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Chen Z, Zeng Y, Ma P, Xu Q, Zeng L, Song X, Yu F. Integrated GMPS and RAMP3 as a signature to predict prognosis and immune heterogeneity in hepatocellular carcinoma. Gene 2025; 933:148958. [PMID: 39312983 DOI: 10.1016/j.gene.2024.148958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 06/14/2024] [Accepted: 09/18/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly fatal malignant worldwide. As different expression levels of specific genes can lead to different HCC outcomes, we aimed to develop a gene signature capable of predicting HCC prognosis. METHODS In this study, transcriptomic sequencing and relevant clinical data were extracted from public platforms. The guanine monophosphate synthase (GMPS)|receptor activity-modifying protein 3 (RAMP3) gene pair was developed based on the relative values of gene expression levels. Nomograms were developed using R software. Immune status was assessed through single-sample gene set enrichment analysis. GMPS knockdown was achieved through siRNA transfection. Quantitative reverse transcription PCR, apoptosis assays, and cell proliferation were performed to verify the function of GMPS|RAMP3 in HCC cells. RESULTS Here, a gene pair containing GMPS and RAMP3 was successfully constructed. We demonstrated that the GMPS|RAMP3 gene pair was an independent predictor with strong prognostic prediction power, based on which a nomogram was established. Functional analysis revealed that the enrichment of cell cycle-related pathways and immune status differed considerably between the two groups, with cell cycle-related genes highly expressed in the high GMPS|RAMP3 value group. Finally, cell experiments indicated that GMPS knockdown significantly repressed proliferation, promoted apoptosis, and enhanced the sensitivity of HCC cells to gemcitabine. CONCLUSIONS The gene pair GMPS|RAMP3 is a novel prognostic predictor of HCC, providing a promising approach to the treatment and assessment of immune heterogeneity in HCC.
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Affiliation(s)
- Zhuoyan Chen
- Department of Gastroenterology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Yuan Zeng
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peipei Ma
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qian Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liuwei Zeng
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xian Song
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Mutonga MBG, Shewarega A, Gross M, Kahl VH, Madoff DC. Investigating synergy between beta-blockers and transarterial chemoembolization in the treatment of hepatocellular carcinoma: preliminary data from a propensity matched analysis. Clin Imaging 2024; 115:110283. [PMID: 39278042 DOI: 10.1016/j.clinimag.2024.110283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 07/02/2024] [Accepted: 08/31/2024] [Indexed: 09/17/2024]
Abstract
PURPOSE Favorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC. METHODS 36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant. RESULTS Comparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03). CONCLUSION Transplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts.
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Affiliation(s)
- Martin B G Mutonga
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, United States
| | - Annabella Shewarega
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, United States; Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen (ÄoR), Essen, Germany
| | - Moritz Gross
- Department of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - Vinzent H Kahl
- Department of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany
| | - David C Madoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, United States; Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, United States; Department of Surgery, Section of Surgical Oncology, Yale School of Medicine, New Haven, CT, United States.
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Becht R, Kiełbowski K, Wasilewicz MP. New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow. Int J Mol Sci 2024; 25:1456. [PMID: 38338736 PMCID: PMC10855889 DOI: 10.3390/ijms25031456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.
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Affiliation(s)
- Rafał Becht
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Michał P. Wasilewicz
- Liver Unit, Department of Gastroenterology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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Manoharan S, Saha S, Murugesan K, Santhakumar A, Perumal E. Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update. Life Sci 2024; 337:122351. [PMID: 38103726 DOI: 10.1016/j.lfs.2023.122351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/23/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Shreejit Saha
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Krishnasanthiya Murugesan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Aksayakeerthana Santhakumar
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
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Liu C, Shi J, Lin B, Zhou M, Shan D, Nie J, Wang Y, Zhang Y, Han P, Zheng T. SHR6390 Combined with Cabozantinib Inhibits Tumor Progression in the Hepatocellular Carcinoma Mouse Model. Curr Gene Ther 2024; 24:453-464. [PMID: 36017825 DOI: 10.2174/1566523222666220825110147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/19/2022] [Accepted: 05/21/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND A novel CDK4/6 inhibitor SHR6390 has shown significant anti-tumor effects. However, its role in hepatocellular carcinoma (HCC) remains unknown. OBJECTIVE To explore the inhibitory effect of combination treatment with SHR6390 and cabozantinib in HCC, and its antitumor mechanism, so as to provide a more effective therapeutic strategy for HCC patients. METHODS We investigated SHR6390, monotherapy or combined with cabozantinib, by CCK8, wound healing, transwell, western blotting, immunohistochemistry and mouse model of a subcutaneous tumor. RESULTS Our results show that SHR6390 exhibited potent anti-proliferative activity against HCC in a dose-dependent manner. SHR6390 combined with cabozantinib exhibited more potent inhibition of cell viability, migration and invasion. In terms of potential mechanisms, we found that cabozantinib could lead to phosphorylation of Rb, which was reduced in SHR6390 and combined groups. SHR6390 monotherapy inhibited the growth of subcutaneous HCC tumors, besides, the combination treatment with SHR6390 and cabozantinib exerted synergistic anti-tumor activity in vivo Conclusion: SHR6390 is effective against HCC, monotherapy or combined with cabozantinib.
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Affiliation(s)
- Caiqi Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
- Key Laboratory of Molecular Oncology of Heilongjiang Province, Harbin, Heilongjiang, People's Republic of China
| | - Jiaqi Shi
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
- Key Laboratory of Molecular Oncology of Heilongjiang Province, Harbin, Heilongjiang, People's Republic of China
| | - Binlin Lin
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Meng Zhou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Dan Shan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Jianhua Nie
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Yan Wang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
| | - Peng Han
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
- Key Laboratory of Molecular Oncology of Heilongjiang Province, Harbin, Heilongjiang, People's Republic of China
- Department of Phase 1 Trials Center, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China
- Key Laboratory of Molecular Oncology, Heilongjiang Cancer Institute, Harbin, People's Republic of China
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Nasir NM, Alsalim TA, El-Arabey AA, Abdalla M. Anticancer, antioxidant activities and molecular docking study of thiazolidine-4-one and thiadiazol derivatives. J Biomol Struct Dyn 2023; 41:3976-3992. [PMID: 35467480 DOI: 10.1080/07391102.2022.2060306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/27/2022] [Indexed: 10/18/2022]
Abstract
Liver cancer accounts for a major portion of the global cancer burden. In many nations, the prevalence of this condition has risen in recent decades. New series of thiazolidinones and thiadiazolidine have been designed, synthesized, and evaluated for potential antioxidant and antihepatocarcinogenic activity. The antioxidant activity was evaluated using a DPPH assay. Furthermore, we examined the compounds against Hepg-2 cells using MTT assay, flow cytometry analysis through the cell cycle, reactive oxygen species, and apoptosis. The result showed that compound 6b has the highest antioxidant activity with IC50 = 60.614 ± 0.739 µM. The anticancer activity showed that compounds 5 and 6b have significant toxicity against liver cancer cells Hepg2, IC50 values (9.082 and 4.712) µM, respectively. Flow cytometry experiments revealed that compound 5 arrested Hepg-2 cells in the S process, while compound 6b arrested Hepg-2 cells in the G1. Compound 6b had a greater reduction in reactive oxygen species and late apoptosis than compound 5. Substantially, compound 5 had affinity energies of -7.6 and -8.5 for Akt and CDK4 proteins, respectively, but compound 6b had affinity energies of -7.8 and -10.1 for Akt1 and CDK4 proteins, respectively. Consequently, compound 6b had lower binding energies than compound 5. In this work, we used multiple bioinformatics methods to shed light on the prospective therapeutic use of these series as novel candidates to target immune cells in the tumor microenvironment of hepatocellular carcinomas such as CD8+ T cells, endothelial cells, and hematopoietic stem cells.
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Affiliation(s)
- Noor M Nasir
- Department of Chemistry, Faculty of Education for Pure Sciences, University of Basrah, Basrah, Iraq
| | - Tahseen A Alsalim
- Department of Chemistry, Faculty of Education for Pure Sciences, University of Basrah, Basrah, Iraq
| | - Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohnad Abdalla
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Shandong Province, People's Republic of China
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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Hsu CH, Weng PW, Chen MY, Yeh CT, Setiawan SA, Yadav VK, Wu ATH, Tzeng DTW, Gong JX, Yang Z, Tzeng YM. Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways. Chem Biol Interact 2023; 370:110329. [PMID: 36565974 DOI: 10.1016/j.cbi.2022.110329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 12/01/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p < 0.001) and tumorsphere formation (p < 0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.
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Affiliation(s)
- Chia-Hung Hsu
- Department of Emergency Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei City, 11031, Taiwan; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Pei-Wei Weng
- Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chi-Tai Yeh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung, 95092, Taiwan
| | - Syahru Agung Setiawan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Vijesh Kumar Yadav
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Alexander T H Wu
- Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - David T W Tzeng
- School of Life Sciences, The Chinese University of Hong Kong, 999077, Hong Kong Special Administrative Region of China; Lifebit, London, EC2A 2AP, UK
| | - Jian-Xian Gong
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China
| | - Zhen Yang
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China.
| | - Yew-Min Tzeng
- Department of Applied Science, National Taitung University, Taitung, 95092, Taiwan; Department of Applied Chemistry, Chaoyang University of Technology, Taichung, 41349, Taiwan.
