: 12/14/2022]
Abstract
As the fifth most common type of malignant cancers globally, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. As a long-time medicinal herb in Traditional Chinese Medicine (TCM), Scutellariae Barbatae Herba (SBH) has also been used for treating various cancers including HCC, but its underlying mechanisms have not been completely clarified. Presently, an innovative network-pharmacology platform was introduced to systematically elucidate the pharmacological mechanisms of SBH against HCC, adopting active ingredients prescreening, target fishing, and network analysis. The results revealed that SBH appeared to work on HCC probably through regulating 4 molecular functions, 20 biological processes, and hitting on 21 candidate targets involved in 40 pathways. By in-depth analysis of the first-ranked signaling pathway and hit genes, only TTR was highly and specially expressed in the liver tissue. TTR might play a crucial role in neutrophil degranulation pathway during SBH against HCC. Hence, TTR might become a therapeutic target of HCC. The study investigated the anti-hepatoma mechanisms of SBH from a holistic perspective, which provided a theoretical foundation for further experimental research and rational clinical application of SBH.
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19
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Zhu Y, Zhu J, Lu C, Zhang Q, Xie W, Sun P, Dong X, Yue L, Sun Y, Yi X, Zhu T, Ruan G, Aebersold R, Huang S, Guo T. Identification of Protein Abundance Changes in Hepatocellular Carcinoma Tissues Using PCT-SWATH. Proteomics Clin Appl 2018; 13:e1700179. [PMID: 30365225 DOI: 10.1002/prca.201700179] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 10/16/2018] [Indexed: 12/16/2022]
Abstract
PURPOSE To rapidly identify protein abundance changes in biopsy-level fresh-frozen hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN The pressure-cycling technology (PCT) is applied and sequential window acquisition of all theoretical mass spectra (SWATH-MS) workflow is optimized to analyze 38 biopsy-level tissue samples from 19 HCC patients. Each proteome is analyzed with 45 min LC gradient. MCM7 is validated using immunohistochemistry (IHC). RESULTS A total of 11 787 proteotypic peptides from 2579 SwissProt proteins are quantified with high confidence. The coefficient of variation (CV) of peptide yield using PCT is 32.9%, and the R2 of peptide quantification is 0.9729. Five hundred forty-one proteins showed significant abundance change between the tumor area and its adjacent benign area. From 24 upregulated pathways and 13 suppressed ones, enhanced biomolecule synthesis and suppressed small molecular metabolism in liver tumor tissues are observed. Protein changes based on α-fetoprotein expression and hepatitis B virus infection are further analyzed. The data altogether highlight 16 promising tumor marker candidates. The upregulation of minichromosome maintenance complex component 7 (MCM7) is further observed in multiple HCC tumor tissues by IHC. CONCLUSIONS AND CLINICAL RELEVANCE The practicality of rapid proteomic analysis of biopsy-level fresh-frozen HCC tissue samples with PCT-SWATH has been demonstrated and promising tumor marker candidates including MCM7 are identified.
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Affiliation(s)
- Yi Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
| | - Jiang Zhu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Cong Lu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Qiushi Zhang
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Wei Xie
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Ping Sun
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Xiaochuan Dong
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Liang Yue
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Yaoting Sun
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Xiao Yi
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Tiansheng Zhu
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Guan Ruan
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China
| | - Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.,Faculty of Science, University of Zürich, Zürich, Switzerland
| | - Shi'ang Huang
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Tiannan Guo
- Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang, P. R. China.,Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland
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20
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Lian Q, Wang S, Zhang G, Wang D, Luo G, Tang J, Chen L, Gu J. HCCDB: A Database of Hepatocellular Carcinoma Expression Atlas. GENOMICS PROTEOMICS & BIOINFORMATICS 2018; 16:269-275. [PMID: 30266410 PMCID: PMC6205074 DOI: 10.1016/j.gpb.2018.07.003] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is highly heterogeneous in nature and has been one of the most common cancer types worldwide. To ensure repeatability of identified gene expression patterns and comprehensively annotate the transcriptomes of HCC, we carefully curated 15 public HCC expression datasets that cover around 4000 clinical samples and developed the database HCCDB to serve as a one-stop online resource for exploring HCC gene expression with user-friendly interfaces. The global differential gene expression landscape of HCC was established by analyzing the consistently differentially expressed genes across multiple datasets. Moreover, a 4D metric was proposed to fully characterize the expression pattern of each gene by integrating data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). To facilitate a comprehensive understanding of gene expression patterns in HCC, HCCDB also provides links to third-party databases on drug, proteomics, and literatures, and graphically displays the results from computational analyses, including differential expression analysis, tissue-specific and tumor-specific expression analysis, survival analysis, and co-expression analysis. HCCDB is freely accessible at http://lifeome.net/database/hccdb.
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Affiliation(s)
- Qiuyu Lian
- MOE Key Laboratory of Bioinformatics, Beijing National Research Center for Information Science and Technology, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Shicheng Wang
- MOE Key Laboratory of Bioinformatics, Beijing National Research Center for Information Science and Technology, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Guchao Zhang
- MOE Key Laboratory of Bioinformatics, Beijing National Research Center for Information Science and Technology, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Dongfang Wang
- MOE Key Laboratory of Bioinformatics, Beijing National Research Center for Information Science and Technology, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Guijuan Luo
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Jing Tang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Lei Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
| | - Jin Gu
- MOE Key Laboratory of Bioinformatics, Beijing National Research Center for Information Science and Technology, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China.
