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Park E, Subasi NB, Wang X, Kmeid M, Chen A, Tooke-Barry C, Lee H. CXCR2 expression is associated with prostate-specific membrane antigen expression in hepatocellular carcinoma: reappraisal of tumor microenvironment and angiogenesis. Clin Transl Oncol 2025; 27:2544-2556. [PMID: 39636498 DOI: 10.1007/s12094-024-03789-7] [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: 09/14/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE Angiogenesis is a critical component of neoplastic progression, and inflammatory cells within the tumor microenvironment contribute to neoangiogenesis. Prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of various solid tumors, including hepatocellular carcinoma (HCC). Also, CXCR2 + inflammatory cells, including CD15 + neutrophils, play crucial roles in HCC progression. We evaluated the associations between PSMA expression and CXCR2 + inflammatory cells in HCC by immunohistochemistry (IHC). METHODS CXCR2 expression and its correlation with PSMA, the PSMA/CD34 ratio, immune markers (CD3, CD15, CD68, and CD163), clinical parameters, and oncologic outcomes were evaluated in 76 HCC and background benign liver tissue. RESULTS PSMA and the PSMA/CD34 ratio showed a positive correlation with intratumoral CXCR2, but not with intratumoral CD15. Intratumoral CXCR2 + cell count was positively associated with intratumoral CD3, CD15, CD68, and CD163 expression levels. In the benign compartment, CXCR2 was significantly associated with CD15. Metabolic dysfunction-associated steatotic liver disease (MASLD) risk factors and cirrhosis had an opposite effect on CXCR2 + cell count in benign liver tissue. Higher CD15 + cell count in the benign liver was associated with decreased overall survival (OS) and recurrence-free survival (RFS). CONCLUSIONS In HCC, intratumoral CXCR2 + cell count is associated with PSMA expression. Intratumoral and benign compartments had different CXCR2 + inflammatory cell makeup. The immune microenvironment of HCC appears to differ depending on underlying risk factors. Further investigations are warranted to elucidate PSMA biology and assess the potential utility of CXCR2 IHC in PSMA-targeted theranostics.
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Affiliation(s)
- Eundong Park
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Nusret Bekir Subasi
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Xin Wang
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Michel Kmeid
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
- Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Anne Chen
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
- Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Chelsea Tooke-Barry
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Hwajeong Lee
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Wada T, Takeda Y, Okekawa A, Komatsu G, Iwasa Y, Onogi Y, Takasaki I, Hamashima T, Sasahara M, Tsuneki H, Sasaoka T. Deletion of platelet-derived growth factor receptor β suppresses tumorigenesis in metabolic dysfunction-associated steatohepatitis (MASH) mice with diabetes. Sci Rep 2024; 14:23829. [PMID: 39394459 PMCID: PMC11470010 DOI: 10.1038/s41598-024-75713-6] [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: 05/28/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024] Open
Abstract
The platelet-derived growth factor (PDGF) family contributes to the progression of steatohepatitis; however, changes in and the characteristics of isoform-specific expression remain unclear. Since diabetes is a major driver of metabolic dysfunction-associated steatohepatitis (MASH), we characterized the mouse model of diabetic MASH (dMASH) by focusing on PDGF signaling. Pdgfa-d expression was markedly higher in hepatic stellate cells among flow-sorted cells in control mice and also increased in dMASH. In contrast, a reanalysis of human single-cell RNA-Seq data showed the distinct distribution of each PDGF isoform with disease progression. Furthermore, inflammation and fibrosis in the liver were less severe in diabetic MASH using tamoxifen-induced PDGF receptor β (PDGFRβ)-deficient mice (KO) than in control dMASH using floxed mice (FL) at 12 weeks old. Despite the absence of tumors, the expression of tumor-related genes was lower in KO than in FL. Tumorigenesis was significantly lower in 20-week-old KO. An Ingenuity Pathway Analysis of differentially expressed miRNA between FL and KO identified functional networks associated with hepatotoxicity and cancer. Therefore, PDGFRβ signals play important roles in the progression of steatohepatitis and tumorigenesis in MASH, with the modulation of miRNA expression posited as a potential underlying mechanism.
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Affiliation(s)
- Tsutomu Wada
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Yuki Takeda
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Akira Okekawa
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Go Komatsu
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yuichi Iwasa
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yasuhiro Onogi
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
- Research Center for Pre-Disease Science, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Ichiro Takasaki
- Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, 3190, Gofuku, Toyama, Japan
| | - Takeru Hamashima
- Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Masakiyo Sasahara
- Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Hiroshi Tsuneki
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
- Department of Integrative Pharmacology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Toshiyasu Sasaoka
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Kader M, Yu YP, Liu S, Luo JH. Immuno-targeting the ectopic phosphorylation sites of PDGFRA generated by MAN2A1-FER fusion in HCC. Hepatol Commun 2024; 8:e0511. [PMID: 39082961 DOI: 10.1097/hc9.0000000000000511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/30/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND HCC is one of the most lethal cancers for humans. Mannosidase alpha class 2A member 1 (MAN2A1)-FER is one of the most frequent oncogenic fusion genes in HCC. In this report, we showed that MAN2A1-FER ectopically phosphorylated the extracellular domains of PDGFRA, MET, AXL, and N-cadherin. The ectopic phosphorylation of these transmembrane proteins led to the activation of their kinase activities and initiated the activation cascades of their downstream signaling molecules. METHODS A panel of mouse monoclonal antibodies was developed to recognize the ectopic phosphorylation sites of PDGFRA. RESULTS AND CONCLUSIONS The analyses showed that these antibodies bound to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The treatment of MAN2A1-FER-positive cancer HUH7 with one of the antibodies called 2-3B-G8 led to the deactivation of cell growth signaling pathways and cell growth arrest while having minimal impact on HUH7ko cells where MAN2A1-FER expression was disrupted. The treatment of 2-3B-G8 antibody also led to a large number of cell deaths of MAN2A1-FER-positive cancer cells such as HUH7, HEPG2, SNU449, etc., while the same treatment had no impact on HUH7ko cells. When severe combined immunodeficiency mice xenografted with HEPG2 or HUH7 were treated with monomethyl auristatin E-conjugated 2-3B-G8 antibody, it slowed the progression of tumor growth, eliminated the metastasis, and reduced the mortality, in comparison with the controls. Targeting the cancer-specific ectopic phosphorylation sites of PDGFRA induced by MAN2A1-FER may hold promise as an effective treatment for liver cancer.
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Affiliation(s)
- Muhamuda Kader
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yan-Ping Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jian-Hua Luo
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- High Throughput Genome Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Kraj L, Chmiel P, Gryziak M, Grabowska-Derlatka L, Szymański Ł, Wysokińska E. Impact of Thrombocytopenia on Survival in Patients with Hepatocellular Carcinoma: Updated Meta-Analysis and Systematic Review. Cancers (Basel) 2024; 16:1293. [PMID: 38610973 PMCID: PMC11011012 DOI: 10.3390/cancers16071293] [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: 02/27/2024] [Revised: 03/24/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Platelets (PLT) have a role in the pathogenesis, progression, and prognosis of hepatocellular carcinoma (HCC) and could represent a readily measurable laboratory parameter to enhance the comprehensive evaluation of HCC patients. METHODS The PubMed, Web of Science, and Scopus databases were searched with a focus on survival as well as patient and tumor-specific characteristics in correlation to reported PLT counts. Survival outcomes were analyzed with both common-effect and random-effects models. The hazard ratio (HR) and its 95% confidence interval (CI) from analyzed trials were incorporated. Studies that did not provide survival data but focused on platelet count correlation with HCC characteristics were reviewed. RESULTS In total, 26 studies, including a total of 9403 patients, met our criteria. The results showed that thrombocytopenia in HCC patients was associated with poor overall survival (common-effect HR = 1.15, 95% CI: 1.06-1.25; random-effect HR = 1.30, 95% CI: 1.05-1.63). Moreover, three studies reveal significant correlations between PLT indices and tumor characteristics such as size, foci number, and etiology of HCC development. CONCLUSION Our meta-analysis confirmed that PLT count could act as a prognostic marker in HCC, especially with a PLT count cut off <100 × 103/mm3. Further prospective studies focusing on the role of PLT in clearly defined subgroups are necessary.