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Gholizadeh M, Mazlooman SR, Hadizadeh M, Drozdzik M, Eslami S. Detection of key mRNAs in liver tissue of hepatocellular carcinoma patients based on machine learning and bioinformatics analysis. MethodsX 2023; 10:102021. [PMID: 36713306 PMCID: PMC9879787 DOI: 10.1016/j.mex.2023.102021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 01/15/2023] [Indexed: 01/19/2023] Open
Abstract
One methodology extensively used to develop biomarkers is the precise detection of highly responsive genes that can distinguish cancer samples from healthy samples. The purpose of this study was to screen for potential hepatocellular carcinoma (HCC) biomarkers based on non-fusion integrative multi-platform meta-analysis method. The gene expression profiles of liver tissue samples from two microarray platforms were initially analyzed using a meta-analysis based on an empirical Bayesian method to robust discover differentially expressed genes in HCC and non-tumor tissues. Then, using the bioinformatics technique of weighted correlation network analysis, the highly associated prioritized Differentially Expressed Genes (DEGs) were clustered. Co-expression network and topological analysis were utilized to identify sub-clusters and confirm candidate genes. Next, a diagnostic model was developed and validated using a machine learning algorithm. To construct a prognostic model, the Cox proportional hazard regression analysis was applied and validated. We identified three genes as specific biomarkers for the diagnosis of HCC based on accuracy and feasibility. The diagnostic model's area under the curve was 0.931 with confidence interval of 0.923-0.952.•Non-fusion integrative multi-platform meta-analysis method.•Classification methods and biomarkers recognition via machine learning method.•Biomarker validation models.
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Affiliation(s)
- Maryam Gholizadeh
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91388-13944, Iran
| | - Seyed Reza Mazlooman
- Department of Computer Engineering, Central Tehran Branch, Islamic Azad University, Tehran 1477893780, Iran
| | - Morteza Hadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Marek Drozdzik
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin 70-111, Poland
| | - Saeid Eslami
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91388-13944, Iran
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10
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State of the art and perspectives in pediatric hepatocellular carcinoma. Biochem Pharmacol 2023; 207:115373. [PMID: 36513143 DOI: 10.1016/j.bcp.2022.115373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022]
Abstract
Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are rare primary malignant liver cancers in children and young adults. HB is the most common and accounts for about 70 % cases; it is usually diagnosed during the first 3 years of life. Instead, pediatric HCC is uncommon, and it is associated with a poor prognosis. Overall, the prognosis of pediatric HCC is dismal with 5-year event-free survival of <30 % as compared to >80 % for HB. Surgery approaches, either resection or transplant, remain the best chance for the cure of pediatric HCC. However, chemotherapy can be helpful as an adjuvant or neoadjuvant treatment. International groups have done trials in pediatric HCC with a chemotherapy regimen, based on cisplatin and doxorubicin (PLADO) as for HB, but the efficacy is limited. Sorafenib, a multi-kinase inhibitor, following positive results in adults and in a pilot study in children, is now tested in conjunction with chemotherapy in the PHITT phase III clinical trial. Some studies have been exploring the genetic profiles of patients to find biological hallmarks that determine the aggressiveness of pediatric HCC. Pathways involved in growth and differentiation are dysregulated and as demonstrated in HB and adult HCC, an important role of the Wnt/CTNNB1 pathway in the pathogenesis of pediatric HCC is also emerging. An extended molecular analysis of tumor samples could give information about pathways as possible targets of biological and immunotherapeutic agents bringing new pharmacological options for the treatment of pediatric HCC.
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11
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Expression of Cell-Cycle Regulatory Proteins pRb, Cyclin D1, and p53 Is Not Associated with Recurrence Rates of Equine Sarcoids. Vet Sci 2022; 9:vetsci9090474. [PMID: 36136690 PMCID: PMC9504470 DOI: 10.3390/vetsci9090474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Sarcoids are among the most common tumors diagnosed in equids; their association with bovine papillomaviruses (BPV) infection has been widely reported, but the mechanism of carcinogenesis has not been fully elucidated. To verify whether BPV infection causes dysregulation of the pRb-Cyclin D1-p16CDKN2A-p53 pathway as reported for human papillomavirus (HPV), the study employed immunohistochemistry to test 55 equine sarcoid biopsies for the expression of pRb, Cyclin D1, and p53 cell cycle regulatory proteins and to evaluate the proliferative rate through Ki67. High Cyclin D1 and pRb expression were observed in 51% and 80% of cases, respectively, while low expression was observed in 49% and 20% of cases, respectively. Significantly higher Ki67 proliferation indexes were observed in fibroblastic, nodular, and mixed sarcoids compared to the occult and verrucous. High proliferation was significantly associated with high Cyclin D1 expression. In contrast with previous studies, p53 positivity was not observed in the cases examined in this study. Moreover, follow-up analysis revealed that fibroblastic, mixed sarcoids were associated with significantly higher local recurrence rates while the verrucous subtype was associated with higher rates of new sarcoid development at distant sites.
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12
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Digiacomo G, Fumarola C, La Monica S, Bonelli M, Cavazzoni A, Galetti M, Terenziani R, Eltayeb K, Volta F, Zoppi S, Bertolini P, Missale G, Alfieri R, Petronini PG. CDK4/6 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells. Front Oncol 2022; 12:942341. [PMID: 35936714 PMCID: PMC9354684 DOI: 10.3389/fonc.2022.942341] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/29/2022] [Indexed: 11/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a poor prognosis and limited treatment options. Considering that alterations of the CDK4/6-cyclin D-Rb pathway occur frequently in HCC, we tested the efficacy of two CDK4/6 inhibitors, abemaciclib and ribociclib, in combination with lenvatinib, a multi-kinase inhibitor approved as first-line therapy for advanced HCC, in a panel of HCC Rb-expressing cell lines. The simultaneous drug combinations showed a superior anti-proliferative activity as compared with single agents or sequential schedules of treatment, either in short or in long-term experiments. In addition, the simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration. Mechanistically, these growth-inhibitory effects were associated with a stronger down-regulation of c-myc protein expression. Depending on the HCC cell model, reduced activation of MAPK, mTORC1/p70S6K or src/FAK signaling was also observed. Abemaciclib combined with lenvatinib arrested the cells in the G1 cell cycle phase, induced p21 accumulation, and promoted a stronger increase of cellular senescence, associated with elevation of β-galactosidase activity and accumulation of ROS, as compared with single treatments. After drug withdrawal, the capacity of forming colonies was significantly impaired, suggesting that the anti-tumor efficacy of abemaciclib and lenvatinib combination was persistent. Our pre-clinical results demonstrate the effectiveness of the simultaneous combination of CDK4/6 inhibitors with lenvatinib in HCC cell models, suggesting that this combination may be worthy of further investigation as a therapeutic approach for the treatment of advanced HCC.
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Affiliation(s)
| | - Claudia Fumarola
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mara Bonelli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maricla Galetti
- Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL - Italian Workers’ Compensation Authority, Rome, Italy
| | - Rita Terenziani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Kamal Eltayeb
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Francesco Volta
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Silvia Zoppi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Patrizia Bertolini
- Paediatric Hematology Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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13
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Zeng F, Zhou Y, Khowtanapanich T, Saengboonmee C. Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract. In Vivo 2022; 36:1580-1590. [PMID: 35738597 PMCID: PMC9301412 DOI: 10.21873/invivo.12868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/28/2022] [Accepted: 06/02/2022] [Indexed: 11/10/2022]
Abstract
Cancer is the leading cause of death worldwide for which effective treatments remain limited. This article aimed to critically review and discuss the potential of targeting cell cycle machineries as a vital tool for cancer treatment. Cyclin dependent kinase (CDK) 4/6 inhibitors were originally approved by the United State Food and Drug Administration (US FDA) for advanced-stage breast cancer treatment. The nearly double-prolonged survival time in patients who received CDK4/6 inhibitors are superior to the conventional chemotherapy or endocrine therapy alone and, thus, these medications have been designated a breakthrough therapy by the US FDA. The requirement of CDK4/6 in the progression of cancer cells, but probably dispensable in normal cells, makes CDK4/6 a popular target for cancer treatment. The effects of CDK4/6 inhibitors in cancer may also involve the tumor microenvironment in which the therapeutic effects are synergistically pronounced. These emerging roles, hence, prompt investigations regarding their therapeutic potential in other cancers, including gastrointestinal cancer. Many preclinical and clinical studies of CDK4/6 inhibitors in gastrointestinal cancers are underway and, as a result, several new potentials are gradually reported. Contrariwise, the primary effect of this drug group is arresting the cell cycle rather than inducing cell death. The efficacy of using CDK4/6 inhibitors as a single regimen in clinical practice is then limited. In this article, the effects of CDK4/6 inhibitors on the progression of gastrointestinal cancers, at both preclinical and clinical levels are reviewed. The future directions for research and the possibility of CDK4/6 inhibitors being "breakthrough therapy" for gastrointestinal cancers are also discussed.