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21
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Gao L, Wang KX, Zhou YZ, Fang JS, Qin XM, Du GH. Uncovering the anticancer mechanism of Compound Kushen Injection against HCC by integrating quantitative analysis, network analysis and experimental validation. Sci Rep 2018; 8:624. [PMID: 29330507 PMCID: PMC5766629 DOI: 10.1038/s41598-017-18325-7] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/08/2017] [Indexed: 12/17/2022] Open
Abstract
Compound Kushen Injection (CKI) is a Traditional Chinese Medicine (TCM) preparation that has been clinically used in China to treat various types of solid tumours. Although several studies have revealed that CKI can inhibit the proliferation of hepatocellular carcinoma (HCC) cell lines, the active compounds, potential targets and pathways involved in these effects have not been systematically investigated. Here, we proposed a novel idea of “main active compound-based network pharmacology” to explore the anti-cancer mechanism of CKI. Our results showed that CKI significantly suppressed the proliferation and migration of SMMC-7721 cells. Four main active compounds of CKI (matrine, oxymatrine, sophoridine and N-methylcytisine) were confirmed by the integration of ultra-performance liquid chromatography/mass spectrometry (UPLC-MS) with cell proliferation assays. The potential targets and pathways involved in the anti-HCC effects of CKI were predicted by a network pharmacology approach, and some of the crucial proteins and pathways were further validated by western blotting and metabolomics approaches. Our results indicated that CKI exerted anti-HCC effects via the key targets MMP2, MYC, CASP3, and REG1A and the key pathways of glycometabolism and amino acid metabolism. These results provide insights into the mechanism of CKI by combining quantitative analysis of components, network pharmacology and experimental validation.
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Affiliation(s)
- Li Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, PR China.
| | - Ke-Xin Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, PR China.,College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, 030006, China
| | - Yu-Zhi Zhou
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, PR China
| | - Jian-Song Fang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, PR China.
| | - Guan-Hua Du
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, PR China.,Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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22
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Genes directly regulated by NF-κB in human hepatocellular carcinoma HepG2. Int J Biochem Cell Biol 2017; 89:157-170. [PMID: 28579529 DOI: 10.1016/j.biocel.2017.05.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/25/2017] [Accepted: 05/29/2017] [Indexed: 12/14/2022]
Abstract
It has been well-known that over activation of NF-κB has close relationship with hepatitis and hepatocellular carcinoma (HCC). However, the complete and exact underlying molecular pathways and mechanisms still remain not fully understood. By manipulating NF-κB activity with its recognized activator TNFα and using ChIP-seq and RNA-seq techniques, this study identified 699 NF-κB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-κB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. In comparison with NF-κB target genes identified in LPS-induced THP-1 and TNFα-induced HeLa cells, only limited numbers (24-46) of genes were shared by the two cell lines, indicating the HCC specificity of identified genes. Functional annotation revealed that NF-κB DTGs in HepG2 cell are mainly related with many typical NF-κB-related biological processes including immune system process, response to stress, response to stimulus, defense response, and cell death, and signaling pathways of MAPK, TNF, TGF-beta, Chemokine, NF-kappa B, and Toll-like receptor. Some NF-κB DTGs are also involved in Hepatitis C and B pathways. It was found that 82 NF-κB DTGs code secretory proteins, which include CCL2 and DKK1 that have already been used as HCC markers. Finally, the NF-κB DTGs were further confirmed by detecting the NF-κB binding and expression of 14 genes with ChIP-PCR and RT-PCR. This study thus provides a useful NF-κB DTG list for future studies of NF-κB-related molecular mechanisms and theranostic biomarkers of HCC.
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23
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Chang NW, Dai HJ, Shih YY, Wu CY, Dela Rosa MAC, Obena RP, Chen YJ, Hsu WL, Oyang YJ. Biomarker identification of hepatocellular carcinoma using a methodical literature mining strategy. Database (Oxford) 2017; 2017:bax082. [PMID: 31725857 PMCID: PMC7243925 DOI: 10.1093/database/bax082] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 10/11/2017] [Accepted: 10/11/2017] [Indexed: 12/31/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the most common causes of cancer-related deaths, carries a 5-year survival rate of 18%, underscoring the need for robust biomarkers. In spite of the increased availability of HCC related literatures, many of the promising biomarkers reported have not been validated for clinical use. To narrow down the wide range of possible biomarkers for further clinical validation, bioinformaticians need to sort them out using information provided in published works. Biomedical text mining is an automated way to obtain information of interest within the massive collection of biomedical knowledge, thus enabling extraction of data for biomarkers associated with certain diseases. This method can significantly reduce both the time and effort spent on studying important maladies such as liver diseases. Herein, we report a text mining-aided curation pipeline to identify potential biomarkers for liver cancer. The curation pipeline integrates PubMed E-Utilities to collect abstracts from PubMed and recognize several types of named entities by machine learning-based and pattern-based methods. Genes/proteins from evidential sentences were classified as candidate biomarkers using a convolutional neural network. Lastly, extracted biomarkers were ranked depending on several criteria, such as the frequency of keywords and articles and the journal impact factor, and then integrated into a meaningful list for bioinformaticians. Based on the developed pipeline, we constructed MarkerHub, which contains 2128 candidate biomarkers extracted from PubMed publications from 2008 to 2017. Database URL: http://markerhub.iis.sinica.edu.tw.