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Affiliation(s)
- Leszek Kraj
- Department of Oncology, University Clinical Centre, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Science, 01-447 Magdalenka, Poland;
| | - Paulina Chmiel
- University Clinical Centre, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Maciej Gryziak
- Department of Oncology, University Clinical Centre, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Laretta Grabowska-Derlatka
- 2nd Department of Clinical Radiology, University Clinical Centre, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Łukasz Szymański
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Science, 01-447 Magdalenka, Poland;
| | - Ewa Wysokińska
- Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
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Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, Varghese J. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21. [PMID: 37726886 PMCID: PMC10512929 DOI: 10.1080/19336918.2023.2258539] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
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Affiliation(s)
- Sugan Panneerselvam
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Cornelia Wilson
- Natural and Applied Sciences, School of Psychology and Life Sciences, Canterbury Christ Church University, Discovery Park, Sandwich, UK
| | - Prem Kumar
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Dinu Abirami
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Jayakrishna Pamarthi
- Multi-Disciplinary Research Unit, Madras Medical College, Chennai, Tamil Nadu, India
| | - Mettu Srinivas Reddy
- The Director and Head, Liver Transplant and HPB surgery, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Joy Varghese
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
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Sariyar E, Firtina Karagonlar Z. Modelling the Sorafenib-resistant Liver Cancer Microenvironment by Using 3-D Spheroids. Altern Lab Anim 2023; 51:301-312. [PMID: 37555318 DOI: 10.1177/02611929231193421] [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] [Indexed: 08/10/2023]
Abstract
Liver cancer is the third leading cause of cancer-related mortality, and hepatocellular carcinoma (HCC) is the most common form of liver cancer, and it usually occurs in the setting of chronic liver disease and cirrhosis. For patients with advanced HCC, systemic treatment is the first choice - however, resistance occurs frequently. Sorafenib was the first tyrosine kinase inhibitor approved for advanced HCC, and resistance to the therapy is a serious concern. When sorafenib therapy fails in a patient, it can be challenging to decide whether they can undergo a second-line therapy, and to determine which therapy they will be able to tolerate. Thus, physiologically relevant in vitro preclinical models are crucial for screening potential therapies, and 3-D tumour spheroids permit studies of tumour pathobiology. In this study, a drug-resistant 3-D tumour spheroid model was developed, based on sorafenib-resistant hepatocellular carcinoma cells, LX2 stellate cells and THP-1 monocytes. Model tumour spheroids that were formed with the sorafenib-resistant cells demonstrated lower diffusion of doxorubicin and exhibited increased resistance to regorafenib. Moreover, in the sorafenib-resistant spheroids, there was increased presence of CD68-positive cells and a reduction in inflammatory marker secretion. The sorafenib-resistant cell line-derived spheroids also showed a higher expression of FGF-19, PDGF-AA and GDF-15, which are known to be involved in malignancies. This multi-cell type spheroid model represents a potentially useful system to test drug candidates in a microenvironment that mimics the drug-resistant tumour microenvironment in HCC.
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Affiliation(s)
- Ece Sariyar
- Department of Genetics and Bioengineering, İzmir University of Economics, Izmir, Turkey
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Chen Y, Zhang XF, Ou-Yang L. Inferring cancer common and specific gene networks via multi-layer joint graphical model. Comput Struct Biotechnol J 2023; 21:974-990. [PMID: 36733706 PMCID: PMC9873583 DOI: 10.1016/j.csbj.2023.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 01/08/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Cancer is a complex disease caused primarily by genetic variants. Reconstructing gene networks within tumors is essential for understanding the functional regulatory mechanisms of carcinogenesis. Advances in high-throughput sequencing technologies have provided tremendous opportunities for inferring gene networks via computational approaches. However, due to the heterogeneity of the same cancer type and the similarities between different cancer types, it remains a challenge to systematically investigate the commonalities and specificities between gene networks of different cancer types, which is a crucial step towards precision cancer diagnosis and treatment. In this study, we propose a new sparse regularized multi-layer decomposition graphical model to jointly estimate the gene networks of multiple cancer types. Our model can handle various types of gene expression data and decomposes each cancer-type-specific network into three components, i.e., globally shared, partially shared and cancer-type-unique components. By identifying the globally and partially shared gene network components, our model can explore the heterogeneous similarities between different cancer types, and our identified cancer-type-unique components can help to reveal the regulatory mechanisms unique to each cancer type. Extensive experiments on synthetic data illustrate the effectiveness of our model in joint estimation of multiple gene networks. We also apply our model to two real data sets to infer the gene networks of multiple cancer subtypes or cell lines. By analyzing our estimated globally shared, partially shared, and cancer-type-unique components, we identified a number of important genes associated with common and specific regulatory mechanisms across different cancer types.
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Affiliation(s)
- Yuanxiao Chen
- Guangdong Key Laboratory of Intelligent Information Processing, Shenzhen Key Laboratory of Media Security, and Guangdong Laboratory of Artificial Intelligence and Digital Economy(SZ), Shenzhen University, Shenzhen, China
| | - Xiao-Fei Zhang
- School of Mathematics and Statistics & Hubei Key Laboratory of Mathematical Sciences, Central China Normal University, Wuhan, China
| | - Le Ou-Yang
- Guangdong Key Laboratory of Intelligent Information Processing, Shenzhen Key Laboratory of Media Security, and Guangdong Laboratory of Artificial Intelligence and Digital Economy(SZ), Shenzhen University, Shenzhen, China,Corresponding author.
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Hepatocellular Carcinoma: Current Therapeutic Algorithm for Localized and Advanced Disease. JOURNAL OF ONCOLOGY 2022; 2022:3817724. [PMID: 36624801 PMCID: PMC9825221 DOI: 10.1155/2022/3817724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer in patients with liver cirrhosis of various etiologies. In recent years, there has been an advance in the knowledge of molecular mechanisms and a better staging definition of patients which has allowed the development of new therapies that have entered the therapeutic workup of these patients. Deep information on molecular drivers of HCC contributed to the development of targeted therapies with remarkable benefits. The novel strategies of targeting immune evasion using immune checkpoint inhibitors and CAR-T and TCR-T therapeutics have also shown promising results. For advanced diseases, the therapeutic algorithm has been recently updated, thanks to the efficacy of combining immunotherapy and antiangiogenic therapy in the first-line setting, and new drugs, both as single-agents or combinations, are currently under investigation.
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10
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Identification of an Immune-Related Gene Signature Associated with Prognosis and Tumor Microenvironment in Esophageal Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7413535. [PMID: 36588538 PMCID: PMC9803573 DOI: 10.1155/2022/7413535] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
Background Esophageal cancer (EC) is a common malignant tumor of the digestive system with high mortality and morbidity. Current evidence suggests that immune cells and molecules regulate the initiation and progression of EC. Accordingly, it is necessary to identify immune-related genes (IRGs) affecting the biological behaviors and microenvironmental characteristics of EC. Methods Bioinformatics methods, including differential expression analysis, Cox regression, and immune infiltration prediction, were conducted using R software to analyze the Gene Expression Omnibus (GEO) dataset. The Cancer Genome Atlas (TCGA) cohort was used to validate the prognostic signature. Patients were stratified into high- and low-risk groups for further analyses, including functional enrichment, immune infiltration, checkpoint relevance, clinicopathological characteristics, and therapeutic sensitivity analyses. Results A prognostic signature was established based on 21 IRGs (S100A7, S100A7A, LCN1, CR2, STAT4, GAST, ANGPTL5, TRAV39, F2RL2, PGLYRP3, KLRD1, TRIM36, PDGFA, SLPI, PCSK2, APLN, TICAM1, ITPR3, MAPK9, GATA4, and PLAU). Compared with high-risk patients, better overall survival rates and clinicopathological characteristics were found in low-risk patients. The areas under the curve of the two cohorts were 0.885 and 0.718, respectively. Higher proportions of resting CD4+ memory T lymphocytes, M2 macrophages, and resting dendritic cells and lower proportions of follicular helper T lymphocytes, plasma cells, and neutrophils were found in the high-risk tumors. Moreover, the high-risk group showed higher expression of CD44 and TNFSF4, lower expression of PDCD1 and CD40, and higher TIDE scores, suggesting they may respond poorly to immunotherapy. High-risk patients responded better to chemotherapeutic agents such as docetaxel, doxorubicin, and gemcitabine. Furthermore, IRGs associated with tumor progression, including PDGFA, ITPR3, SLPI, TICAM1, and GATA4, were identified. Conclusion Our immune-related signature yielded reliable value in evaluating the prognosis, microenvironmental characteristics, and therapeutic sensitivity of EC and may help with the precise treatment of this patient population.
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11
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SGLT-2 Inhibitors in Cancer Treatment-Mechanisms of Action and Emerging New Perspectives. Cancers (Basel) 2022; 14:cancers14235811. [PMID: 36497303 PMCID: PMC9738342 DOI: 10.3390/cancers14235811] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/11/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
A new group of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), have recently been shown to have anticancer effects and their expression has been confirmed in many cancer cell lines. Given the metabolic reprogramming of these cells in a glucose-based model, the ability of SGLT-2 inhibitors to block the glucose uptake by cancer cells appears to be an attractive therapeutic approach. In addition to tumour cells, SGLT-2s are only found in the proximal tubules in the kidneys. Furthermore, as numerous clinical trials have shown, the use of SGLT-2 inhibitors is well-tolerated and safe in patients with diabetes and/or heart failure. In vitro cell culture studies and preclinical in vivo studies have confirmed that SGLT-2 inhibitors exhibit antiproliferative effects on certain types of cancer. However, the mechanisms of this action remain unclear. Even in those tumour cell types in which SGLT-2 is present, there is sometimes an SGLT-2-independent mechanism of anticancer action of this group of drugs. This article presents the current state of knowledge of the potential mechanisms of the anticancer action of SGLT-2 inhibitors and their possible future application in clinical oncology.
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12
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Wu Z, Xu J, Tang R, Wang W, Zhang B, Yu X, Liu J, Shi S. The Role of PDGFRA in Predicting Oncological and Immune Characteristics in Pancreatic Ductal Adenocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:4148805. [PMID: 35378770 PMCID: PMC8976608 DOI: 10.1155/2022/4148805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/23/2022] [Accepted: 03/04/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid gastrointestinal malignancy with poor immune infiltration and a limited response to immunotherapy. The aim of our study was to explore the predictive value of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs), which are widely expressed in various tumor cells. METHODS Transcriptomic data with follow-up information were obtained from the GEO, TCGA and ArrayExpress. The Kaplan-Meier (KM) method and univariate Cox (UniCox) proportional hazard regression were used to show the survival outcomes of the groups. Immune infiltration was analyzed using the online databases TISCH, TISIDB, TIMER2.0, and TIDE as well as the R packages "estimate" and "GSVA." Mutation and functional enrichment analyses were conducted using the R packages "maftools," "clusterProfiler," and online repository HOME for Researchers. Finally, the results were validated in 79 samples from our cancer center. RESULTS Survival analysis using public databases and the FUSCC cohort indicated PDGFRA to be associated with prolonged overall survival (OS) (both p < 0.05). PDGFRA expression was highest in cancer-associated fibroblasts (CAFs) of PDAC, as validated in public databases and cell lines from our cancer center. The high expression of PDGFRA was associated with increased immune infiltration and potent T cell cytotoxicity in PDAC. CONCLUSION In summary, high PDGFRA expression is associated with increased immune infiltration and prolonged OS. This finding might provide a new strategy for regulating immune cell infiltration in PDAC and improving the efficacy of immunotherapy.