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Affiliation(s)
- Fuchun Zeng
- Department of Thoracic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, P.R. China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, P.R. China
| | - Yubin Zhou
- Department of Thoracic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, P.R. China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, P.R. China
| | | | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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14
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Wei ZL, Zhou X, Lan CL, Huang HS, Liao XW, Mo ST, Wei YG, Peng T. Clinical implications and molecular mechanisms of Cyclin-dependent kinases 4 for patients with hepatocellular carcinoma. BMC Gastroenterol 2022; 22:77. [PMID: 35193513 PMCID: PMC8864914 DOI: 10.1186/s12876-022-02152-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis. Cyclin-dependent kinases (CDK) 4 was considered to be cell-cycle-related CDK gene. In this study, we explored the clinical significance of CDK4 in HCC patients. Methods Data of HCC patients were obtained from The Cancer Genome Atlas database (TCGA) and the Gene Expression Omnibus (GEO) database. Kaplan–Meier analysis and Cox regression model were performed to calculate median survival time (MST) and the hazard ration (HR), respectively. The joint-effect analysis and prognostic risk score model were constructed to demonstrate significance of prognosis-related genes. The differential expression of prognostic genes was further validated using reverse transcription-quantitative PCR (RT-qPCR) of 58 pairs of HCC samples. Results CDK1 and CDK4 were considered prognostic genes in TCGA and GSE14520 cohort. The result of joint-effect model indicated patients in CDK1 and CDK4 low expression groups had a better prognosis in TCGA (adjusted HR = 0.491; adjusted P = 0.003) and GSE14520 cohort (adjusted HR = 0.431; adjusted P = 0.002). Regarding Kaplan–Meier analysis, high expression of CDK1 and CDK4 was related to poor prognosis in both the TCGA (P < 0.001 and = 0.001 for CDK1 and CDK4, respectively) and the GSE14520 cohort (P = 0.006 and = 0.033 for CDK1 and CDK4, respectively). However, only CDK4 (P = 0.042) was validated in RT-qPCR experiment, while CDK1 (P = 0.075) was not. Conclusion HCC patients with high CDK4 expression have poor prognosis, and CDK4 could be a potential candidate diagnostic biomarker for HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02152-w.
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Affiliation(s)
- Zhong-Liu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chen-Lu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Shu-Tian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yong-Guang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
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15
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Bazzi ZA, Tai IT. CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene. Front Oncol 2021; 11:655479. [PMID: 34277407 PMCID: PMC8278820 DOI: 10.3389/fonc.2021.655479] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/16/2021] [Indexed: 11/13/2022] Open
Abstract
Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.
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Affiliation(s)
- Zainab A Bazzi
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.,Canada's Michael Smith Genome Sciences Centre, British Columbia (BC) Cancer, Vancouver, BC, Canada
| | - Isabella T Tai
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.,Canada's Michael Smith Genome Sciences Centre, British Columbia (BC) Cancer, Vancouver, BC, Canada
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16
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Ho YJ, Chang J, Yeh KT, Gong Z, Lin YM, Lu JW. Prognostic and Clinical Implications of WNK Lysine Deficient Protein Kinase 1 Expression in Patients With Hepatocellular Carcinoma. In Vivo 2021; 34:2631-2640. [PMID: 32871793 DOI: 10.21873/invivo.12081] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM Hepatocellular carcinoma (HCC) is a particularly malignant form of cancer prevalent throughout the world; however, there is a pressing need for HCC biomarkers to facilitate prognosis and risk assessment. PATIENTS AND METHODS This paper reports on the potential prognostic value of WNK lysine deficient protein kinase 1 (WNK1) in cases of HCC. We analyzed the expression of WNK1 at the mRNA level using omics data from the UALCAN database. We then verified our findings through the immunohistochemical (IHC) staining of various human cancer tissue as well as 59 HCC samples paired with corresponding normal tissues. The prognostic value of mRNA or protein expression by WNK1 was evaluated using the Kaplan-Meier method. RESULTS Initial screening results revealed significantly higher WNK1 expression levels in HCC tissue compared to normal tissue. Verification using the paired HCC samples confirmed that the expression of WNK1 was indeed significantly higher in HCC tissue samples than in adjacent normal tissues. High WNK1 expression levels were significantly correlated with clinicopathological variables, including gender and histologic grade. Kaplan-Meier survival analysis revealed that high WNK1 expression levels were associated with poor HCC prognosis. Finally, univariate and multivariate analysis identified WNK1 as a prognostic factor for TNM stage in cases of HCC. CONCLUSION In summary, WNK1 is overexpressed at the mRNA and protein levels, and correlated with poor prognosis. Thus, WNK1 expression could potentially be used as a biomarker in HCC prognosis.
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Affiliation(s)
- Yi-Jung Ho
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, R.O.C.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Jungshan Chang
- Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C
| | - Kun-Tu Yeh
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Yueh-Min Lin
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C. .,School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C.,Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
| | - Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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17
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Yang X, Yang S, Song J, Yang W, Ji Y, Zhang F, Rao J. Dysregulation of miR-23b-5p promotes cell proliferation via targeting FOXM1 in hepatocellular carcinoma. Cell Death Discov 2021; 7:47. [PMID: 33723252 PMCID: PMC7960996 DOI: 10.1038/s41420-021-00440-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/29/2021] [Accepted: 02/13/2021] [Indexed: 12/12/2022] Open
Abstract
Growing evidence demonstrates that MicroRNAs (miRNAs) play an essential role in contributing to tumor development and progression. However, the underlying role and mechanisms of miR-23b-5p in hepatocellular carcinoma (HCC) formation remain unclear. Our study showed that miR-23b-5p was downregulated in the HCC tissues and cell lines, and lower expression of miR-23b-5p was associated with more severe tumor size and poorer survival. Gain- or loss-of-function assays demonstrated that miR-23b-5p induced G0/G1 cell cycle arrest and inhibited cell proliferation both in vitro and in vivo. qRT-PCR, western blot and luciferase assays verified that Mammalian transcription factor Forkhead Box M1 (FOXM1), upregulated in HCC specimens, was negatively correlated with miR-23b-5p expression and acted as a direct downstream target of miR-23b-5p. In addition, miR-23b-5p could regulate cyclin D1 and c-MYC expression by directly targeting FOXM1. Further study revealed that restoration of FOXM1 neutralized the cell cycle arrest and cell proliferation inhibition caused by miR-23b-5p. Taken together, our findings suggest that miR-23b-5p acted as a tumor suppressor role in HCC progression by targeting FOXM1 and may serve as a potential novel biomarker for HCC diagnosis and prognosis.
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Affiliation(s)
- Xinchen Yang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China
| | - Shikun Yang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China
| | - Jinhua Song
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China
| | - Wenjie Yang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China
| | - Yang Ji
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China
| | - Feng Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China.
| | - Jianhua Rao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Nanjing, China.
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Ram AK, Vairappan B, Srinivas BH. Nimbolide inhibits tumor growth by restoring hepatic tight junction protein expression and reduced inflammation in an experimental hepatocarcinogenesis. World J Gastroenterol 2020; 26:7131-7152. [PMID: 33362373 PMCID: PMC7723674 DOI: 10.3748/wjg.v26.i45.7131] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/28/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Altered tight junction (TJ) proteins are correlated with carcinogenesis and tumor development. Nimbolide is a tetranotriterpenoid that has been shown to have antioxidant and anti-proliferative properties; however, its anticancer effects and molecular mechanism in hepatocellular carcinoma (HCC) remains obscure. AIM To investigate the effect of nimbolide on TJ proteins, cell cycle progression, and hepatic inflammation in a mouse model of HCC. METHODS HCC was induced in male Swiss albino mice (CD-1 strain) by a single intraperitoneal injection of 100 mg/kg diethylnitrosamine (DEN) followed by 80 ppm N-nitrosomorpholine (NMOR) in drinking water for 28 wk. After 28 wk, nimbolide (6 mg/kg) was given orally for four consecutive weeks in DEN/NMOR induced HCC mice. At the end of the 32nd week, all the mice were sacrificed and blood and liver samples were collected for various analyses. Macroscopic examinations of hepatic nodules were assessed. Liver histology and HCC tumor markers such as alpha-fetoprotein (AFP) and glypican-3 were measured. Expression of TJ proteins, cell proliferation, and cell cycle markers, inflammatory markers, and oxidative stress markers were analyzed. In silico analysis was performed to confirm the binding and modulatory effect of nimbolide on zonula occludens 1 (ZO-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB), and tumor necrosis factor alpha (TNF-α). RESULTS We found nimbolide treatment at a concentration of 6 mg/kg to HCC mice reduced hepatic tumor size by 52.08% and tumor volume (P < 0.01), and delayed tumor growth in HCC mice with a concomitant reduction in tumor markers such as AFP levels (P < 0.01) and glypican-3 expression (P < 0.05). Furthermore, nimbolide treatment increased tight junction proteins such as ZO-1 and occludin expression (P < 0.05, respectively) and reduced ZO-1 associated nucleic acid binding protein expression (P < 0.001) in HCC mice liver. Nimbolide treatment to HCC mice also inhibited cell proliferation and suppressed cell cycle progression by attenuating proliferating cell nuclear antigen (P < 0.01), cyclin dependent kinase (P < 0.05), and CyclinD1 (P < 0.05) expression. In addition, nimbolide treatment to HCC mice ameliorated hepatic inflammation by reducing NF-κB, interleukin 1 beta and TNF-α expression (P < 0.05, respectively) and abrogated oxidative stress by attenuating 4-hydroxynonenal expression (P < 0.01). Molecular docking studies further confirmed that nimbolide interacts with ZO-1, NF-κB, and TNF-α. CONCLUSION Our current study showed for the first time that nimbolide exhibits anticancer effect by reducing tumor size, tumor burden and by suppressing cell cycle progression in HCC mice. Furthermore, nimbolide treatment to HCC mice ameliorated inflammation and oxidative stress, and improved TJ proteins expression. Consequently, nimbolide could be potentially used as a natural therapeutic agent for HCC treatment, however further human studies are warranted.