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Affiliation(s)
- Nai-Wen Chang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Hong-Jie Dai
- Department of Computer Science and Information Engineering, National Taitung University, Taitung, Taiwan
- Interdisciplinary Program of Green and Information Technology, National Taitung University, Taitung, Taiwan
| | - Yung-Yu Shih
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Chi-Yang Wu
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | | | | | - Yu-Ju Chen
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - Wen-Lian Hsu
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Yen-Jen Oyang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
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24
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Gupta MK, Behara SK, Vadde R. In silico analysis of differential gene expressions in biliary stricture and hepatic carcinoma. Gene 2016; 597:49-58. [PMID: 27777109 DOI: 10.1016/j.gene.2016.10.032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 10/15/2016] [Accepted: 10/19/2016] [Indexed: 12/16/2022]
Abstract
In-silico attempt was made to identify the key hub genes which get differentially expressed in biliary stricture and hepatic carcinoma. Gene expression data, GSE34166, was downloaded from the GEO database, which contains 10 biliary stricture samples (4 benign control and 6 malignant carcinoma), for screening of key hub genes associated with the disease. R packages scripts were identified 85 differentially expressed genes. Further these genes were uploaded in WebGestalt database and identified nine key genes. Using STRING database and Gephi software, the protein-protein interaction networks were constructed and also studied gene ontology through WebGestalt. Finally, we identified four key genes (CXCR4, ADH1C, ABCB1 and ADH1A) are associated with liver carcinoma and further cross-validated with Liverome, Protein Atlas database and bibliography. In addition, transcription factors and their binding sites also studied. These identified hub genes and their transcription factors are the probable potential targets for possible future drug design.
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Affiliation(s)
- Manoj Kumar Gupta
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa 516003, Andhra Pradesh, India.
| | - Santosh Kumar Behara
- Biomedical Informatics Centre, Regional Medical Research Centre (ICMR), Bhubaneswar 751023, Odisha, India.
| | - Ramakrishna Vadde
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa 516003, Andhra Pradesh, India.
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25
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Shen J, Siegel AB, Remotti H, Wang Q, Santella RM. Identifying microRNA panels specifically associated with hepatocellular carcinoma and its different etiologies. ACTA ACUST UNITED AC 2016; 2:151-162. [PMID: 28243631 DOI: 10.20517/2394-5079.2015.66] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM Deregulation of microRNAs (miRNAs) expression has been identified in hepatocellular carcinoma (HCC), but few results are consistent. The objective of this study is to investigate "HCC tumor type specific" and "tumor common" miRNA panels. METHODS The authors integrate and analyze clinical, etiologic and miRNA profiles data from 9 types of solid tumors in The Cancer Genome Atlas (TCGA) and HCC data from Columbia University Medical Center (CUMC). RESULTS Levels of 33 miRNAs were significant different between HCC tumor and paired non-tumor tissues (over 2-fold changes) after Bonferroni correction for multiple comparisons, and most (28 miRNAs) were down-regulated in HCC tumors. Using this panel, the authors well classified HCC tumor tissues with 4 misclassifications among 48 paired tissues. Validating this panel in an additional 302 HCC tumor tissues, the authors almost perfectly distinguished tumor from non-tumor tissues with only two misclassifications (99% of HCC tissues correctly classified). Evaluating miRNA profiles in 32 independent HCC paired tissues from CUMC, the authors observed 40 miRNAs significantly deregulated in HCC with over 2-fold changes; 14 overlapped with those identified in TCGA. Subgroup analyses by HCC etiology found that 4 upregulated and 8 downregulated miRNAs were significantly associated with alcohol-related HCC. There were 7 and 4 miRNAs significantly associated with hepatitis B virus- and hepatitis C virus-related HCC, respectively. Data for the first time revealed that miR-24-1, miR-130a and miR-505 were significantly down-regulated only in HCC tumors; miR-142 and miR-455 were significantly down-regulated in HCC, but up-regulated in 5 other solid tumors; suggesting their HCC "tumor type specific" characteristics. A panel of 8 miRNAs was significant in at least 5 tumor types, including HCC, and was identified as "tumor common" marker. CONCLUSION The authors concluded that aberrant miRNA panels have HCC "tumor type specificity" and may be affected by etiologic factors.
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Affiliation(s)
- Jing Shen
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | - Abby B Siegel
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Helen Remotti
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Qiao Wang
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | - Regina M Santella
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
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26
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Gao L, Wang XD, Niu YY, Duan DD, Yang X, Hao J, Zhu CH, Chen D, Wang KX, Qin XM, Wu XZ. Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology. Sci Rep 2016; 6:24944. [PMID: 27143508 PMCID: PMC4855233 DOI: 10.1038/srep24944] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/07/2016] [Indexed: 12/15/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan-Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc.