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Affiliation(s)
- Zijian Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Rong Tang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Hu CT, Mandal JP, Wu WS. Regulation on tumor metastasis by Raf kinase inhibitory protein: New insight with reactive oxygen species signaling. Tzu Chi Med J 2021; 33:332-338. [PMID: 34760627 PMCID: PMC8532577 DOI: 10.4103/tcmj.tcmj_296_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/19/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Targeted therapy aiming at the metastatic signal pathway, such as that triggered by receptor tyrosine kinase (RTK), for the prevention of tumor progression is promising. However, RTK-based targeted therapy frequently suffered from drug resistance due to the co-expression of multiple growth factor receptors that may raise compensatory secondary signaling and acquired mutations after treatment. One alternative strategy is to manipulate the common negative regulators of the RTK signaling. Among them, Raf kinase inhibitory protein (RKIP) is highlighted and focused on this review. RKIP can associate with Raf-1, thus suppressing the downstream mitogen-activated protein kinase (MAPK) cascade. RKIP also negatively regulates other metastatic signal molecules including NF-κB, STAT3, and NOTCH1. In general, RKIP achieves this task via associating and blocking the activity of the critical molecules on upstream of the aforementioned pathways. One novel RKIP-related signaling involves reactive oxygen species (ROS). In our recent report, we found that PKCδ-mediated ROS generation may interfere with the association of RKIP with heat shock protein 60 (HSP60)/MAPK complex via oxidation of HSP60 triggered by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The departure of RKIP may impact the downstream MAPK in two aspects. One is to trigger the Mt→cytosol translocation of HSP60 coupled with MAPKs. The other is to change the conformation of HSP60, favoring more efficient activation of the associated MAPK by upstream kinases in cytosol. It is worthy of investigating whether various RTKs capable of generating ROS can drive metastatic signaling via affecting RKIP in the same manner.
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Affiliation(s)
- Chi-Tan Hu
- Division of Gastroenterology, Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Research Centre for Hepatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | | | - Wen-Sheng Wu
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan
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Hora S, Asad M, Jain SK, Katare DP. Identification of potential targets with high centrality indicated by diethylnitrosamine + thioacetamide-induced hepatocellular carcinoma model. J Cancer Res Ther 2021; 17:1081-1092. [PMID: 34528568 DOI: 10.4103/jcrt.jcrt_948_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background and Aim Hepatocellular carcinoma (HCC), a primary liver malignancy, represents a continuous challenge to clinicians as it is a leading cause of death due to cancer widely. Early detection is the only hope to cure patients from this deadly disease or possibly increase life expectancy. Mouse models are most acceptable studies as they have ability to manipulate their genome and transcriptome to evaluate mechanistic changes. In addition, system biology can improvise the understanding of molecular mechanism of HCC and also can reveal the protein hub involved in every stage of HCC. Materials and Methods Herein, diethylnitrosamine and thioacetamide (TAA) were used to develop stage-specific HCC in Wistar rats. Histopathological changes, biochemical parameters, and the oxidative stress were measured in hepatocytes. We have reanalyzed the microarray dataset to identify the complex signaling pathways involved in hepatocarcinogenesis induced by TAA. GSE45050 dataset was downloaded from Gene Expression Omnibus database, and the gene expression profile of nontumor, cirrhosis, and HCC was compared. Results The study reveals stage-specific development of chronic HCC rat model and promising stage-specific targets (EHMT2, GMPS, and SPRY2) of HCC. Conclusions EHMT2, GMPS, and SPRY found as high centrality nodes in protein-protein interaction studies using high-throughput microarray data which tend to be present in signaling pathways and co-occur in a biological state of HCC. These genes can be targeted to understand the possible pathology, molecular changes, and target strategy under cirrhosis and HCC condition.
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Affiliation(s)
- Sandhya Hora
- Department of Biotechnology, HIMT Group of Institutions, Greater Noida; Proteomic and Translational Research Laboratory, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, New Delhi, India
| | - Mohammad Asad
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Uttar Pradesh, New Delhi, India
| | - Swatantra Kumar Jain
- Department of Biotechnology, School of Chemical and Life Sciences; Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, Uttar Pradesh, New Delhi, India
| | - Deepshikha Pande Katare
- Proteomic and Translational Research Laboratory, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, New Delhi, India
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Lu JF, Hu ZQ, Yang MX, Liu WY, Pan GF, Ding JB, Liu JZ, Tang L, Hu B, Li HC. Downregulation of PDGF-D Inhibits Proliferation and Invasion in Breast Cancer MDA-MB-231 Cells. Clin Breast Cancer 2021; 22:e173-e183. [PMID: 34272173 DOI: 10.1016/j.clbc.2021.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 05/06/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The platelet derived growth factor-D (PDGF-D) plays an important role in breast tumor aggressiveness. However, limited study has investigated the effect of silencing PDGF-D on the biological function of breast cancer. The purpose of this study is to clarify the potential value of PDGF-D as a target for breast cancer treatment. METHODS Reverse transcription-polymerase chain reaction and western blot were used to detect PDGF-D expression in 5 different breast cancer cells. The lentiviral vector was usd to silence PDGF-D in MDA-MB-231 cells. Then, Methyl Thiazolyl Tetrazolium was used to detect cell viability, 5-Ethynyl-2'- deoxyuridine and a soft agar assay were used to detect cell proliferation and clonality. Additionally, cell apoptosis after PDGF-D knockdown was measured by Annexin V/ Prodium Iodide staining, and cell migration was detected by trans-well assay. Survival rate and tumor size were measured by nude mice transplantation. RESULTS The MDA-MB-231 and SK-BR-3 cell lines showed higher PDGF-D expression than the MCF7 cell lines (P<.05). After the PDGF-D gene was silenced, the growth and colony forming abilitys ignificantly decreased (P<.05) together with the induction of apoptosis in MDA-MB-231 cells (P<.05). Moreover, MDA-MB-231 cells with PDGF-D silencing showed significantly diminished aggressive migration and invasion potential compared to other cells (P<.05). In vivo experiments also indicated that PDGF-D silencing inhibited tumor growth and improved the survival rate of tumor-bearing mice. CONCLUSION Downregulation of PDGF-D had dramatic effects on breast cancer cell proliferation, apoptosis and migration, which indicates that it plays an important role in breast cancer development and progression.
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Affiliation(s)
- Jing-Feng Lu
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Zhi-Qiu Hu
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Meng-Xuan Yang
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Wei-Yan Liu
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Gao-Feng Pan
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Jun-Bin Ding
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Jia-Zhe Liu
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Lang Tang
- Department of Ultrasonography Department, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China
| | - Bin Hu
- Department of Ultrasonography Department, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China.
| | - Hong-Chang Li
- Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China.
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Ao J, Chiba T, Shibata S, Kurosugi A, Qiang N, Ma Y, Kan M, Iwanaga T, Sakuma T, Kanzaki H, Kanayama K, Kojima R, Kusakabe Y, Nakamura M, Saito T, Nakagawa R, Kondo T, Ogasawara S, Suzuki E, Muroyama R, Kato J, Mimura N, Kanda T, Maruyama H, Kato N. Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells. Biochem Biophys Res Commun 2021; 549:171-178. [PMID: 33676186 DOI: 10.1016/j.bbrc.2021.02.097] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 02/06/2023]
Abstract
Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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Affiliation(s)
- Junjie Ao
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Shuhei Shibata
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akane Kurosugi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Na Qiang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yaojia Ma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motoyasu Kan
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Mimura
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Patel S, Nanavati P, Sharma J, Chavda V, Savjani J. Functional Role of Novel Indomethacin Derivatives for the Treatment of Hepatocellular Carcinoma Through Inhibition of Platelet-Derived Growth Factor. Arch Med Res 2021; 52:483-493. [PMID: 33551224 DOI: 10.1016/j.arcmed.2021.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 11/30/2020] [Accepted: 01/21/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Several studies suggested anticancer potential of NSAIDs. Therefore, we aimed to evaluate novel indomethacin derivatives for the treatment of hepatocellular carcinoma. METHODS The molecular docking of derivatives was carried out for prediction of inhibitory effect on PDGFR-α using pass online software, followed by cytotoxicity study by performing MTT assay. The disease was induced with N-Nitrosodiethylamine (200 mg/kg, i.p.) followed by 2-acetylaminofluorene orally for two weeks. After 12 weeks of induction, treatment was given for one week and blood was collected for determination of biochemical parameters and tumor markers. Liver samples were isolated for immunohistochemistry, histopathology, and gene expression study for VEGF. RESULTS JI-MT has shown maximum inhibitory activity for PDGFRα in docking study also showed good cytotoxic effect in the HepG2 cell line and based on the IC50 values, JI-MT was selected for in-vivo study. We have found statistically significant reduction in body weight gain, number of nodules and liver weight to body weight ratio with treatment with JI-MT. Hepatoprotective role of JI-MT has been observed in tumor-specific markers like α-fetoprotein levels, carcinoembryonic antigen and PDGF-α levels. Liver markers like ALT, ALP, AST, LDH and total bilirubin levels were found to be reduced with treatments. Also, on histopathological examination, the protective effect of JI-MT was observed. Treatment also showed increased expression of P53 in immunohistochemical analysis and up-regulation of VEGF gene by JI-MT. CONCLUSION From the present study, we can conclude that JI-MT has potential in treatment of HCC by the virtue of PDGFRα inhibitory activity.