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Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab,Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab,Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
| | - BH Srinivas
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
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19
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Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma. Cell Death Dis 2020; 11:823. [PMID: 33009370 PMCID: PMC7532449 DOI: 10.1038/s41419-020-03031-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023]
Abstract
Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.
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20
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Digiacomo G, Fumarola C, La Monica S, Bonelli MA, Cretella D, Alfieri R, Cavazzoni A, Galetti M, Bertolini P, Missale G, Petronini PG. Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines. Front Oncol 2020; 10:563249. [PMID: 33072590 PMCID: PMC7539564 DOI: 10.3389/fonc.2020.563249] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/20/2020] [Indexed: 12/28/2022] Open
Abstract
Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models.
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Affiliation(s)
| | - Claudia Fumarola
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mara A Bonelli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Daniele Cretella
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maricla Galetti
- Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro (INAIL) Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Rome, Italy
| | - Patrizia Bertolini
- Paediatric Hematology Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
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21
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Wang Y, Xie Y, Ma J, Wang Y, Gong R. Development and validation of a prognostic and immunotherapeutically relevant model in hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1177. [PMID: 33241026 PMCID: PMC7576066 DOI: 10.21037/atm-20-6112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Background The tumor immune microenvironment is pivotal in predicting clinical outcomes and therapeutic efficacy in cancer patients. This study aims to develop an immune prediction model (IPM) to effectively predict prognosis and immunotherapeutic response in patients with hepatocellular carcinoma (HCC). Methods An IPM was constructed and validated based on immune-related genes. The influence of IPM on the HCC immune microenvironment, as well as the possible mechanism, was comprehensively analyzed. The value of the model in predicting the response of HCC patients to immunotherapy was also evaluated. Results A novel IPM based on eight genes was developed and validated to predict the prognosis of HCC patients. These genes are matrix metalloproteinase 12 (MMP12), heme oxygenase 1 (HMOX1), C-X-C motif chemokine receptor 6 (CXCR6), hepatoma-derived growth factor (HDGF), placental growth factor (PGF), tyrosine kinase 2 (TYK2), retinoid X receptor beta (RXRB), and cyclin-dependent kinase 4 (CDK4). High-risk patients showed significantly poorer survival than low-risk patients. A nomogram was also established based on the IPM and tumor, node, metastasis (TNM) classification, which showed some net clinical benefit. Gene set enrichment analysis (GSEA) revealed several significantly enriched oncological signatures and immunologic signatures. Furthermore, high-risk patients were characterized by severe clinicopathological characteristics and immune cell infiltration. Finally, we found the that the IPM showed a significant positive correlation with programmed cell death 1 (PDCD1), cluster of differentiation 274 (CD274), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression, suggesting a potentially enhanced effects of immunotherapy antibodies in HCC patients with a high risk score. Conclusions A novel IPM that could predict clinical prognosis and immunotherapeutic response in HCC patients was developed. Our findings not only provide new insights into the identification of HCC patients with poor survival, but also deepen our understanding of the immune microenvironment, as well as the mechanism of immunotherapy, in HCC.
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Affiliation(s)
- Yu Wang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Yanting Xie
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Junyong Ma
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Yizhou Wang
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
| | - Renyan Gong
- Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China
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22
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Xiao H, Wang B, Xiong HX, Guan JF, Wang J, Tan T, Lin K, Zou SB, Hu ZG, Wang K. A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis. J Cell Physiol 2020; 236:2572-2591. [PMID: 32853412 DOI: 10.1002/jcp.30015] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/09/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023]
Abstract
Changes in immune responses to hepatocellular carcinoma (HCC) are closely related to the occurrence, development, and prognosis of this disease. Exploring the role of immune-related genes (IRGs) in HCC would provide insights into the mechanisms regulating this disease. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) provide a platform for such research, owing to a large number of HCC samples available for comprehensive and systematic immunogenomics analyses. We analyzed the IRGs expression profile and clinical information of patients with HCC based on the TCGA and ICGC database. Potential molecular mechanisms and properties of the screened IRGs were analyzed across multiple databases. And we analyzed the correlation between IRGs, single-nucleotide polymorphisms, and copy number variation. A novel prognostic index, based on IRGs, was developed using the LASSO Cox regression algorithm, followed by univariate and multivariate Cox regression analyses to analyze the prognostic index. Information in the ICGC database was used to verify the reliability of the prognostic index. A total of 54 differentially expressed IRGs were found to be significantly associated with HCC prognosis, and there is a significant correlation between their expression level and copy number variation. Functional enrichment analyses indicated that the genes play active roles in tumor and immune-related signaling pathways. In addition, five potential biomarkers namely IRG, MAPK3, HSP90AA1, HSP90AB1, HSPA4, and CDK4, were identified. Finally, a novel prognostic index, based on IRGs (PSMD14, FABP6, ISG20L2, HGF, BIRC5, IL17D, and STC2), was found useful as an independent prognostic factor, not only for prognosis but also to reflect levels of infiltration in a variety of immune cells. Our team conducted a genomics study of IRGs in HCC and screened several clinically significant IRGs, and our model provides an effective approach for stratification and characterization of patients using IRG-based immunolabeling tools to monitor the prognosis of HCC.
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Affiliation(s)
- Han Xiao
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Ben Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Hai-Xia Xiong
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Jia-Fu Guan
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Jian Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Tao Tan
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Kang Lin
- Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Gastrointestinal Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shu-Bing Zou
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Zhi-Gang Hu
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Kai Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
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23
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Wang S, Zhou D, Xu Z, Song J, Qian X, Lv X, Luan J. Anti-tumor Drug Targets Analysis: Current Insight and Future Prospect. Curr Drug Targets 2020; 20:1180-1202. [PMID: 30947670 DOI: 10.2174/1389450120666190402145325] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 12/13/2022]
Abstract
The incidence and mortality of malignant tumors are on the rise, which has become the second leading cause of death in the world. At present, anti-tumor drugs are one of the most common methods for treating cancer. In recent years, with the in-depth study of tumor biology and related disciplines, it has been gradually discovered that the essence of cell carcinogenesis is the infinite proliferation of cells caused by the disorder of cell signal transduction pathways, followed by a major shift in the concept of anti-tumor drugs research and development. The focus of research and development is shifting from traditional cytotoxic drugs to a new generation of anti-tumor drugs targeted at abnormal signaling system targets in tumor cells. In this review, we summarize the targets of anti-tumor drugs and analyse the molecular mechanisms of their effects, which lay a foundation for subsequent treatment, research and development.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Dexi Zhou
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Zhenyu Xu
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jing Song
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Xueyi Qian
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
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24
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Cervello M, Emma MR, Augello G, Cusimano A, Giannitrapani L, Soresi M, Akula SM, Abrams SL, Steelman LS, Gulino A, Belmonte B, Montalto G, McCubrey JA. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020; 12:3053-3094. [PMID: 32018226 PMCID: PMC7041742 DOI: 10.18632/aging.102777] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/12/2020] [Indexed: 04/12/2023]
Abstract
Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.
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Affiliation(s)
- Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Maria R. Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Lydia Giannitrapani
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maurizio Soresi
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Shaw M. Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Stephen L. Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S. Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Alessandro Gulino
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Beatrice Belmonte
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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25
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Moradi Binabaj M, Bahrami A, Khazaei M, Ryzhikov M, Ferns GA, Avan A, Mahdi Hassanian S. The prognostic value of cyclin D1 expression in the survival of cancer patients: A meta-analysis. Gene 2019; 728:144283. [PMID: 31838249 DOI: 10.1016/j.gene.2019.144283] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/30/2019] [Accepted: 12/05/2019] [Indexed: 01/21/2023]
Abstract
BACKGROUND The relationship between the expression of cyclin D1 and cancer prognosis and outcomes in different malignancies has not been fully elucidated. AIMS In the presented meta-analysis, we assessed the association between the expression level of cyclin D1 with overall survival (OS) in several cancers. METHODS Eligible studies were identified using PubMed, EMBase, Scopus, Web of Sciences and Cochrane Library databases. For the prognostic meta-analysis, study-specific hazard ratios (HRs) of tissue cyclin D1 for survival were obtained. Finally we pooled data derived from one hundred and eight studies comprising 19,224 patients with 10 different cancer types. RESULTS In the pooled analysis, high expression of cyclin D1 was significantly related to a poor OS with a pooled HR of 1.11 (95% CI: 1.02-1.20, P = 0.015; random-effects). Sub-group analysis revealed that high expression of cyclin D1 was related to worse OS of head and neck cancers (HR = 2.08, 95% CI: 1.75-2.47; P < 0.001), but not in breast (HR = 1.033, 95% CI: 0.873-1.223, P = 0.702), gastrointestinal (HR = 1.025, 95% CI:0.824-1.275; P = 0.825), bladder (HR = 0.937, CI: 0.844-1.041; P = 0.225) and in lung cancer patients (HR = 1.092, CI: 0.819-1.455; P = 0.549). CONCLUSION Further large, prospective, and well-designed trials are warranted to elucidate the precise clinical importance of cyclin D1 overexpression in the prognosis of cancer patients receiving different treatment regimens.