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Affiliation(s)
- Li Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, PR China
| | - Xiao-dong Wang
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Yang-yang Niu
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Dan-dan Duan
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, PR China
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, PR China
| | - Xue Yang
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Jian Hao
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Cui-hong Zhu
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Dan Chen
- Department of Pharmacology, Basic Medical College, Tianjin Medical University, Tianjin, 300070, China
| | - Ke-xin Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, PR China
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, PR China
| | - Xue-mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, PR China
| | - Xiong-zhi Wu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Tianjin People’s Hospital, NO.190 Jieyuan Road, Hongqiao, District, 300000, China
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27
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Ouyang J, Sun Y, Li W, Zhang W, Wang D, Liu X, Lin Y, Lian B, Xie L. dbPHCC: a database of prognostic biomarkers for hepatocellular carcinoma that provides online prognostic modeling. Biochim Biophys Acta Gen Subj 2016; 1860:2688-95. [PMID: 26940364 DOI: 10.1016/j.bbagen.2016.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/27/2016] [Accepted: 02/26/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a poor prognosis. For decades, more and more biomarkers were found to effect on HCC prognosis, but these studies were scattered and there were no unified identifiers. Therefore, we built the database of prognostic biomarkers and models for hepatocellular carcinoma (dbPHCC). METHODS dbPHCC focuses on biomarkers which were related to HCC prognosis by traditional experiments rather than high-throughput technology. All of the prognostic biomarkers came from literatures issued during 2002 to 2014 in PubMed and were manually selected. dbPHCC collects comprehensive information of candidate biomarkers and HCC prognosis. RESULTS dbPHCC mainly contains 567 biomarkers: 323 proteins, 154 genes, and 90 microRNAs. For each biomarker, the reference information, experimental conditions, and prognostic information are shown. Based on two available patient cohort data sets, an exemplified prognostic model was constructed using 15 phosphotransferases in dbPHCC. The web interface does not only provide a full range of browsing and searching, but also provides online analysis tools. dbPHCC is available at http://lifecenter.sgst.cn/dbphcc/ CONCLUSIONS dbPHCC provides a comprehensive and convenient search and analysis platform for HCC prognosis research. GENERAL SIGNIFICANCE dbPHCC is the first database to focus on experimentally verified individual biomarkers, which are related to HCC prognosis. Prognostic markers in dbPHCC have the potential to be therapeutic drug targets and may help in designing new treatments to improve survival of HCC patients. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
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Affiliation(s)
- Jian Ouyang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Ying Sun
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
| | - Wei Li
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Wen Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of People Libration Army General Hospital, Beijing 100048, China
| | - Dandan Wang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Xiangqiong Liu
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yong Lin
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Baofeng Lian
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China; Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200240, China.
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China.
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28
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HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma. J Transl Med 2015; 13:379. [PMID: 26653219 PMCID: PMC4676172 DOI: 10.1186/s12967-015-0743-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 11/30/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Orthotopic liver transplantation (OLT) can be an effective treatment option for certain patients with early stage hepatocellular carcinoma (HCC) meeting Milan, UCSF, or Hangzhou criteria. However, HCC recurrence rates post-OLT range from 20 to 40 %, with limited follow-up options. Elucidating genetic drivers common to primary and post-OLT recurrent tumors may further our understanding and help identify predictive biomarkers of recurrence-both to ultimately help manage clinical decisions for patients undergoing OLT. METHODS Whole exome and RNA sequencing in matched primary and recurrent tumors, normal adjacent tissues, and blood from four Chinese HCC patients was conducted. SiRNA knockdown and both qRT-PCR and Western assays were performed on PLCPRF5, SNU449 and HEPG2 cell lines; immunohistochemistry and RNA Sequencing were conducted on the primary tumors of Chinese HCC patients who experienced tumor recurrence post-OLT (n = 9) or did not experience tumor recurrence (n = 12). RESULTS In three independent HCC studies of patients undergoing transplantation (n = 21) or surgical resection (n = 242, n = 44) of primary tumors (total n = 307), HERC5 mRNA under-expression correlated with shorter: time to tumor recurrence (p = 0.007 and 0.02) and overall survival (p = 0.0063 and 0.023), even after adjustment for relevant clinical variables. HERC5 loss drives CCL20 mRNA and protein over-expression and associates with regulatory T cell infiltration as measured by FOXP3 expression. Further, matched primary and recurrent tumors from the 4 HCC patients indicated clonal selection advantage of Wnt signaling activation and CDKN2A inactivation. CONCLUSIONS HERC5 plays a crucial role in HCC immune evasion and has clinical relevance as a reproducible prognostic marker for risk of tumor recurrence and survival in patients.
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29
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Li W, Freudenberg J, Oswald M. Principles for the organization of gene-sets. Comput Biol Chem 2015; 59 Pt B:139-49. [PMID: 26188561 DOI: 10.1016/j.compbiolchem.2015.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 04/08/2015] [Indexed: 12/23/2022]
Abstract
A gene-set, an important concept in microarray expression analysis and systems biology, is a collection of genes and/or their products (i.e. proteins) that have some features in common. There are many different ways to construct gene-sets, but a systematic organization of these ways is lacking. Gene-sets are mainly organized ad hoc in current public-domain databases, with group header names often determined by practical reasons (such as the types of technology in obtaining the gene-sets or a balanced number of gene-sets under a header). Here we aim at providing a gene-set organization principle according to the level at which genes are connected: homology, physical map proximity, chemical interaction, biological, and phenotypic-medical levels. We also distinguish two types of connections between genes: actual connection versus sharing of a label. Actual connections denote direct biological interactions, whereas shared label connection denotes shared membership in a group. Some extensions of the framework are also addressed such as overlapping of gene-sets, modules, and the incorporation of other non-protein-coding entities such as microRNAs.