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Affiliation(s)
- Snehal Patel
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat India.
| | | | | | - Vishal Chavda
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat India
| | - Jignasa Savjani
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat India
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Liang M, Wang B, Schneider A, Vainshtein I, Roskos L. A Novel Pharmacodynamic Biomarker and Mechanistic Modeling Facilitate the Development of Tovetumab, a Monoclonal Antibody Directed Against Platelet-Derived Growth Factor Receptor Alpha, for Cancer Therapy. AAPS JOURNAL 2020; 23:4. [PMID: 33210183 DOI: 10.1208/s12248-020-00523-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/09/2020] [Indexed: 11/30/2022]
Abstract
Tovetumab (MEDI-575) is a fully human IgG2κ monoclonal antibody that specifically binds to human platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor signal transduction by PDGF ligands. The affinity of tovetumab determined using surface plasmon resonance technology and flow cytometry demonstrated comparable binding affinity for human and monkey PDGFRα. In single and repeat-dose monkey pharmacokinetic-pharmacodynamic (PK-PD) studies, tovetumab administration resulted in dose-dependent elevation of circulating levels of PDGF-AA, a member of the PDGF ligand family, due to displacement of PDGF-AA from PDGFRα by tovetumab and subsequent blockade of PDGFRα-mediated PDGF-AA degradation. As such, PDGF-AA accumulation is an indirect measurement of receptor occupancy and is a novel PD biomarker for tovetumab. The nonlinear PK of tovetumab and dose-dependent increase in circulating PDGF-AA profiles were well described by a novel mechanistic model, in which tovetumab and PDGF-AA compete for the binding to PDGFRα. To facilitate translational simulation, the internalization half-lives of PDGF-AA and tovetumab upon binding to PDGFRα were determined using confocal imaging to be 14 ± 4 min and 30 ± 8 min, respectively. By incorporating PDGFRα internalization kinetics, the model not only predicted the target receptor occupancy by tovetumab, but also the biologically active agonistic ligand-receptor complex. This work described a novel PD biomarker approach applicable for anti-receptor therapeutics and the first mechanistic model to delineate the in vivo tri-molecular system of a drug, its target receptor, and a competing endogenous ligand, which collectively have been used for optimal dose recommendation supporting clinical development of tovetumab.
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Affiliation(s)
- Meina Liang
- Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA.
| | - Bing Wang
- Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA.,Amador Bioscience, Pleasanton, California, 94588, USA
| | - Amy Schneider
- Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA.,The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Inna Vainshtein
- Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA.,Exelixis, Alameda, California, 94502, USA
| | - Lorin Roskos
- Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA. .,Exelixis, Alameda, California, 94502, USA.
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Creeden JF, Alganem K, Imami AS, Brunicardi FC, Liu SH, Shukla R, Tomar T, Naji F, McCullumsmith RE. Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases. Int J Mol Sci 2020; 21:ijms21228679. [PMID: 33213062 PMCID: PMC7698519 DOI: 10.3390/ijms21228679] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/12/2020] [Accepted: 11/14/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
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Affiliation(s)
- Justin F. Creeden
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
- Correspondence: ; Tel.: +1-419-383-6474
| | - Khaled Alganem
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - Ali S. Imami
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - F. Charles Brunicardi
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Shi-He Liu
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Rammohan Shukla
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
| | - Tushar Tomar
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Faris Naji
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Robert E. McCullumsmith
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (R.S.); (R.E.M.)
- Neurosciences Institute, ProMedica, Toledo, OH 43606, USA
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Current perspectives on the tumor microenvironment in hepatocellular carcinoma. Hepatol Int 2020; 14:947-957. [PMID: 33188512 DOI: 10.1007/s12072-020-10104-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/22/2020] [Indexed: 12/24/2022]
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Patel SS, Tripathi R, Chavda VK, Savjani JK. Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property. Anticancer Agents Med Chem 2020; 20:998-1008. [DOI: 10.2174/1871520620666200415100614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/25/2019] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
Background:
Numerous studies suggest that non-steroidal anti-inflammatory drugs reduce cancer
cell proliferation, progression, angiogenesis, apoptosis, and invasiveness.
Objective:
The current study focuses on the evaluation of novel mefenamic acid derivatives for the treatment of
hepatocellular carcinoma.
Methods:
Derivatives were subjected to molecular modeling for prediction of pharmacological activity using
software, followed by synthesis and in vitro assay. In in vivo study, disease was induced with N-Nitrosodiethylamine
followed by 2-acetylaminofluorene orally for 2 weeks. After 12 weeks of induction, treatment was given for a
period of one week. At the end of the treatment, determination of liver weight, a number of nodules, biochemical
parameters, immunohistochemistry, histopathology, and gene expression studies, were carried out.
Results:
Based on molecular docking score for PDGF-α (Platelet-Derived Growth Factor) and IC50 values in
HepG2 cell line study, JS-PFA was selected for the in vivo study where JS-PFA showed a statistically significant
reduction in a number of nodules and liver weight. Protective role of JS-PFA has been observed in tumorspecific
markers like α-fetoprotein, carcinoembryonic antigen, and lactate dehydrogenase levels. The JS-PFA
has shown a significant reduction in PDGF-α levels as well as liver markers and total bilirubin levels. Histopathological
analysis also showed a protective effect. The results of immunohistochemical analysis of P53 and
down-regulation of vascular endothelial growth factor and matrix metalloproteinases-9 genes suggest that derivative
inhibits PDGF mediated tumor growth and leads to apoptosis, inhibition of angiogenesis, and metastasis.
Conclusion:
The effectiveness of JS-PFA in our studies suggests targeting PDGF by COX 2 inhibitor can serve
as a novel treatment strategy for the treatment of HCC.
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Affiliation(s)
- Snehal S. Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Richa Tripathi
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Vishal K. Chavda
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Jignasa K. Savjani
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
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22
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Du ZQ, Dong J, Li MX, Zhang JF, Bi JB, Ren YF, Zhang LN, Wu RQ, Monga SP, Lv Y, Zhang XF, Wang HC. Overexpression of Platelet-Derived Growth Factor Receptor Α D842V Mutants Prevents Liver Regeneration and Chemically Induced Hepatocarcinogenesis via Inhibition of MET and EGFR. J Cancer 2020; 11:4614-4624. [PMID: 32489479 PMCID: PMC7255377 DOI: 10.7150/jca.44492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022] Open
Abstract
Platelet-derived growth receptor α (PDGFRα) is a key factor in many pathophysiological processes. The expression level of PDGFRα is significantly elevated in the early stage of liver development and maintained at a lower level in adult normal livers. In this study, we constructed a liver-specific PDGFRαD842 mutant transgenic (TG) mice model to explore the effect of continuous activation of PDGFRα on liver regeneration and hepatocarcinogenesis. 14-day-old TG and wild-type (WT) mice were intraperitoneally injected with diethylnitrosamine (DEN) at a dose of 25 μg/g body weight. Two-month-old male TG and WT mice were subjected to partial hepatectomy (PH). The liver tissues were collected for further analysis at different time points. Overexpression of PDGFRα D842V and its target genes, Akt, c-myc and cyclin D1 in hepatocytes with no overt phenotype versus WT mice were compared. Unexpectedly, a dramatic decrease in hepatocyte proliferation was noted after PH in TG versus WT mice, possibly due to the downregulation of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR). No TG mice developed HCC spontaneously after 14 months follow-up. However, TG mice were more resistant to DEN-induced hapatocarcinogenesis at 6, 10, and 12 months of age, showing delayed hepatocyte proliferation and apoptosis, lower tumor incidence, smaller size and fewer number, compared with age-matched WTs, partially through downregulation of MET and EGFR. In conclusion, continuous activation of PDGFRα signaling by expression of PDGFRα D842V does not promote, but inhibit hepatic regeneration and hepatocarcinogenesis, possibly through compensatory downregulation of MET and EGFR.