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Affiliation(s)
- Maryam Moradi Binabaj
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, USA
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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26
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Shen S, Dean DC, Yu Z, Duan Z. Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway. Hepatol Res 2019; 49:1097-1108. [PMID: 31009153 DOI: 10.1111/hepr.13353] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 02/23/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022]
Abstract
Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two-thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin-dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin-dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK-targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.
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Affiliation(s)
- Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
| | - Dylan C Dean
- Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
| | - Zujiang Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenfeng Duan
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
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27
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Predictors of ribociclib-mediated antitumour effects in native and sorafenib-resistant human hepatocellular carcinoma cells. Cell Oncol (Dordr) 2019; 42:705-715. [PMID: 31250364 DOI: 10.1007/s13402-019-00458-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The cyclin-dependent kinases (CDKs) CDK4 and CDK6 are important regulators of the cell cycle and represent promising targets in cancer treatment. We aimed to investigate the relevance of CDK4/6 in the development of hepatocellular carcinoma (HCC) and the potential of ribociclib, a novel orally available CDK4/6 inhibitor, as a treatment for HCC. METHODS The effect of ribociclib was assessed in native and sorafenib-resistant HCC cell lines using viability assays, colony formation assays and FACS-based analyses. The expression of potential biomarkers of ribociclib response was assessed in cell lines and primary human hepatocytes using Western blotting. In addition, the prognostic relevance of the cyclin D-CDK4/6-retinoblastoma protein (Rb) pathway was assessed by analysing mRNA expression data from The Cancer Genome Atlas (TCGA). RESULTS We found that ribociclib downregulated Rb and caused a profound loss of cell viability by inducing G1 cell cycle arrest in HCC cell lines exhibiting Rb-high/p16-low protein expression profiles, but not in Rb-low/p16-high cells, regardless their sensitivity to sorafenib. siRNA-based Rb silencing decreased cell proliferation, but did not diminish the sensitivity of HCC cells to ribociclib. Furthermore, we found that ribociclib synergized with sorafenib to cause cell death. mRNA analysis of primary human HCC specimens showed that CDK4 expression was correlated with patient survival and that the expression of Rb and the p16-encoding CDKN2A gene were inversely correlated. CONCLUSIONS From our data we conclude that impairment of the cyclin D-CDK4/6-Rb pathway is a frequent feature of HCC and that it is associated with a unfavourable prognosis. We also found that ribociclib exhibits a preferential antineoplastic activity in Rb-high HCC cells. Our results warrant further investigation of Rb and p16 expression as markers of HCC sensitivity to ribociclib.
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Noorwali A, Faidah M, Ahmed N, Bima A. Tracking iron oxide labelled mesenchymal stem cells(MSCs) using magnetic resonance imaging (MRI) in a rat model of hepatic cirrhosis. Bioinformation 2019; 15:1-10. [PMID: 31359992 PMCID: PMC6651036 DOI: 10.6026/97320630015001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 12/24/2018] [Indexed: 01/07/2023] Open
Abstract
Homing and tumor attenuation potential of BM-MSCs labelled with superparamagnetic iron-oxide nanoparticles (SPIONs) in a rat model of hepatic cirrhosis was evaluated. Rat BM-MSCs were derived, characterized and labelled with SPIONs (200 nm; 25 mg Fe/ml). Hepatic cirrhosis was induced in Wistar rats (n=30; 10/group) with carbon tetrachloride (CCl4; 0.3 mL/kg body weight) injected twice a week for 12 weeks. Group-I was administered vehicle (castor-oil) alone; Group-II received two doses of unlabelled BM-MSCs (3x106 cells) and Group-III received two doses of SPIONs labelled BM-MSCs (3x106 cells) via tail vein injection (0.5 ml) at weekly intervals. All animals were sacrificed after two weeks for histological, radiological and biochemical analysis. Derived BM-MSCs demonstrated MSCs related CD markers. Histology confirmed induction of hepatic cirrhosis with CCL4. Levels of alanine-aminotransferase, aspartate-aminotransferase,alkaline-phosphatase and gamma glutamyl-transferase returned to normal levels following treatment with BM-MSCs. Uptake and homing of SPIONs labelled BM-MSCs, and reduction in the size of cirrhotic nodules were confirmed using transmission electron microscopy and magnetic resonance imaging respectively. BM-MSCs reduced the pathological effects of CCL4 induced hepatic cirrhosis and labelling BMMSCs with SPIONs were non-toxic and enabled efficient tracking using non-invasive methods.
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Affiliation(s)
- Abdulwahab Noorwali
- Stem Cell Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mamdooh Faidah
- Department of Medical Laboratory,College of Health Sciences,King Abdulaziz University,Jeddah 21589 Saudi Arabia
| | - Naushad Ahmed
- Department of Radiology,King Abdulaziz University Hospital,King Abdulaziz University,Jeddah 21589, Saudi Arabia
| | - Abdulhadi Bima
- Department of Clinical Biochemistry,King Abdulaziz University Hospital,King Abdulaziz University,Jeddah 21 89,Saudi Arabia
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29
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Menyhárt O, Nagy Á, Győrffy B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. ROYAL SOCIETY OPEN SCIENCE 2018; 5:181006. [PMID: 30662724 PMCID: PMC6304123 DOI: 10.1098/rsos.181006] [Citation(s) in RCA: 334] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/08/2018] [Indexed: 05/03/2023]
Abstract
Background: Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. Methods: The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, n = 371; Affymetrix arrays, n = 91; Illumina gene chips, n = 135) by uni- and multivariate Cox regression and Mann-Whitney U-test, separately for Asian and Caucasian patients. Results: One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at p < 0.05. After multiple testing correction BIRC5 (p = 1.9 × 10-10), CDC20 (p = 2.5 × 10-9) and PLK1 (p = 3 × 10-9) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage (p = 0.0018) and expression of CENPH (p = 0.0038) and CDK4 (p = 0.038). KIF18A was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts (p = 0.003 and p = 0.025, respectively). Conclusion: Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.
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Affiliation(s)
- Otília Menyhárt
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Ádám Nagy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Balázs Győrffy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
- Author for correspondence: Balázs Győrffy e-mail:
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Chen G, Hu M, Qu X, Wang K, Qu Y. MicroRNA‑584 directly targets CCND1 and inhibits cell proliferation and invasion in pancreatic cancer. Mol Med Rep 2018; 19:719-726. [PMID: 30431107 DOI: 10.3892/mmr.2018.9651] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 10/16/2018] [Indexed: 11/06/2022] Open
Abstract
Multiple previous studies have demonstrated that the dysregulation of microRNAs (miRNAs) is implicated in the occurrence and development of pancreatic cancer. Therefore, a further characterisation of deregulated miRNAs in pancreatic cancer may provide novel insight into the oncogenesis and progression of pancreatic cancer, which may facilitate the identification of effective therapeutic targets for treating patients with this disease. In the present study, reverse transcription‑quantitative polymerase chain reaction analysis demonstrated that the expression level of miRNA‑584‑5p (miR‑584) was significantly decreased in pancreatic cancer tissues and cell lines. It was demonstrated that restoration of miR‑584 expression significantly suppressed the proliferative and invasive ability of pancreatic cancer cells. Bioinformatics analysis predicted that cyclin D1 (CCND1) was a putative target of miR‑584. Subsequent experiments demonstrated that CCND1 was a direct target gene of miR‑584 in pancreatic cancer cells. Furthermore, the inhibition of CCND1 mimicked the suppressive effect of miR‑584 overexpression in pancreatic cancer cells. The restoration of CCND1 expression significantly abolished the inhibitory effects of miR‑584 overexpression on pancreatic cancer cells. Collectively, the present results demonstrated that miR‑584 inhibited the development of pancreatic cancer by directly targeting CCND1, suggesting that this miRNA may represent a potential therapeutic target for this fatal disease.
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Affiliation(s)
- Gang Chen
- Department of Gastroenterology, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Ming Hu
- Department of General Surgery, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Xiusheng Qu
- Department of Radiochemotherapy, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Kaifeng Wang
- Department of Vascular Surgery, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
| | - Yikun Qu
- Department of General Surgery, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154003, P.R. China
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Yang H, Zhao X, Zhao L, Liu L, Li J, Jia W, Liu J, Huang G. PRMT5 competitively binds to CDK4 to promote G1-S transition upon glucose induction in hepatocellular carcinoma. Oncotarget 2018; 7:72131-72147. [PMID: 27708221 PMCID: PMC5342150 DOI: 10.18632/oncotarget.12351] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 09/20/2016] [Indexed: 01/07/2023] Open
Abstract
Although cancer cells are known to be "addicted" to glucose, the effect of glucose in proliferation of these cells remains elusive. Here, we report that upon glucose induction, protein arginine methyltransferase 5 (PRMT5) exerts a profound effect on the G1-S cell cycle progression via directly interacting with cyclin dependent kinase 4 (CDK4) in hepatocellular carcinoma (HCC). Upregulation of both PRMT5 and CDK4 predicts more malignant characteristics in human HCC tissues. Mechanistically, glucose promotes the interaction between PRMT5 and CDK4, which leads to activation of CDK4-RB-E2F-mediated transcription via releasing CDKN2A from CDK4. Moreover, the PRMT5 competitive inhibition of the interaction between CDK4 and CDKN2A is important for glucose-induced growth of HCC cells. Furthermore, the CDK4 mutant R24A weakly binds to PRMT5, inhibiting HCC cell cycle progression and tumor growth. Thus, our findings uncover a critical function for PRMT5 and CDK4 and provide an improved therapeutic strategy against HCC.