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Affiliation(s)
- Wentian Li
- The Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA.
| | - Jan Freudenberg
- The Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA
| | - Michaela Oswald
- The Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA
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Tyakht AV, Ilina EN, Alexeev DG, Ischenko DS, Gorbachev AY, Semashko TA, Larin AK, Selezneva OV, Kostryukova ES, Karalkin PA, Vakhrushev IV, Kurbatov LK, Archakov AI, Govorun VM. RNA-Seq gene expression profiling of HepG2 cells: the influence of experimental factors and comparison with liver tissue. BMC Genomics 2014; 15:1108. [PMID: 25511409 PMCID: PMC4378340 DOI: 10.1186/1471-2164-15-1108] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 12/11/2014] [Indexed: 12/12/2022] Open
Abstract
Background Human hepatoma HepG2 cells are used as an in vitro model of the human liver. High-throughput transcriptomic sequencing is an advanced approach for assessing the functional state of a tissue or cell type. However, the influence of experimental factors, such as the sample preparation method and inter-laboratory variation, on the transcriptomic profile has not been evaluated. Results The whole-transcriptome sequencing of HepG2 cells was performed using the SOLiD platform and validated using droplet digital PCR. The gene expression profile was compared to the results obtained with the same sequencing method in another laboratory and using another sample preparation method. We also compared the transcriptomic profile HepG2 cells with that of liver tissue. Comparison of the gene expression profiles between the HepG2 cell line and liver tissue revealed the highest variation, followed by HepG2 cells submitted to two different sample preparation protocols. The lowest variation was observed between HepG2 cells prepared by two different laboratories using the same protocol. The enrichment analysis of the genes that were differentially expressed between HepG2 cells and liver tissue mainly revealed the cancer-associated gene signature of HepG2 cells and the activation of the response to chemical stimuli in the liver tissue. The HepG2 transcriptome obtained with the SOLiD platform was highly correlated with the published transcriptome obtained with the Illumina and Helicos platforms, with moderate correspondence to microarrays. Conclusions In the present study, we assessed the influence of experimental factors on the HepG2 transcriptome and identified differences in gene expression between the HepG2 cell line and liver cells. These findings will facilitate robust experimental design in the fields of pharmacology and toxicology. Our results were supported by a comparative analysis with previous HepG2 gene expression studies. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1108) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alexander V Tyakht
- Research Institute of Physico-Chemical Medicine, Malaya Pirogovskaya 1a, Moscow 119435, Russia.
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Zhang Y, Guo X, Yang M, Yu L, Li Z, Lin N. Identification of AKT kinases as unfavorable prognostic factors for hepatocellular carcinoma by a combination of expression profile, interaction network analysis and clinical validation. MOLECULAR BIOSYSTEMS 2014; 10:215-22. [PMID: 24247267 DOI: 10.1039/c3mb70400a] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIM identification of key markers that differentiate occurrence and progression of hepatocellular carcinoma (HCC) is of great significance to develop novel prognostic factors and improve therapeutic strategies. The aim of this study was to screen novel markers for HCC by combining expression profile, interaction network analysis and clinical validation. METHODS & RESULTS HCC significant molecules which were differentially expressed in HCC tissues were obtained from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome). The protein-protein interaction network of HCC significant proteins was constructed and 331 candidate HCC markers were identified by calculating four topological features of the network ('Degree', 'Betweenness', 'Closeness' and 'K-coreness'). According to the enrichment analysis on Gene ontology items and KEGG pathways, these candidate HCC markers were more frequently involved in cellular protein metabolic processes, translational elongation and intracellular signaling cascade, which are associated with cancer development and metastasis. Among 331 candidate HCC markers, the three AKT kinase family members (AKT1-AKT3) were selected for clinical validation by immunohistochemistry analysis using 130 HCC specimens and matched adjacent non-neoplastic liver tissues. Interestingly, the upregulation of AKT1, AKT2 and AKT3 proteins were all significantly associated with tumor aggressiveness and poor prognosis in patients with HCC. CONCLUSION this study provided an integrated analysis by combining expression profile and interaction network analysis to identify a list of biologically significant HCC related markers and pathways. Further experimental validation also indicated that AKT1, AKT2 and AKT3 proteins may all be novel unfavorable prognostic factors for patients with HCC.
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Affiliation(s)
- Yanqiong Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, China.
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Titz B, Elamin A, Martin F, Schneider T, Dijon S, Ivanov NV, Hoeng J, Peitsch MC. Proteomics for systems toxicology. Comput Struct Biotechnol J 2014; 11:73-90. [PMID: 25379146 PMCID: PMC4212285 DOI: 10.1016/j.csbj.2014.08.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Current toxicology studies frequently lack measurements at molecular resolution to enable a more mechanism-based and predictive toxicological assessment. Recently, a systems toxicology assessment framework has been proposed, which combines conventional toxicological assessment strategies with system-wide measurement methods and computational analysis approaches from the field of systems biology. Proteomic measurements are an integral component of this integrative strategy because protein alterations closely mirror biological effects, such as biological stress responses or global tissue alterations. Here, we provide an overview of the technical foundations and highlight select applications of proteomics for systems toxicology studies. With a focus on mass spectrometry-based proteomics, we summarize the experimental methods for quantitative proteomics and describe the computational approaches used to derive biological/mechanistic insights from these datasets. To illustrate how proteomics has been successfully employed to address mechanistic questions in toxicology, we summarized several case studies. Overall, we provide the technical and conceptual foundation for the integration of proteomic measurements in a more comprehensive systems toxicology assessment framework. We conclude that, owing to the critical importance of protein-level measurements and recent technological advances, proteomics will be an integral part of integrative systems toxicology approaches in the future.