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Affiliation(s)
- Zhao-Qing Du
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Jian Dong
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Mu-Xing Li
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- Department of General Surgery, Peking University Third Hospital, Beijing, 100083, China
| | - Jian-Fei Zhang
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Jian-Bin Bi
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Yi-Fan Ren
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Li-Na Zhang
- Department of Pharmacy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rong-Qian Wu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Satdarshan P.S. Monga
- Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Yi Lv
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
- National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
| | - Hai-Chen Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China
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Shi L, Chen H, Qin YY, Gan TQ, Wei KL. Clinical and biologic roles of PDGFRA in papillary thyroid cancer: a study based on immunohistochemical and in vitro analyses. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1094-1107. [PMID: 32509085 PMCID: PMC7270701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/27/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Platelet-derived growth factor receptor alpha (PDGFRA) plays essential roles in several malignant tumors. Nevertheless, its clinical function in papillary thyroid cancer (PTC) is still unclear. This study aimed to examine the clinicopathologic implication and potential molecular underpinning of PDGFRA in PTC. MATERIAL AND METHODS Relative PDGFRA expression levels in eight cases of normal thyroid tissue, 15 cases of benign thyroid disease, and 90 cases of PTC were examined by immunohistochemistry (IHC). The prognostic value of PDGFRA was assessed by data mining of The Cancer Genome Atlas dataset. LV-PDGFRA overexpression and negative control CON220 lentivirus vectors were constructed and transfected into a PTC cell line. The capacity for cell proliferation, status of the cell cycle, efficiency of colony-forming, and migration ability of the PTC cells after PDGFRA were detected by multiple assays including methyl thiazolyl tetrazolium, flow cytometry, colony formation, transwell assay, and wound healing. Furthermore, bioinformatics analyses were conducted to determine the potential biologic mechanisms of PDGFRA. RESULTS Results of IHC showed that PDGFRA expression was significantly upregulated in PTC samples and was associated with an advanced pathologic stage. Furthermore, patients with PDGFRA overexpression showed poor survival. Ectopically overexpressed PDGFRA accelerated the migration and invasion of PTC cells. Results of the bioinformatics analyses suggested that PDGFRA was involved in several cell proliferation-related pathways. CONCLUSION Collectively, our results indicate that PDGFRA overexpression is associated with the poor survival of patients with PTC and that PDGFRA is a potent oncogene in PTC because it significantly increases PTC cell migration and invasion. Thus, PDGFRA may be a promising novel biomarker and therapeutic target for treating PTC.
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Affiliation(s)
- Lin Shi
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical UniversityNanning, People’s Republic of China
| | - Hao Chen
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical UniversityNanning, People’s Republic of China
| | - Yong-Ying Qin
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical UniversityNanning, People’s Republic of China
| | - Ting-Qing Gan
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical UniversityNanning, People’s Republic of China
| | - Kang-Lai Wei
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical UniversityNanning, People’s Republic of China
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24
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Sakurai K, Tomihara K, Yamazaki M, Heshiki W, Moniruzzaman R, Sekido K, Tachinami H, Ikeda A, Imaue S, Fujiwara K, Noguchi M. CD36 expression on oral squamous cell carcinoma cells correlates with enhanced proliferation and migratory activity. Oral Dis 2020; 26:745-755. [DOI: 10.1111/odi.13210] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 09/03/2019] [Accepted: 09/25/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Kotaro Sakurai
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Kei Tomihara
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Manabu Yamazaki
- Division of Oral Pathology Department of Tissue Regeneration and Reconstruction Graduate School of Medical and Dental Sciences Niigata University Niigata city Japan
| | - Wataru Heshiki
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Rohan Moniruzzaman
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Katsuhisa Sekido
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Hidetake Tachinami
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Atsushi Ikeda
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Shuichi Imaue
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Kumiko Fujiwara
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
| | - Makoto Noguchi
- Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research University of Toyama Toyama city Japan
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25
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Lai Q, Vitale A, Manzia TM, Foschi FG, Levi Sandri GB, Gambato M, Melandro F, Russo FP, Miele L, Viganò L, Burra P, Giannini EG. Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics. Cancers (Basel) 2019; 11:1568. [PMID: 31618961 PMCID: PMC6826649 DOI: 10.3390/cancers11101568] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.
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Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Umberto I Hospital, Sapienza University, 00161 Rome, Italy.
| | - Alessandro Vitale
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Tommaso M Manzia
- Department of Transplant Surgery, Polyclinic Tor Vergata Foundation, Tor Vergata University, 00133 Rome, Italy.
| | - Francesco G Foschi
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, 48018 Faenza, Italy.
| | | | - Martina Gambato
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Fabio Melandro
- Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, 56126 Pisa, Italy.
| | - Francesco P Russo
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Luca Miele
- Internal Medicine, Gastroenterology and Liver Unit, A. Gemelli Polyclinic, Sacro Cuore Catholic University, 20123 Rome, Italy.
| | - Luca Viganò
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Università di Genova, IRCCS-Ospedale Policlinico San Martino, 16132 Genoa, Italy.
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26
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Supplementary Sorafenib Therapies for Hepatocellular Carcinoma-A Systematic Review and Meta-Analysis: Supplementary Sorafenib for Liver Cancer. J Clin Gastroenterol 2019; 53:486-494. [PMID: 30939505 DOI: 10.1097/mcg.0000000000001175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Sorafenib is considered a supplementary treatment to surgical or locoregional therapies for improving outcomes. We evaluated the efficacy of sorafenib as a supplementary therapy for HCC. METHODS We conducted a meta-analysis including 11 randomized controlled trials. Patients with HCC and studies in which sorafenib was administered alone and compared with placebo or those in which sorafenib was administered in combination with another treatment and compared with that treatment alone were included. The overall effects (OEs) on overall survival and time to progression were pooled as hazard ratios. RESULTS The OEs of sorafenib as a first-line therapy versus placebo for unresectable HCC were 0.62 [95% confidence interval (CI): 0.50-0.77] and 0.58 (95% CI: 0.47-0.70), respectively. The OEs of sorafenib as a second-line therapy versus placebo for progressive HCC were 0.73 (95% CI: 0.47-1.13) and 0.54 (95% CI: 0.30-0.97), respectively. The OEs of sorafenib as an adjuvant therapy versus placebo for early HCC were 1.00 (95% CI: 0.76-1.30) and 0.89 (95% CI: 0.74-1.08), respectively. The OEs of sorafenib combined with transarterial chemoemboliztion (TACE) versus placebo combined with TACE were 0.80 (95% CI: 0.54-1.21) and 0.85 (95% CI: 0.70-1.04), respectively. The OEs of sorafenib as an adjuvant to TACE versus placebo as an adjuvant to TACE for intermediate HCC were 1.06 (95% CI: 0.69-1.64) and 0.65 (95% CI: 0.31-1.36), respectively. CONCLUSIONS Sorafenib was effective as a first-line therapy for unresectable HCC, but it was ineffective as a second-line or adjuvant therapy. Sorafenib did not increase the efficacy of TACE.
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Ni W, Zhang S, Jiang B, Ni R, Xiao M, Lu C, Liu J, Qu L, Ni H, Zhang W, Zhou P. Identification of cancer-related gene network in hepatocellular carcinoma by combined bioinformatic approach and experimental validation. Pathol Res Pract 2019; 215:152428. [PMID: 31064721 DOI: 10.1016/j.prp.2019.04.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/06/2019] [Accepted: 04/26/2019] [Indexed: 12/27/2022]
Abstract
HCC (hepatocellular carcinoma) is a highly aggressive malignancy that cause a mass of deaths world widely. We chose gene expression datasets of GSE27635 and GSE28248 from GEO database to find out key genes and their interaction network during the progression and metastasis of HCC. GEO2R online tool was used to screen differentially expressed genes (DEGs) between tumor and peri-tumor tissues based on these two datasets. The identified differentially expressed genes were prepared for further analysis such as GO function, KEGG pathway, PPI network analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Retrieval of Interacting Genes (STRING). Two modules were constructed by MOCDE plugin in Cytoscape and 21 genes were selected as hub genes during this analysis. The expression heatmap and GO function of hub genes were performed using R pheatmap package and BiNGO plugin in Cytoscape respectively. Six hub genes including CDC25 A, CDK1, HMMR, MYBL2, TOP2A were recollected for survival analysis and their expression was validated using Kaplan Meier-plotter and GEPIA website. We also investigated the DEGs between metastasis and non-metastasis tissues and two genes (NQO1 and PTHLH) are highly associated with the metastasis in HCC. Further verification using woundhealing and transwell assay confirmed their ability to mediate cell migration and invasion. In summary, our results obtained by bioinformatic analysis and experimental validation revealed the dominant genes and their interaction networks that are associated with the progression and metastasis of HCC and might serve as potential targets for HCC therapy and diagnosis.