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Affiliation(s)
- Hao Yang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China
| | - Xiaoping Zhao
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Li Zhao
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Liu Liu
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jiajin Li
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Wenzhi Jia
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Gang Huang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China.,Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.,Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
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Zhang Y, Jiang F, He H, Ye J, Mao X, Guo Q, Wu SL, Zhong W, Wu CL, Lin N. Identification of a novel microRNA-mRNA regulatory biomodule in human prostate cancer. Cell Death Dis 2018; 9:301. [PMID: 29467540 PMCID: PMC5833360 DOI: 10.1038/s41419-018-0293-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 12/06/2017] [Accepted: 01/04/2018] [Indexed: 12/29/2022]
Abstract
Our recent study identified a list of differentially expressed microRNAs (miRNAs) in human prostate cancer (PCa) tissues compared to adjacent benign prostate tissues. In the current study, to identify the crucial miRNA-mRNA regulatory biomodule involved into prostate carcinogenesis based on the previous miRNA expression profile in PCa, we proposed an integrated systematic approach which combined miRNA-mediated gene expression regulatory network analysis, experimental validations in vitro and in vivo, as well as clinical significance evaluation. As a result, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis was identified as a bottleneck in the miRNA-mediated gene expression regulatory network of PCa according to network topological analysis. The direct binding relationship between TP73 and PCa downregulated miR-193a-5p, and the direct binding relationship between UBE2I and PCa upregulated miR-188-5p were both experimentally validated. In addition, miR-193a-5p had a more significant regulatory effect on the tumor promoter isoform of TP73-deltaNp73 than on the tumor suppressive isoform of TP73-TAp73. Importantly, the deregulation of either the miR-193a-5p-TP73 or miR-188-5p-UBE2I axes was significantly associated with aggressive progression and poor prognosis in PCa patients. Gain- and loss-of-function experiments showed that miR-193a-5p efficiently inhibited in vitro PCa cell proliferation, migration, and invasion, and in vivo tumor growth, and markedly induced PCa cell apoptosis via regulating TP73 with a corresponding suppression of the CCND1-RNASEL-CDKN1A-MDM2 axis. In contrast, miR-188-5p exerted its tumor promoter roles through targeting UBE2I with a subsequent activation of the CCND1-RNASEL-CDKN1A-MDM2 axis. Taken together, this integrated analysis revealed the potential roles of the miR-193a-5p/TP73 and miR-188-5p/UBE2i negative regulation pairs in PCa. In addition to the significant clinical relevance, miR-193a-5p- and miR-188-5p-regulated CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I signaling may be a novel regulatory biomodule in prostate carcinogenesis.
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Affiliation(s)
- Yanqiong Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.,Department of Urology & Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Funeng Jiang
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Huichan He
- Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, China
| | - Jianheng Ye
- Department of Urology & Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.,Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Xia Mao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Qiuyan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Shu-Lin Wu
- Department of Urology & Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Weide Zhong
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China. .,Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, China.
| | - Chin-Lee Wu
- Department of Urology & Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
| | - Na Lin
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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Ho YJ, Lin YM, Huang YC, Chang J, Yeh KT, Lin LI, Gong Z, Tzeng TY, Lu JW. Significance of histone methyltransferase SETDB1 expression in colon adenocarcinoma. APMIS 2017; 125:985-995. [PMID: 28913972 DOI: 10.1111/apm.12745] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022]
Abstract
This study investigated the clinical implications of SETDB1 (also known as KMT1E) in human colon adenocarcinoma. Expression levels of SETDB1 proteins were analyzed by immunohistochemistry staining, and tissue microarrays were used to examine expression profiles in human patients. Our results revealed that SETDB1 protein expression was significantly higher in tumor tissue than in normal tissue for the breast, colon, liver, and lung (p < 0.05). Moreover, an analysis with SurvExpress software suggested that elevated expression of SETDB1 mRNA was significantly associated with the overall survival of colon adenocarcinoma patients (p < 0.05); and additional analysis involving 90 paired samples of colon adenocarcinoma tissue and normal tissue revealed that SETDB1 protein expression was 82% higher in cancerous cells (p < 0.001). High SETDB1 expression was also found to be significantly correlated with histological grade (p = 0.005), TNM stage (p = 0.003), T-class/primary tumor (p = 0.001), and N-class/regional lymph nodes (p = 0.017); and Kaplan-Meier survival curves indicated that SETDB1 protein expression was significantly associated with poor survival. Finally, univariate analysis demonstrated that SETDB1 protein expression was related to TNM stage (p = 0.004) and SETDB1 score (p = 0.001), whereas multivariate analysis showed that the influence of SETDB1 on overall colon adenocarcinoma survival was independent from other risk factors. Taken together, our results suggest that the SETDB1 protein could serve as a clinical prognostic indicator for colon adenocarcinoma.
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Affiliation(s)
- Yi-Jung Ho
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.,Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Yen-Chi Huang
- Department of Styling & Cosmetology, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan
| | - Jungshan Chang
- Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Liang-In Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
| | - Tsai-Yu Tzeng
- VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Jeng-Wei Lu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.,Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
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Miao Z, Wu L, Lu M, Meng X, Gao B, Qiao X, Zhang W, Xue D. Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget 2016; 6:21493-506. [PMID: 26046465 PMCID: PMC4673281 DOI: 10.18632/oncotarget.4085] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Accepted: 05/11/2015] [Indexed: 12/12/2022] Open
Abstract
Liver is the major organ for arsenic methylation metabolism and may be the potential target of arsenic-induced cancer. In this study, normal human liver cell was treated with arsenic trioxide, and detected using DNA methylation microarray. Some oncogenes, tumor suppressor genes, transcription factors (TF), and tumor-associated genes (TAG) that have aberrant DNA methylation have been identified. However, simple functional studies of genes adjacent to aberrant methylation sites cannot well reflect the regulatory relationship between DNA methylation and gene transcription during the pathogenesis of arsenic-induced liver cancer, whereas a further analysis of the cis-regulatory elements and their trans-acting factors adjacent to DNA methylation can more precisely reflect the relationship between them. MYC and MAX (MYC associated factor X) were found to participating cell cycle through a bioinformatics analysis. Additionally, it was found that the hypomethylation of cis-regulatory sites in the MYC promoter region and the hypermethylation of cis-regulatory sites in the MAX promoter region result in the up-regulation of MYC mRNA expression and the down-regulation of MAX mRNA, which increased the hepatocyte carcinogenesis tendency.
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Affiliation(s)
- Zhuang Miao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Lin Wu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Ming Lu
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Xianzhi Meng
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Bo Gao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Xin Qiao
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China
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Ho YJ, Lin YM, Huang YC, Yeh KT, Lin LI, Lu JW. Tissue microarray-based study of hepatocellular carcinoma validating SPIB as potential clinical prognostic marker. Acta Histochem 2016; 118:38-45. [PMID: 26610895 DOI: 10.1016/j.acthis.2015.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/07/2015] [Accepted: 11/09/2015] [Indexed: 01/11/2023]
Abstract
Currently, the prognostic significance of SPIB protein overexpression in human hepatocellular carcinoma (HCC) is unclear. The aim of the present study was to investigate the level of SPIB expression in human HCC in order to determine possible correlations between SPIB expression and clinicopathological findings. The expression of SPIB proteins was detected using immunohistochemical staining in commercial multiple-tissue microarrays as a means of examining expression profiles in patients. Using online biomarker validation tool SurvExpress, we focused on the correlation between SPIB overexpression and survival as well as relapse-free survival (RFS). Results show that SPIB protein expression levels were significantly higher in colon, liver, and stomach tumors than in non-tumor tissues (p<0.05). SPIB overexpression in patients with HCC was also significantly higher than that of the normal samples (p<0.001). Among patients with liver disease, SPIB protein expression levels differ significantly according to the stage of liver disease, specifically between stages I, II, and III of HCC (p<0.05). SPIB expression was also shown to be significantly correlated with age (p=0.046) and histological grade (p=0.027). Furthermore, the SurvExpress analysis suggested that high SPIB and KI-67 mRNA expression were significantly associated with the poor survival of patients with HCC (p<0.05). Our results indicate that cross-talk in the expression of SPIB and KI-67 may be associated with poor prognosis and may potentially serve as a clinical prognostic indicator of HCC. This is the first time that such an association has been reported.
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Affiliation(s)
- Yi-Jung Ho
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
| | - Yen-Chi Huang
- Department of Styling & Cosmetology, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
| | - Liang-In Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
| | - Jeng-Wei Lu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
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Maynard JP, Lee JS, Sohn BH, Yu X, Lopez-Terrada D, Finegold MJ, Goss JA, Thevananther S. P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients. Oncotarget 2015; 6:41162-79. [PMID: 26517690 PMCID: PMC4747397 DOI: 10.18632/oncotarget.6240] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 09/17/2015] [Indexed: 01/01/2023] Open
Abstract
UNLABELLED P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATP-mediated activation of P2X3 receptors promotes proliferation in HCC cells. CONCLUSION Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.