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Jiang M, Chen Y, Zhang Y, Chen L, Zhang N, Huang T, Cai YD, Kong X. Identification of hepatocellular carcinoma related genes with k-th shortest paths in a protein-protein interaction network. MOLECULAR BIOSYSTEMS 2014; 9:2720-8. [PMID: 24056857 DOI: 10.1039/c3mb70089e] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide and one of the deadliest cancers in Asia. But at present, effective targets for HCC clinical therapy are still limited. The "guilt by association" rule suggests that interacting proteins share the same or similar functions and hence may be involved in the same pathway. This assumption can be used to identify disease related genes from protein association networks constructed from existing PPI data. Given the close association between Hepatitis B virus and Hepatitis B which may lead to HCC, here we develop a computational method to identify hepatocellular carcinoma related genes based on k-th shortest paths in the protein-protein interaction (PPI) network (we set k=1, 2 in this study). Finally, we found 33 genes whose p-values were less than 0.05, and most of them have been reported to be involved in HCC tumorigenesis and development. The results also provide a new reference for research into HCC oncogenesis and for development of new strategies for HCC clinical therapies.
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Affiliation(s)
- Min Jiang
- State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Jiaotong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, P.R. China.
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Wu M, Chan C. Prediction of therapeutic microRNA based on the human metabolic network. Bioinformatics 2014; 30:1163-1171. [PMID: 24403541 PMCID: PMC3982155 DOI: 10.1093/bioinformatics/btt751] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 12/08/2013] [Accepted: 12/22/2013] [Indexed: 12/17/2022] Open
Abstract
MOTIVATION MicroRNA (miRNA) expression has been found to be deregulated in human cancer, contributing, in part, to the interest of the research community in using miRNAs as alternative therapeutic targets. Although miRNAs could be potential targets, identifying which miRNAs to target for a particular type of cancer has been difficult due to the limited knowledge on their regulatory roles in cancer. We address this challenge by integrating miRNA-target prediction, metabolic modeling and context-specific gene expression data to predict therapeutic miRNAs that could reduce the growth of cancer. RESULTS We developed a novel approach to simulate a condition-specific metabolic system for human hepatocellular carcinoma (HCC) wherein overexpression of each miRNA was simulated to predict their ability to reduce cancer cell growth. Our approach achieved >80% accuracy in predicting the miRNAs that could suppress metastasis and progression of liver cancer based on various experimental evidences in the literature. This condition-specific metabolic system provides a framework to explore the mechanisms by which miRNAs modulate metabolic functions to affect cancer growth. To the best of our knowledge, this is the first computational approach implemented to predict therapeutic miRNAs for human cancer based on their functional role in cancer metabolism. Analyzing the metabolic functions altered by the miRNA-identified metabolic genes essential for cell growth and proliferation that are targeted by the miRNAs. AVAILABILITY AND IMPLEMENTATION See supplementary protocols and http://www.egr.msu.edu/changroup/Protocols%20Index.html CONTACT: krischan@egr.msu.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Ming Wu
- Department of Computer Science and Engineering, Department of Chemical Engineering and Materials Science and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Christina Chan
- Department of Computer Science and Engineering, Department of Chemical Engineering and Materials Science and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA Department of Computer Science and Engineering, Department of Chemical Engineering and Materials Science and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA Department of Computer Science and Engineering, Department of Chemical Engineering and Materials Science and Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
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A systems biology-based investigation into the therapeutic effects of Gansui Banxia Tang on reversing the imbalanced network of hepatocellular carcinoma. Sci Rep 2014; 4:4154. [PMID: 24561634 PMCID: PMC3932480 DOI: 10.1038/srep04154] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 01/29/2014] [Indexed: 12/31/2022] Open
Abstract
Several complex molecular events are involved in tumorigenesis of hepatocellular carcinoma (HCC). The interactions of these molecules may constitute the HCC imbalanced network. Gansui Banxia Tang (GSBXT), as a classic Chinese herbal formula, is a popular complementary and alternative medicine modality for treating HCC. In order to investigate the therapeutic effects and the pharmacological mechanisms of GSBXT on reversing HCC imbalanced network, we in the current study developed a comprehensive systems approach of integrating disease-specific and drug-specific networks, and successfully revealed the relationships of the ingredients in GSBXT with their putative targets, and with HCC significant molecules and HCC related pathway systems for the first time. Meanwhile, further experimental validation also demonstrated the preventive effects of GSBXT on tumor growth in mice and its regulatory effects on potential targets.