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Affiliation(s)
- Wenkai Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China; Endoscopy Centre and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Shiqing Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Bo Jiang
- Department of Gastroenterology, SuQian First Hospital, No. 120, Suzhi Road, Sucheng District, Suqian, Jiangsu, 223800, PR China
| | - Runzhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Mingbing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China; Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, PR China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Lishuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Hongbing Ni
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, PR China
| | - Wenwen Zhang
- Department of Radiotherapy, Affiliated Hospital of Nantong University, No. 20, XiSi Road, Nantong, Jiangsu, 226001, PR China
| | - Pinghong Zhou
- Endoscopy Centre and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
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28
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Kawaguchi T, Nakano D, Okamura S, Shimose S, Hayakawa M, Niizeki T, Koga H, Torimura T. Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis-related cytokines after treatment with sodium-glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus. Hepatol Res 2019; 49:479-486. [PMID: 30180287 DOI: 10.1111/hepr.13247] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/28/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023]
Abstract
Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event, and the pathogenesis remains unclear. Here, we present a case of spontaneous regression of HCC after treatment with sodium-glucose cotransporter 2 inhibitor (SGLT2i) in a cirrhotic patient with diabetes mellitus (DM). A 68-year-old man regularly visited our hospital for follow-up of HCC after treatment with transcatheter arterial chemoembolization, and management of liver cirrhosis and type 2 DM. Contrast-enhanced computed tomography scan showed a hypervascular tumor in the liver and elevated serum α-fetoprotein levels, indicating the recurrence of HCC. Simultaneously, the hemoglobin A1c value increased to 8.0%; therefore, he was treated with SGLT2i (canagliflozin 100 mg/day). Ten weeks after the initiation of SGLT2i treatment, he was admitted to our hospital for treatment of recurrent HCC. However, the hypervascular tumor had disappeared, and the elevated serum α-fetoprotein level had decreased to normal limits, indicating spontaneous regression of HCC. In addition, an angiogenesis array analysis revealed downregulated protein expression of matrix metalloproteinase-8, angiopoietin-1/2, platelet-derived growth factor-AA, and prolactin at 10 weeks after SGLT2i treatment. In this report, we first describe a case of spontaneous regression of HCC with reduction in angiogenesis-related cytokines after SGLT2i treatment.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Masako Hayakawa
- Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.,Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.,Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
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29
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Zhong B, Gu DY, Du JT, Chen F, Liu YF, Liu SX. May the change of platelet to lymphocyte ratio be a prognostic factor for T3-T4 laryngeal squamous cell carcinoma: A retrospective study. PLoS One 2018; 13:e0210033. [PMID: 30596765 PMCID: PMC6312301 DOI: 10.1371/journal.pone.0210033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 12/14/2018] [Indexed: 02/05/2023] Open
Abstract
Background Many blood markers have been shown to predict the recurrence and survival of various malignancies, but the effects of surgery on the body's inflammatory levels may cause changes in these inflammatory markers. Therefore, in this study, we assessed the relationship between changes in platelet to lymphocyte ratio (PLR) and survival and recurrence in patients with T3-T4 laryngeal squamous cell carcinoma (LSCC). Methods Data of patients with T3-T4 HSCC were reviewed. Continuous variables were expressed as mean ± SD and were compared using t test or Mann-Whitney U test. The covariate distributions were compared by Chi-square test. Survival curve was estimated by Kaplan-Meier analysis, and Log-Rank test were performed to estimate the survival curve and significance of the difference in survival distribution between groups, respectively. The prognostic value was uncovered by univariate and multivariate Cox hazards analysis. Results The 413 consecutive patients with LSCC were reviewed. Of these, 362 patients who met the criteria were selected, multi-factor analysis found that pathological T classification(hazard ratio [HR] = 1.878; 95% confidence interval [CI] = 1.342–3.023; P<0.001), pathological N classification (HR = 1.212; 95% CI = 0.867–2.125; P< 0.001) and change of PLR (HR = 2.158; 95% CI = 1.332–2.889; P = 0.004) associated with postoperative recurrence of T3-T4 LSCC. In addition, the pathological T classification (HR = 1.901; 95% CI = 1.255–2.999; P<0.001), pathological N classification (HR = 1.244; 95% CI = 0.810–2.212; P<0.001) and change of PLR (HR = 2.011; 95% CI = 1.354–2.753; P = 0.001) associated with postoperative survival in patients with T3-T4 LSCC. Conclusions Results demonstrate that change in PLR may serve as a useful prognostic predictor for patients with T3-T4 LSCC.
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Affiliation(s)
- Bing Zhong
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - De-Ying Gu
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Jin-Tao Du
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
| | - Fei Chen
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
- * E-mail: (YFL); (FC)
| | - Ya-Feng Liu
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
- * E-mail: (YFL); (FC)
| | - Shi-Xi Liu
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan province, China
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30
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Li D, Yang W, Arthur C, Liu JS, Cruz-Niera C, Yang MQ. Systems biology analysis reveals new insights into invasive lung cancer. BMC SYSTEMS BIOLOGY 2018; 12:117. [PMID: 30547817 PMCID: PMC6293490 DOI: 10.1186/s12918-018-0637-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background Adenocarcinoma in situ (AIS) is a pre-invasive lesion in the lung and a subtype of lung adenocarcinoma. The patients with AIS can be cured by resecting the lesion completely. In contrast, the patients with invasive lung adenocarcinoma have very poor 5-year survival rate. AIS can develop into invasive lung adenocarcinoma. The investigation and comparison of AIS and invasive lung adenocarcinoma at the genomic level can deepen our understanding of the mechanisms underlying lung cancer development. Results In this study, we identified 61 lung adenocarcinoma (LUAD) invasive-specific differentially expressed genes, including nine long non-coding RNAs (lncRNAs) based on RNA sequencing techniques (RNA-seq) data from normal, AIS, and invasive tissue samples. These genes displayed concordant differential expression (DE) patterns in the independent stage III LUAD tissues obtained from The Cancer Genome Atlas (TCGA) RNA-seq dataset. For individual invasive-specific genes, we constructed subnetworks using the Genetic Algorithm (GA) based on protein-protein interactions, protein-DNA interactions and lncRNA regulations. A total of 19 core subnetworks that consisted of invasive-specific genes and at least one putative lung cancer driver gene were identified by our study. Functional analysis of the core subnetworks revealed their enrichment in known pathways and biological progresses responsible for tumor growth and invasion, including the VEGF signaling pathway and the negative regulation of cell growth. Conclusions Our comparison analysis of invasive cases, normal and AIS uncovered critical genes that involved in the LUAD invasion progression. Furthermore, the GA-based network method revealed gene clusters that may function in the pathways contributing to tumor invasion. The interactions between differentially expressed genes and putative driver genes identified through the network analysis can offer new targets for preventing the cancer invasion and potentially increase the survival rate for cancer patients. Electronic supplementary material The online version of this article (10.1186/s12918-018-0637-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dan Li
- MidSouth Bioinformatics Center and Joint Bioinformatics Ph.D. Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, 2801 S. University Avenue, Little Rock, AR, 72204, USA
| | - William Yang
- Department of Computer Science, Carnegie Mellon University School of Computer Science, Pittsburgh, PA, 15213, USA.,Department of Genetics, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
| | - Carolyn Arthur
- MidSouth Bioinformatics Center and Joint Bioinformatics Ph.D. Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, 2801 S. University Avenue, Little Rock, AR, 72204, USA
| | - Jun S Liu
- Department of Statistics, Harvard University, One Oxford Street, Cambridge, MA, 02138, USA
| | - Carolina Cruz-Niera
- MidSouth Bioinformatics Center and Joint Bioinformatics Ph.D. Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, 2801 S. University Avenue, Little Rock, AR, 72204, USA.,Department of Information Science and Department of Computer Science, Member of United States National Academy of Engineering, George Washington Donaghey College of Engineering & IT, University of Arkansas at Little Rock, 2801 S. University Avenue, Little Rock, AR, 72204, USA
| | - Mary Qu Yang
- MidSouth Bioinformatics Center and Joint Bioinformatics Ph.D. Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, 2801 S. University Avenue, Little Rock, AR, 72204, USA.
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31
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Lu L, Fu X, Li Z, Qiu Y, Li W, Zhou Z, Xue W, Wang Y, Jin M, Zhang M. Platelet-derived growth factor receptor alpha (PDGFRα) is overexpressed in NK/T-cell lymphoma and mediates cell survival. Biochem Biophys Res Commun 2018; 504:525-531. [PMID: 30201265 DOI: 10.1016/j.bbrc.2018.08.181] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 08/28/2018] [Indexed: 11/19/2022]
Abstract
Nasal-type natural killer/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma (NHL) that is clinically aggressive and has a poor prognosis. Platelet-derived growth factor receptors (PDGFRs) and their ligands (PDGFs) play important roles in angiogenesis, cancer cell proliferation, survival, migration and poor prognosis in various tumours. However, the significance of PDGFRs in NKTCL remains unknown. Herein, the present study aimed to investigate the important role of PDGFRα in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFRα expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFRα expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFRα blockade in two NKTCL cell lines was conducted through proliferation assay, cell-cycle evaluation and apoptosis detection by flow cytometry analyses. Furthermore, we detected in vivo activity of imatinib in mouse model of NKTCL. We found that the expression of PDGFRα was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFRα expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFRα expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFRα expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFRα expression (P = 0.003) were independent prognostic factors in NKTCL patients. Biological assessment assays in two NKTCL cell lines revealed that a specific PDGFR antagonist, imatinib, inhibited cell viability, blocked cell cycle progression at G0/G1 stage and induced apoptosis. Similarly, the in vivo assay showed that imatinib delayed mouse model tumour growth. In conclusion, NKTCL tumour cells have prominent PDGFRα expression, which can serve as a candidate prognostic marker. PDGFR antagonists have significant biological effect on NKTCL and may be useful therapeutic agents for treatment of NKTCL.
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Affiliation(s)
- Lisha Lu
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Xiaorui Fu
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Zhaoming Li
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yajuan Qiu
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Weiming Li
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Zhiyuan Zhou
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Weili Xue
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yingjun Wang
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Mengyuan Jin
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Mingzhi Zhang
- Lymphoma Diagnosis and Treatment Center, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
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32
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Soliman B, Salem A, Ghazy M, Abu-Shahba N, El Hefnawi M. Bioinformatics functional analysis of let-7a, miR-34a, and miR-199a/b reveals novel insights into immune system pathways and cancer hallmarks for hepatocellular carcinoma. Tumour Biol 2018; 40:1010428318773675. [PMID: 29775159 DOI: 10.1177/1010428318773675] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Let-7a, miR-34a, and miR-199 a/b have gained a great attention as master regulators for cellular processes. In particular, these three micro-RNAs act as potential onco-suppressors for hepatocellular carcinoma. Bioinformatics can reveal the functionality of these micro-RNAs through target prediction and functional annotation analysis. In the current study, in silico analysis using innovative servers (miRror Suite, DAVID, miRGator V3.0, GeneTrail) has demonstrated the combinatorial and the individual target genes of these micro-RNAs and further explored their roles in hepatocellular carcinoma progression. There were 87 common target messenger RNAs (p ≤ 0.05) that were predicted to be regulated by the three micro-RNAs using miRror 2.0 target prediction tool. In addition, the functional enrichment analysis of these targets that was performed by DAVID functional annotation and REACTOME tools revealed two major immune-related pathways, eight hepatocellular carcinoma hallmarks-linked pathways, and two pathways that mediate interconnected processes between immune system and hepatocellular carcinoma hallmarks. Moreover, protein-protein interaction network for the predicted common targets was obtained by using STRING database. The individual analysis of target genes and pathways for the three micro-RNAs of interest using miRGator V3.0 and GeneTrail servers revealed some novel predicted target oncogenes such as SOX4, which we validated experimentally, in addition to some regulated pathways of immune system and hepatocarcinogenesis such as insulin signaling pathway and adipocytokine signaling pathway. In general, our results demonstrate that let-7a, miR-34a, and miR-199 a/b have novel interactions in different immune system pathways and major hepatocellular carcinoma hallmarks. Thus, our findings shed more light on the roles of these miRNAs as cancer silencers.