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MESH Headings
- Adenosine Triphosphate/pharmacology
- Adolescent
- Adult
- Aged
- Blotting, Western
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Cycle/drug effects
- Cell Cycle/genetics
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Cells, Cultured
- Cohort Studies
- Disease-Free Survival
- Female
- Gene Expression Regulation, Neoplastic
- Hepatitis C/complications
- Hepatitis C/genetics
- Hepatitis C/metabolism
- Humans
- Immunohistochemistry
- Liver Neoplasms/complications
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Male
- Middle Aged
- Neoplasm Recurrence, Local
- Receptors, Purinergic P2X3/genetics
- Receptors, Purinergic P2X3/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Young Adult
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Affiliation(s)
- Janielle P. Maynard
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, TX, USA
- Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ju-Seog Lee
- Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Bo Hwa Sohn
- Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoying Yu
- Department of Medicine, Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - Dolores Lopez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Milton J. Finegold
- Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - John A. Goss
- Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Sundararajah Thevananther
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, TX, USA
- Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
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Zhang Y, Guo X, Li Z, Li B, Li Z, Li R, Guo Q, Xiong L, Yu L, Zhao J, Lin N. A systematic investigation based on microRNA-mediated gene regulatory network reveals that dysregulation of microRNA-19a/Cyclin D1 axis confers an oncogenic potential and a worse prognosis in human hepatocellular carcinoma. RNA Biol 2015; 12:643-57. [PMID: 25985117 DOI: 10.1080/15476286.2015.1022702] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) contribute to a wide variety of human diseases by regulating gene expression, leading to imbalances in gene regulatory networks. To discover novel hepatocellular carcinoma (HCC)-related miRNA-target axes and to elucidate their functions, we here performed a systematic investigation combining biological data acquisition and integration, miRNA-target prediction, network construction, functional assay and clinical validation. As a result, a total of 117 HCC differentially expressed miRNAs were identified, and 728 high confident target genes of these miRNAs were collected. Then, the interaction network of target genes was constructed and 221 key nodes with topological importance in the network were identified according to their topological features including degree, node-betweenness, closeness and K-coreness. Among these key nodes, Cyclin D1 had the highest node-betweenness, implying its bottleneck role in the network. Luciferase reporter assay confirmed that miRNA-19a, which was one of HCC downregulated miRNAs, directly targeted Cyclin D1 in HCC cells. Moreover, miR-19a might play inhibitory roles in HCC malignancy via regulating Cyclin D1 expression. Further clinical evidence also highlighted the prognostic potential of miR-19a/Cyclin D1 axis in HCC. In conclusion, this systematic investigation provides a framework to identify featured miRNAs and their target genes which are potent effectors in the occurrence and development of HCC. More importantly, miR-19a/Cyclin D1 axis might have promising applications as a therapeutic target and a prognostic marker for patients with HCC.
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Affiliation(s)
- Yanqiong Zhang
- a Institute of Chinese Materia Medica; China Academy of Chinese Medical Sciences ; Beijing , China
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Zhang S, Shi W, Chen Y, Xu Z, Zhu J, Zhang T, Huang W, Ni R, Lu C, Zhang X. Overexpression of SYF2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma. Mol Cell Biochem 2015; 410:1-9. [PMID: 26260052 DOI: 10.1007/s11010-015-2533-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 08/06/2015] [Indexed: 01/17/2023]
Abstract
SYF2, also known as p29/NTC31/CBPIN, encodes a nuclear protein that interacts with Cyclin D-type binding-protein 1. SYF2 has been reported to be involved in pre-mRNA splicing and cell cycle regulation. In the present study, we observed that SYF2 was obviously upregulated in HCC tumor tissues and cell lines, and its level was positively correlated with the tumor grade and Ki-67 expression, as well as poor prognosis of HCC. In vitro, using serum starvation-refeeding experiment, our results suggested that SYF2 was upregulated in proliferating HCC cells, and was positive correlated with the expression of PCNA and Cyclin D1. In addition, depletion of SYF2 decreased PCNA and Cyclin D1 levels. Accordingly, interference of SYF2 resulted in cells cycle arrest at G1/S phase in Huh7 HCC cells. Furthermore, we found that SYF2 might interact with Cyclin D1 and could confer doxorubicin resistance in HCC cells. These findings revealed that SYF2 might play a regulatory role in the proliferation of HCC cells. In summary, SYF2 may be a novel prognostic marker and serve as a potential therapeutic target in HCC.
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Affiliation(s)
- Shusen Zhang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Weidong Shi
- Department of Oncology, The Second People's Hospital of Nantong, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuyan Chen
- Class 5 Grade 13, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Zhiwei Xu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Jia Zhu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Tingting Zhang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Wei Huang
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Runzhou Ni
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Cuihua Lu
- Department of Digestion, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Xiubing Zhang
- Department of Oncology, The Second People's Hospital of Nantong, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
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Zeng Z, Tu J, Cheng J, Yao M, Wu Y, Huang X, Xie X, Zhang X, Lu F, Chen X. Influence of CCND1 G870A polymorphism on the risk of HBV-related HCC and cyclin D1 splicing variant expression in Chinese population. Tumour Biol 2015; 36:6891-900. [PMID: 25851350 PMCID: PMC4644212 DOI: 10.1007/s13277-015-3401-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/26/2015] [Indexed: 01/15/2023] Open
Abstract
The G870A polymorphism in the exon 4/intron 4 boundary of CCND1 gene is thought to influence the generation of two mRNAs (cyclin D1a and cyclin D1b). The "A" allele codes for a truncated variant, cyclin D1b, which may have higher transforming activity. Herein, the tumor relevance of G870A polymorphism, the association between cyclin D1 variant expression and G870A genotype, and the oncogenic potential of cyclin D1 variants in HBV-related hepatocellular carcinoma (HCC) were examined. We found that there is no significant difference of G870A distribution among the HCC, chronic HBV (CHB) infection, cirrhotic CHB, and healthy control groups. Stratification analysis revealed that in younger patients (ages ≤ 50), cirrhotic CHB patients with AA genotype had an increased risk of developing HCC with odds ratio of 1.943 (95 % CI 1.022-3.694, p = 0.0411) as compared with AG/GG genotypes. The two variants were both transcripted from "A" and "G" alleles, and neither cyclin D1a nor D1b production was influenced by G870A genotype in HCC. The expression of both cyclins D1a and D1b decreased in HCC tissues (p = 0.003, p = 0.005), while increased in adjacent nontumor tissues as compared with normal liver tissues (p = 0.045, p = 0.034). Overexpression of cyclin D1a or D1b could promote the cell proliferation and cell-cycle progression in Huh-7 and LO2 cell lines. Collectively, our data suggest that G870A polymorphism has only very limited predictive value for HBV-related HCC. Both cyclins D1a and D1b could promote cell proliferation, which might contribute to the potential oncogenic role of cyclin D1 variants during the precancerous cirrhotic stage of hepatocarcinogenesis.
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Affiliation(s)
- Zhenzhen Zeng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Jing Tu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Jin Cheng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Mingjie Yao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Yali Wu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Xiangbo Huang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Xiaomeng Xie
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xiaolei Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
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Mikhail S, Albanese C, Pishvaian MJ. Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1185-97. [PMID: 25747534 DOI: 10.1016/j.ajpath.2015.01.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 12/23/2014] [Accepted: 01/13/2015] [Indexed: 01/14/2023]
Abstract
The cell cycle is a highly conserved and tightly regulated biological system that controls cellular proliferation and differentiation. The cell cycle regulatory proteins, which include the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors, are critical for the proper temporal and spatial regulation of cellular proliferation. Conversely, alterations in cell cycle regulatory proteins, leading to the loss of normal cell-cycle control, are a hallmark of many cancers, including gastrointestinal cancers. Accordingly, overexpression of CDKs and cyclins and by contrast loss of CDK inhibitors, are all linked to gastrointestinal cancers and are often associated with less favorable prognoses and outcomes. Because of the importance that the cell cycle regulatory proteins play in tumorigenesis, currently there is a broad spectrum of cell-cycle inhibitors under development that, as a group, hold promise as effective cancer treatments. In support of this approach to cancer treatment, the growing availability of molecular diagnostics techniques may help in identifying patients who have driving abnormalities in the cell-cycle machinery and are thus more likely to respond to cell-cycle inhibitors. In this review, we discuss the prevalence of cell-cycle abnormalities in patients with gastrointestinal cancers and provide a preclinical and clinical overview of new agents that target cell-cycle abnormalities with a special emphasis on gastrointestinal cancers.
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Affiliation(s)
- Sameh Mikhail
- James Cancer Hospital and Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Christopher Albanese
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia.
| | - Michael J Pishvaian
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
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Scaggiante B, Kazemi M, Pozzato G, Dapas B, Farra R, Grassi M, Zanconati F, Grassi G. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol 2014; 20:1268-1288. [PMID: 24574801 PMCID: PMC3921509 DOI: 10.3748/wjg.v20.i5.1268] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 11/10/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of (1) molecular and biochemical cellular markers; (2) micro-interfering RNAs; (3) epigenetic variations; and (4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets.