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Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM, Giordano S, Columbano A. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology 2014; 59:228-41. [PMID: 23857252 DOI: 10.1002/hep.26616] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 06/29/2013] [Indexed: 12/17/2022]
Abstract
UNLABELLED Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions in humans. Experimental models recapitulating human hepatocellular carcinoma (HCC) are then used to perform this analysis. We performed miRNA and gene expression profiling to characterize the molecular events involved in the multistep process of hepatocarcinogenesis in the resistant-hepatocyte rat model. A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in early preneoplastic lesions positive for the stem/progenitor cell marker cytokeratin-19, indicating that several HCC-associated alterations occur from the very beginning of the carcinogenic process. Our analysis also identified miRNA/gene-target networks aberrantly activated at the initial stage of hepatocarcinogenesis. Activation of the nuclear factor erythroid related factor 2 (NRF2) pathway and up-regulation of the miR-200 family were among the most prominent changes. The relevance of these alterations in the development of HCC was confirmed by the observation that NRF2 silencing impaired while miR-200a overexpression promoted HCC cell proliferation in vitro. Moreover, T3-induced in vivo inhibition of the NRF2 pathway accompanied the regression of cytokeratin-19-positive nodules, suggesting that activation of this transcription factor contributes to the onset and progression of preneoplastic lesions towards malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat HCC have been previously associated with human HCC as well underlines the translational value of our results. CONCLUSION This study indicates that most of the molecular changes found in HCC occur in the very early stages of hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may represent a new therapeutic target.
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Affiliation(s)
- Annalisa Petrelli
- IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Torino, Italy
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Identification of GRB2 and GAB1 coexpression as an unfavorable prognostic factor for hepatocellular carcinoma by a combination of expression profile and network analysis. PLoS One 2013; 8:e85170. [PMID: 24391994 PMCID: PMC3877332 DOI: 10.1371/journal.pone.0085170] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 11/24/2013] [Indexed: 12/25/2022] Open
Abstract
Aim To screen novel markers for hepatocellular carcinoma (HCC) by a combination of expression profile, interaction network analysis and clinical validation. Methods HCC significant molecules which are differentially expressed or had genetic variations in HCC tissues were obtained from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome). Then, the protein-protein interaction (PPI) network of these molecules was constructed. Three topological features of the network ('Degree', 'Betweenness', and 'Closeness') and the k-core algorithm were used to screen candidate HCC markers which play crucial roles in tumorigenesis of HCC. Furthermore, the clinical significance of two candidate HCC markers growth factor receptor-bound 2 (GRB2) and GRB2-associated-binding protein 1 (GAB1) was validated. Results In total, 6179 HCC significant genes and 977 HCC significant proteins were collected from existing HCC related databases. After network analysis, 331 candidate HCC markers were identified. Especially, GAB1 has the highest k-coreness suggesting its central localization in HCC related network, and the interaction between GRB2 and GAB1 has the largest edge-betweenness implying it may be biologically important to the function of HCC related network. As the results of clinical validation, the expression levels of both GRB2 and GAB1 proteins were significantly higher in HCC tissues than those in their adjacent nonneoplastic tissues. More importantly, the combined GRB2 and GAB1 protein expression was significantly associated with aggressive tumor progression and poor prognosis in patients with HCC. Conclusion This study provided an integrative analysis by combining expression profile and interaction network analysis to identify a list of biologically significant HCC related markers and pathways. Further experimental validation indicated that the aberrant expression of GRB2 and GAB1 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of GRB2 in combination with upregulation of GAB1 may be an unfavorable prognostic factor for HCC.
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Caboux E, Paciencia M, Durand G, Robinot N, Wozniak MB, Galateau-Salle F, Byrnes G, Hainaut P, Le Calvez-Kelm F. Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples. PLoS One 2013; 8:e79826. [PMID: 24278187 PMCID: PMC3835918 DOI: 10.1371/journal.pone.0079826] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 10/03/2013] [Indexed: 12/31/2022] Open
Abstract
The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as “warm ischemia”. Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analyzed gene expression variation in samples of 3 hepatocellular carcinomas (HCC) and 3 lung carcinomas (LC) cryopreserved at times up to 2 hours after resection. RNA Integrity Numbers (RIN) revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of −3.5%/hr (95% CI: −7.0%/hr to 0.1%/hr; p = 0.054). In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5) and 6 down-regulated genes (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1) was identified (FDR <0.05). Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes.
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Affiliation(s)
- Elodie Caboux
- Laboratory Services and Biobank, International Agency for Research on Cancer, Lyon, France
| | - Maria Paciencia
- Department of Pathology, Centre Hospitalier Universitaire de Caen, Caen, France
| | - Geoffroy Durand
- Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
| | - Nivonirina Robinot
- Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
| | - Magdalena B. Wozniak
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | | | - Graham Byrnes
- Biostatistics Group, International Agency for Research on Cancer, Lyon, France
| | - Pierre Hainaut
- International Agency for Research on Cancer, Lyon, France
- International Prevention Research Institute, Lyon, France
| | - Florence Le Calvez-Kelm
- Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
- * E-mail:
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Bysani M, Wallerman O, Bornelöv S, Zatloukal K, Komorowski J, Wadelius C. ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer. BMC Med Genomics 2013; 6:50. [PMID: 24206787 PMCID: PMC3831757 DOI: 10.1186/1755-8794-6-50] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 10/31/2013] [Indexed: 02/06/2023] Open
Abstract
Background Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.
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Affiliation(s)
| | | | | | | | | | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, BMC, Uppsala University, PO BOX 815, Uppsala, SE 751 08, Sweden.