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Affiliation(s)
- Bangly Soliman
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt
| | - Ahmed Salem
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed Ghazy
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Nourhan Abu-Shahba
- 3 Stem Cells Research Group, Medical Centre of Excellence, Medical Molecular Genetics Department, National Research Centre, Cairo, Egypt
| | - Mahmoud El Hefnawi
- 2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt.,4 Centre for Informatics, Nile University, Sheikh Zayed City, Egypt
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33
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Cartier F, Indersie E, Lesjean S, Charpentier J, Hooks KB, Ghousein A, Desplat A, Dugot-Senant N, Trézéguet V, Sagliocco F, Hagedorn M, Grosset CF. New tumor suppressor microRNAs target glypican-3 in human liver cancer. Oncotarget 2018; 8:41211-41226. [PMID: 28476031 PMCID: PMC5522324 DOI: 10.18632/oncotarget.17162] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/25/2017] [Indexed: 12/22/2022] Open
Abstract
Glypican-3 (GPC3) is an oncogene, frequently upregulated in liver malignancies such as hepatocellular carcinoma (HCC) and hepatoblastoma and constitutes a potential molecular target for therapy in liver cancer. Using a functional screening system, we identified 10 new microRNAs controlling GPC3 expression in malignant liver cells, five of them e.g. miR-4510, miR-203a-3p, miR-548aa, miR-376b-3p and miR-548v reduce GPC3 expression. These 5 microRNAs were significantly downregulated in tumoral compared to non-tumoral liver and inhibited tumor cell proliferation. Interestingly, miR-4510 inversely correlated with GPC3 mRNA and protein in HCC samples. This microRNA also induced apoptosis of hepatoma cells and blocked tumor growth in vivo in the chick chorioallantoic membrane model. We further show that the tumor suppressive effect of miR-4510 is mediated through direct targeting of GPC3 mRNA and inactivation of Wnt/β-catenin transcriptional activity and signaling pathway. Moreover, miR-4510 up-regulated the expression of several tumor suppressor genes while reducing the expression of other pro-oncogenes. In summary, we uncovered several new microRNAs targeting the oncogenic functions of GPC3. We provided strong molecular, cellular and in vivo evidences for the tumor suppressive activities of miR-4510 bringing to the fore the potential value of this microRNA in HCC therapy.
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Affiliation(s)
- Flora Cartier
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Emilie Indersie
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Sarah Lesjean
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Justine Charpentier
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Katarzyna B Hooks
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Amani Ghousein
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Angélique Desplat
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Nathalie Dugot-Senant
- INSERM US005 - TBM Core, Service for Experimental Histopathology, F-33000 Bordeaux, France
| | - Véronique Trézéguet
- University of Bordeaux, F-33000 Bordeaux, France.,CNRS, UMR5248, Chimie & Biologie des Membranes & des Nano-objets, CBMN, F-33600 Pessac, France
| | - Francis Sagliocco
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Martin Hagedorn
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
| | - Christophe F Grosset
- University of Bordeaux, Inserm, Groupe de Recherche pour l'Etude du Foie, GREF, U1053, F-33076 Bordeaux, France.,University of Bordeaux, Inserm, Biothérapies des Maladies Génétiques Inflammatoires et Cancers, BMGIC, U1035, F-33076 Bordeaux, France
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34
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Liu D, Zhang Y, Wei Y, Liu G, Liu Y, Gao Q, Zou L, Zeng W, Zhang N. Activation of AKT pathway by Nrf2/PDGFA feedback loop contributes to HCC progression. Oncotarget 2018; 7:65389-65402. [PMID: 27588483 PMCID: PMC5323163 DOI: 10.18632/oncotarget.11700] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 08/24/2016] [Indexed: 01/10/2023] Open
Abstract
Nuclear factor erythroid-2-related factor 2 (Nrf2), a master transcription factor in the antioxidant response, has been found to be ubiquitously expressed in various cancer cells and in the regulation tumor proliferation, invasion, and chemoresistance activities. The regulatory roles of Nrf2 in controlling Hepatocellular carcinoma (HCC) progression remain unclear. In this study, we demonstrated that Nrf2 was significantly elevated in HCC cells and tissues and was correlated with poor prognosis of HCCs. Consistently, Nrf2 significantly promoted HCC cell growth both in vitro and in vivo. Further investigation suggested a novel association of Nrf2 with Platelet-Derived Growth Factor-A (PDGFA). Nrf2 promoted PDGFA transcription by recruiting specificity protein 1 (Sp1) to its promoter, resulting in increased activation of the AKT/p21 pathway and cell cycle progression of HCC cells. As a feedback loop, PDGFA enhanced Nrf2 expression and activation in an AKT dependent manner. In line with these findings, expression of Nrf2 and PDGFA were positively correlated in HCC tissues. Taken together, this study uncovers a novel mechanism of the Nrf2/PDGFA regulatory loop that is crucial for AKT-dependent HCC progression, and thereby provides potential targets for HCC therapy.
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Affiliation(s)
- Danyang Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonglong Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yingze Wei
- Department of Pathology, Tumor Hospital of Nantong, Nantong, China
| | - Guoyuan Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yufeng Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qiongmei Gao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Liping Zou
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenjiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Nong Zhang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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35
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Mogler C, König C, Wieland M, Runge A, Besemfelder E, Komljenovic D, Longerich T, Schirmacher P, Augustin HG. Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin. EMBO Mol Med 2018; 9:741-749. [PMID: 28373218 PMCID: PMC5452049 DOI: 10.15252/emmm.201607222] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC‐expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis. Indeed, the histological analysis of human HCC samples revealed an inverse correlation between tumor cell proliferation and stromal endosialin expression. Correspondingly, global genetic inactivation of endosialin resulted in accelerated tumor growth in an inducible mouse HCC model. A candidate‐based screen of tumor lysates and differential protein arrays of cultured HSC identified several established hepatotropic cytokines, including IGF2, RBP4, DKK1, and CCL5 as being negatively regulated by endosialin. Taken together, the experiments identify endosialin‐expressing HSC as a negative regulator of HCC progression.
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Affiliation(s)
- Carolin Mogler
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Institute of Pathology, Heidelberg University, Heidelberg, Germany.,Institute of Pathology, Technical University Munich, Munich, Germany
| | - Courtney König
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Matthias Wieland
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Anja Runge
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Eva Besemfelder
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Dorde Komljenovic
- Department of Medical Physics in Radiology, German Cancer Research Center Heidelberg, Heidelberg, Germany
| | | | | | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany .,Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
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36
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Heldin CH, Lennartsson J, Westermark B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J Intern Med 2018; 283:16-44. [PMID: 28940884 DOI: 10.1111/joim.12690] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins of the receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.
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Affiliation(s)
- C-H Heldin
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.,Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - J Lennartsson
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.,Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - B Westermark
- Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
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37
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Govaere O, Petz M, Wouters J, Vandewynckel YP, Scott EJ, Topal B, Nevens F, Verslype C, Anstee QM, Van Vlierberghe H, Mikulits W, Roskams T. The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma. Oncogene 2017; 36:6605-6616. [PMID: 28783171 PMCID: PMC5702717 DOI: 10.1038/onc.2017.260] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/30/2017] [Accepted: 06/08/2017] [Indexed: 02/07/2023]
Abstract
Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2β1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.
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Affiliation(s)
- O Govaere
- Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK
| | - M Petz
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - J Wouters
- Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Y-P Vandewynckel
- Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium
| | - E J Scott
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK
| | - B Topal
- Department of Abdominal Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - F Nevens
- Department of Hepatology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - C Verslype
- Department of Hepatology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Q M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK
| | - H Van Vlierberghe
- Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium
| | - W Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - T Roskams
- Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
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38
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Liu C, Ren YF, Dong J, Ke MY, Ma F, Monga SPS, Wu R, Lv Y, Zhang XF. Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma. Cancer Lett 2017; 410:20-31. [PMID: 28942012 DOI: 10.1016/j.canlet.2017.09.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 08/31/2017] [Accepted: 09/15/2017] [Indexed: 02/08/2023]
Abstract
Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13.5 months). Overexpression of SRY in male TG and ectopic expression of SRY in female TG livers promoted DEN-induced hepatocarcinogenesis compared to age- and sex-matched WT. This accelerated tumorigenesis in TG of both genders was a consequence of increased injury and inflammation, fibrosis, and compensatory enhancement in hepatocytes proliferation secondary to activation of downstream targets Sox9 and platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFRα pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC.