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Lu JW, Liao CY, Yang WY, Lin YM, Jin SLC, Wang HD, Yuh CH. Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway. PLoS One 2014; 9:e85318. [PMID: 24416389 PMCID: PMC3885696 DOI: 10.1371/journal.pone.0085318] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 12/04/2013] [Indexed: 12/11/2022] Open
Abstract
Hepatocarcinogenesis commonly involves the gradual progression from hepatitis to fibrosis and cirrhosis, and ultimately to hepatocellular carcinoma (HCC). Endothelin 1 (Edn1) has been identified as a gene that is significantly up-regulated in HBx-induced HCC in mice. In this study, we further investigated the role of edn1 in hepatocarcinogenesis using a transgenic zebrafish model and a cell culture system. Liver-specific edn1 expression caused steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC in zebrafish. Overexpression of EDN1 in 293T cells enhanced cell proliferation and cell migration in in vitro and xenotransplantation assays and was accompanied with up-regulation of several cell cycle/proliferation- and migration-specific genes. Furthermore, expression of the unfolded protein response (UPR) pathway-related mediators, such as spliced XBP1, ATF6, IRE1, and PERK, was also up-regulated at both the RNA and protein levels. In the presence of an EDN1 inhibitor or an AKT inhibitor, these increases were diminished and the EDN1-induced migration ability also was disappeared, suggesting that the EDN1 effects act through activation of the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes. Additionally, p-AKT is enhanced in the edn1 transgenic fish compared to the GFP-mCherry control. The micro RNA miR-1 was found to inhibit the expression of EDN1. We also observed an inverse correlation between EDN1 and miR-1 expression in HCC patients. In conclusion, our data suggest that EDN1 plays an important role in HCC progression by activating the PI3K/AKT pathway and is regulated by miR-1.
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Affiliation(s)
- Jeng-Wei Lu
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
- Department of Life Sciences, National Central University, Jhongli City, Taoyuan, Taiwan
| | - Chung-Yi Liao
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Wan-Yu Yang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua City, Changhua County, Taiwan
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | | | - Horng-Dar Wang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Chiou-Hwa Yuh
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
- * E-mail:
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New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int J Hepatol 2014; 2014:513787. [PMID: 24868470 PMCID: PMC4020372 DOI: 10.1155/2014/513787] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 04/07/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also in vivo in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.
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Jiang Q, Mai C, Yang H, Wu Q, Hua S, Yan C, Long Y, Zhang Y, Long X, Fang W, Liu Z. Nuclear expression of CDK4 correlates with disease progression and poor prognosis in human nasopharyngeal carcinoma. Histopathology 2013; 64:722-30. [PMID: 24168228 DOI: 10.1111/his.12319] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 10/26/2013] [Indexed: 01/16/2023]
Abstract
AIMS The purpose of this study was to examine the correlation between nuclear expression of cyclin-dependent kinase 4 (CDK4) and clinicopathological data in nasopharyngeal carcinoma (NPC), including patient survival. METHODS AND RESULTS Using real-time PCR and immunohistochemistry, the expression of CDK4 was examined in NPC and nasopharyngeal (NP) tissues. We observed that mRNA expression of CDK4 was elevated significantly in NPC tissues compared to NP tissues. Further, we found that CDK4 protein was expressed in both the nucleus and cytoplasm. Nuclear expression of CDK4 was correlated positively with clinical stage (P = 0.048), but not associated with other clinical features. Patients with tumours showing nuclear expression of CDK4 had poorer overall survival rates than those without nuclear tumour expression of CDK4. Nuclear expression of CDK4 was associated inversely with survival time for NPC patients in stages T1-2, stages N2-3 and clinical stages III-IV, and after treatment with radiotherapy or chemotherapy. Nuclear expression of CDK4 was an independent and unfavourable prognostic factor for patients with NPC. CONCLUSIONS Our findings suggest that nuclear expression of CDK4 is a potential marker for the progression and poor prognosis of NPC.
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Affiliation(s)
- Qingping Jiang
- Department of Pathology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Department of Pathology, Guangzhou Medical University, Guangzhou, China; Cancer Research Institute, Southern Medical University, Guangzhou, China
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Lian M, Fang J, Han D, Ma H, Feng L, Wang R, Yang F. Microarray gene expression analysis of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. PLoS One 2013; 8:e84854. [PMID: 24386425 PMCID: PMC3873425 DOI: 10.1371/journal.pone.0084854] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 11/19/2013] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Laryngeal squamous cell carcinoma (LSCC) is the most common type in head and neck squamous cell carcinoma (HNSCC), and the development and progression of LSCC are multistep processes accompanied by changes of molecular biology. OBJECTIVE The purpose of this study was to investigate the molecular basis of tumorigenesis and regional lymph node metastasis in LSCC, and provide a set of genes that may be useful for the development of novel diagnostic markers and/or more effective therapeutic strategies. METHODS A total number of 10 patients who underwent surgery for primary laryngeal squamous cell carcinoma were recruited for microarray analysis. LSCC tissues compared with corresponding adjacent non-neoplastic tissues were analysed by Illumina mRNA microarrays, and LSCC tissues with regional lymph node metastasis and LSCC tissues without regional lymph node metastasis were analyzed in the same manner. The most frequently differently expressed genes screened by microarrays were also validated by qRT-PCR in another 42 patients diagnosed for LSCC. RESULTS Analysed by Illumina mRNA microarrays, there were 361 genes significantly related to tumorigenesis while 246 genes significantly related to regional lymph node metastasis in LSCC. We found that the six genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4) were most frequently differently expressed functional genes related to tumorigenesis while eIF3a and RPN2 were most frequently differently expressed functional genes related to regional lymph node metastasis in LSCC. The expressions of these genes were also validated by qRT-PCR. CONCLUSIONS The research revealed a gene expression signature of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. The result will contribute to the understanding of the molecular basis of LSCC and help to improve diagnosis and treatment.
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Affiliation(s)
- Meng Lian
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jugao Fang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- * E-mail: (JF); (DH)
| | - Demin Han
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Otorhinolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otorhinolaryngology, Beijing, China
- * E-mail: (JF); (DH)
| | - Hongzhi Ma
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ling Feng
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ru Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Fan Yang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Horváth Z, Kovalszky I, Fullár A, Kiss K, Schaff Z, Iozzo RV, Baghy K. Decorin deficiency promotes hepatic carcinogenesis. Matrix Biol 2013; 35:194-205. [PMID: 24361483 DOI: 10.1016/j.matbio.2013.11.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/26/2013] [Accepted: 11/26/2013] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21(Waf1/Cip1) levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21(Waf1/Cip1), and enhanced c-Myc protein levels. In addition, translocation of β-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and β-catenin was observed in Dcn(-/-) livers likely due to the hindered GSK3β-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRα, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates experimental carcinogenesis by providing an environment devoid of this potent pan-RTK inhibitor. Thus, our results support future utilization of decorin as an antitumor agent in liver cancer.
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Affiliation(s)
- Zsolt Horváth
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Alexandra Fullár
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Katalin Kiss
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Renato V Iozzo
- Department of Pathology, Anatomy, and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Kornélia Baghy
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
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Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep 2013; 31:933-9. [PMID: 24336972 DOI: 10.3892/or.2013.2917] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 11/27/2013] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing worldwide incidence, and there are few therapeutics options available for patients with HCC. Thus, novel therapeutic targets for this disease are desperately needed. Chronic infection with hepatitis B virus (HBV) is the major risk factor for the development of HCC, while hepatitis B virus X protein (HBx) is essential for HBV-associated HCC. Based on our previous studies showing that HBx promoted hepatocarcinogenesis of the human non-tumor hepatic cell line L02 and activated Notch1 signaling, Notch1 short hairpin RNA (shRNA) was utilized to inhibit Notch1 mRNA in the present study. We observed that Notch1 shRNA inhibited cell proliferation together with decreased activity of the Notch1 pathway in vitro, and also markedly suppressed tumor formation of L02/HBx cells in a BALB/c nude mouse model in vivo. Furthermore, the blockade of Notch1 was capable of arresting the cell cycle in the G0/G1 phase through the downregulation of CyclinD1, CDK4, E2F1 and the upregulation of p21 and Rb, while all of these factors were involved in the CyclinD1/CDK4 pathway. Inhibition of Notch1 by shRNA markedly promoted the apoptosis of L02/HBx cells via the caspase-9-caspase-3 pathway. These data suggest that inhibition of Notch1 impairs the growth of human HBx-transformed L02 cells, and Notch1 may be a putative therapeutic target for human HBx-associated HCC.
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Kyotani Y, Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Zhao J, Ozawa K, Nagayama K, Ito S, Takasawa S, Kimura H, Uno M, Yoshizumi M. Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor. Exp Cell Res 2013; 319:3042-50. [DOI: 10.1016/j.yexcr.2013.08.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 07/31/2013] [Accepted: 08/06/2013] [Indexed: 11/25/2022]
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Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. Life Sci 2013; 93:664-72. [DOI: 10.1016/j.lfs.2013.09.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 07/30/2013] [Accepted: 09/05/2013] [Indexed: 11/19/2022]
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