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Costantini S, Di Bernardo G, Cammarota M, Castello G, Colonna G. Gene expression signature of human HepG2 cell line. Gene 2013; 518:335-345. [PMID: 23357223 DOI: 10.1016/j.gene.2012.12.106] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 12/21/2012] [Accepted: 12/24/2012] [Indexed: 01/12/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is associated with various clinico-pathological characteristics such as genetic mutations and viral infections. Therefore, numerous laboratories look out for identifying always new putative markers for the improvement of HCC diagnosis/prognosis. Many molecular profiling studies investigated gene expression changes related to HCC. HepG2 represents a pure cell line of human liver carcinoma, often used as HCC model due to the absence of viral infection. In this study we compare gene expression profiles associated with HepG2 (as HCC model) and normal hepatocyte cells by microarray technology. Hierarchical cluster analysis of genes evidenced that 2646 genes significantly down-regulated in HepG2 cells compared to hepatocytes whereas a further 3586 genes significantly up-regulated. By using the Ingenuity Pathway Analysis (IPA) program, we have classified the genes that were differently expressed and studied the functional networks correlating these genes in the complete human interactome. Moreover, to confirm the differentially expressed genes as well as the reliability of our microarray data, we performed a quantitative Real time RT-PCR analysis on 9 up-regulated and 11 down-regulated genes, respectively. In conclusion this work i) provides a gene signature of human hepatoma cells showing genes that change their expression as a consequence of liver cancer in the absence of any genetic mutations or viral infection, ii) evidences new differently expressed genes found in our signature compared to previous published studies and iii) suggests some genes on which to focus future studies to understand if they can be used to improve the HCC prognosis/diagnosis.
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Affiliation(s)
- S Costantini
- INT Pascale, Cancer Research Centre of Mercogliano, Mercogliano, Italy.
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Filmus J, Capurro M. Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J 2013; 280:2471-6. [DOI: 10.1111/febs.12126] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 01/03/2013] [Accepted: 01/07/2013] [Indexed: 12/11/2022]
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Wu S, Li N, Ma J, Shen H, Jiang D, Chang C, Zhang C, Li L, Zhang H, Jiang J, Xu Z, Ping L, Chen T, Zhang W, Zhang T, Xing X, Yi T, Li Y, Fan F, Li X, Zhong F, Wang Q, Zhang Y, Wen B, Yan G, Lin L, Yao J, Lin Z, Wu F, Xie L, Yu H, Liu M, Lu H, Mu H, Li D, Zhu W, Zhen B, Qian X, Qin J, Liu S, Yang P, Zhu Y, Xu P, He F. First proteomic exploration of protein-encoding genes on chromosome 1 in human liver, stomach, and colon. J Proteome Res 2013; 12:67-80. [PMID: 23256928 DOI: 10.1021/pr3008286] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The launch of the Chromosome-Centric Human Proteome Project provides an opportunity to gain insight into the human proteome. The Chinese Human Chromosome Proteome Consortium has initiated proteomic exploration of protein-encoding genes on human chromosomes 1, 8, and 20. Collaboration within the consortium has generated a comprehensive proteome data set using normal and carcinomatous tissues from human liver, stomach, and colon and 13 cell lines originating in these organs. We identified 12,101 proteins (59.8% coverage against Swiss-Prot human entries) with a protein false discovery rate of less than 1%. On chromosome 1, 1,252 proteins mapping to 1,227 genes, representing 60.9% of Swiss-Prot entries, were identified; however, 805 proteins remain unidentified, suggesting that analysis of more diverse samples using more advanced proteomic technologies is required. Genes encoding the unidentified proteins were concentrated in seven blocks, located at p36, q12-21, and q42-44, partly consistent with correlation of these blocks with cancers of the liver, stomach, and colon. Combined transcriptome, proteome, and cofunctionality analyses confirmed 23 coexpression clusters containing 165 genes. Biological information, including chromosome structure, GC content, and protein coexpression pattern was analyzed using multilayered, circular visualization and tabular visualization. Details of data analysis and updates are available in the Chinese Chromosome-Centric Human Proteome Database ( http://proteomeview.hupo.org.cn/chromosome/ ).
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Affiliation(s)
- Songfeng Wu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
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Schönbach C, Tan TW, Kelso J, Rost B, Nathan S, Ranganathan S. InCoB celebrates its tenth anniversary as first joint conference with ISCB-Asia. BMC Genomics 2011; 12 Suppl 3:S1. [PMID: 22369160 PMCID: PMC3333168 DOI: 10.1186/1471-2164-12-s3-s1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
In 2009 the International Society for Computational Biology (ISCB) started to roll out regional bioinformatics conferences in Africa, Latin America and Asia. The open and competitive bid for the first meeting in Asia (ISCB-Asia) was awarded to Asia-Pacific Bioinformatics Network (APBioNet) which has been running the International Conference on Bioinformatics (InCoB) in the Asia-Pacific region since 2002. InCoB/ISCB-Asia 2011 is held from November 30 to December 2, 2011 in Kuala Lumpur, Malaysia. Of 104 manuscripts submitted to BMC Genomics and BMC Bioinformatics conference supplements, 49 (47.1%) were accepted. The strong showing of Asia among submissions (82.7%) and acceptances (81.6%) signals the success of this tenth InCoB anniversary meeting, and bodes well for the future of ISCB-Asia.
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Affiliation(s)
- Christian Schönbach
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, Japan.
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