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Affiliation(s)
- Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Yi-Fan Ren
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Jian Dong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Meng-Yun Ke
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Feng Ma
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Satdarshan P S Monga
- Department of Pathology and Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rongqian Wu
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China.
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China; Shaanxi Provincial Regenerative Medicine and Surgical Engineering Research Center, Xi'an, Shaanxi Province, 710061, China.
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Schachtschneider KM, Schwind RM, Darfour-Oduro KA, De AK, Rund LA, Singh K, Principe DR, Guzman G, Ray CE, Ozer H, Gaba RC, Schook LB. A validated, transitional and translational porcine model of hepatocellular carcinoma. Oncotarget 2017; 8:63620-63634. [PMID: 28969016 PMCID: PMC5609948 DOI: 10.18632/oncotarget.18872] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 06/05/2017] [Indexed: 12/29/2022] Open
Abstract
Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic TP53R167H and KRASG12D, and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including TERT reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.
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Affiliation(s)
- Kyle M. Schachtschneider
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Animal Breeding and Genomics Centre, Wageningen University, Wageningen, The Netherlands
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Regina M. Schwind
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Arun K. De
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Lauretta A. Rund
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Kuldeep Singh
- Veterinary Diagnostic Laboratory, University of Illinois, Urbana, IL, USA
| | - Daniel R. Principe
- College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Charles E. Ray
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA
| | - Howard Ozer
- Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Lawrence B. Schook
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
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Vincenzi B, Badalamenti G, Napolitano A, Spalato Ceruso M, Pantano F, Grignani G, Russo A, Santini D, Aglietta M, Tonini G. Olaratumab: PDGFR-α inhibition as a novel tool in the treatment of advanced soft tissue sarcomas. Crit Rev Oncol Hematol 2017; 118:1-6. [PMID: 28917265 DOI: 10.1016/j.critrevonc.2017.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/06/2017] [Accepted: 06/15/2017] [Indexed: 12/19/2022] Open
Abstract
Advanced soft tissue sarcomas are aggressive cancers with limited therapeutic options. Recently, inhibition of platelet-derived growth factor receptor (PDGFR)-α by the monoclonal antibody olaratumab showed promising clinical activity. If confirmed, this would be one of the first examples of targeted therapy effective in advanced soft tissue sarcomas therapy independently of the histologic subtype. Here, we reviewed the biology of the PDGF/PDGFR axis, particularly focusing on its role in cancer, and then we discussed on the effects of PDGFR-α inhibition in the therapy of advanced soft tissue sarcomas.
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Affiliation(s)
- Bruno Vincenzi
- Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, Palermo University Hospital, Palermo, Italy
| | - Andrea Napolitano
- Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy
| | | | - Francesco Pantano
- Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy
| | - Giovanni Grignani
- Division of Medical Oncology, Candiolo Cancer Institue-FPO, IRCCS, Candiolo, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, Palermo University Hospital, Palermo, Italy.
| | - Daniele Santini
- Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy
| | - Massimo Aglietta
- Candiolo Cancer Institute-IRCCS, Laboratory of Medical Oncology, Experimental Cell Therapy, Candiolo, Turin, Italy
| | - Giuseppe Tonini
- Medical Oncology Department, Campus Bio-Medico, University of Rome, Rome, Italy
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Yu JH, Kim JM, Kim JK, Choi SJ, Lee KS, Lee JW, Chang HY, Lee JI. Platelet-derived growth factor receptor α in hepatocellular carcinoma is a prognostic marker independent of underlying liver cirrhosis. Oncotarget 2017; 8:39534-39546. [PMID: 28465473 PMCID: PMC5503630 DOI: 10.18632/oncotarget.17134] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/22/2017] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND AND AIMS Platelet-derived growth factor receptor alpha (PDGFRα) is suggested as a prognosis marker for hepatocellular carcinoma (HCC). Since PDGFRα is also known as a marker for activated hepatic stellate cells (HSCs), this study aimed to investigate whether PDGFRα expression in HCC was dependent on the background liver fibrous condition. RESULTS Strong PDGFRα expression in the tumor lesions was associated with decreased survival after curative HCC resection. Expression of PDGFRα in the tumor correlated with increased collagen α1(I), lecithin retinol acyltransferase, and smooth muscle α-actin suggesting increased HSCs in tumor sites. The expression of PDGFRα in the tumor sites was associated neither with underlying liver fibrosis/cirrhosis nor with the expression of PDGFRα in adjacent non-tumor sites of the liver. MATERIALS AND METHODS Patients with HCC who underwent liver resection as curative treatment were included in this study. Using liver samples of 95 patients, tissue microarray was constructed and immunohistochemical study of PDGFRα was conducted in both tumor and non-tumor sites. PDGFRα expression in tumor and matching non-tumor sites was compared. Freshly frozen liver tissue specimens of 16 HCC patients were used for gene expression analysis of PDGFRα and fibrosis related genes. CONCLUSIONS Our results suggest that PDGFRα overexpression in HCC is a prognostic marker independent of adjacent non-tumor site liver fibrosis status.
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Affiliation(s)
- Jung-Hwan Yu
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Republic of Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Suk Jin Choi
- Department of Pathology, Inha University School of Medicine, Incheon, Republic of Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea
| | - Hye Young Chang
- Medical Research Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget 2017; 8:55715-55730. [PMID: 28903454 PMCID: PMC5589693 DOI: 10.18632/oncotarget.18382] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients.
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Ma Y, Han CC, Li Y, Wang Y, Wei W. Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells by controlling bFGF and PDGF autocrine/paracrine loops. Biochem Biophys Res Commun 2016; 478:964-9. [DOI: 10.1016/j.bbrc.2016.08.059] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 08/09/2016] [Indexed: 01/04/2023]
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Differences in Dural Penetration of Clival Chordomas Are Associated with Different Prognosis and Expression of Platelet-Derived Growth Factor Receptor-β. World Neurosurg 2016; 98:288-295. [PMID: 27506406 DOI: 10.1016/j.wneu.2016.07.096] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 07/24/2016] [Accepted: 07/27/2016] [Indexed: 11/23/2022]
Abstract
OBJECTIVE We sought to compare the prognosis of clival chordomas with different dural penetration and establish the relationship between dural penetration and platelet-derived growth factor receptor (PDGFR)-β signaling pathway. METHODS Tumors in Type I (33 cases) showed limited dural penetration, while those in Type II (34 cases) had more serious dural penetration. Cox multivariate regression analysis was used to analyze risk factors affecting survival. Kaplan-Meier analysis measured overall survival (OS) and progression-free survival (PFS). To determine the relationship between dural penetration and PDGFR-β signaling, expression of PDGFR-β, Akt, mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) expression was compared using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blotting. RESULTS Total resection was achieved in 9 cases in Type I and 11 in Type II. There were significant correlations between OS and dural penetration (P = 0.032) and age (P = 0.034). PFS correlated significantly with dural penetration (P = 0.022), gender (P = 0.001), and degree of resection (P = 0.001). Mean OS in Type I was significantly longer than in Type II (P = 0.046). Patients aged <55 years had longer OS than those aged ≥55 years (P = 0.004). Total resection was correlated with longer PFS (P = 0.011). Among patients with tumors totally resected, mean PFS in Type I was significantly longer than in Type II (P = 0.007). Expression of PDGFR-β in Type II was higher than in Type I. CONCLUSIONS Clival chordomas have different degrees of dural penetration. Patients with chordomas with serious dural penetration have poorer prognosis. Higher expression of PDGFR-β is related to more serious dural penetration of clival chordomas.
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PDGF-D/PDGFRβ promotes tongue squamous carcinoma cell (TSCC) progression via activating p38/AKT/ERK/EMT signal pathway. Biochem Biophys Res Commun 2016; 478:845-51. [PMID: 27507215 DOI: 10.1016/j.bbrc.2016.08.035] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/05/2016] [Indexed: 01/07/2023]
Abstract
Platelet-derived growth factor D (PDGF-D) signaling plays significant roles during the development and progression of human malignancies via interacting with the receptor of PDGF-D (PDGFR). Meanwhile, the majority of human tumor metastasis is closely associated with epithelial-mesenchymal transition (EMT). However, the underlying mechanism between PDGF-D/PDGFR signaling and EMT which involved in tumor metastasis remain dismal. This study aimed to investigate the role of PDGF-D signaling during EMT process of tongue squamous cell carcinoma (TSCC). In our study, the expression of PDGF-D and PDGFR were examined in primary TSCC samples and the expression of PDGF-D was also determined in TSCC cell lines. In addition, the correlation between PDGF-D expression and TSCC aggressive histopathological features was analyzed. Our results implied that upregulation of PDGFRβ in UM1 cells induced with exogenous PDGF-D can remarkably promote tumor cells invasiveness; conversely, when using small interfering RNA (siRNA), the invasiveness can be severely prohibited. Furthermore, PDGF-D downstream signal molecules p38, AKT, ERK and EMT biomarkers (E-cadherin, N-cadherin, Vimentin and snail) were measured using Western blot. Our results showed that PDGF-D can induce p38, AKT and ERK phosphorylation; downregulate epithelial markers and upregulate mesenchymal markers. On the contrary, PDGFRβ siRNA significantly prohibited p38, AKT and ERK phosphorylation; inhibited EMT process. Function analysis revealed that PDGFRβ siRNA obviously interfered with UM1 cell migration and invasion, according to transwell and wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the PDGF-D/PDGFRβ axis in TSCC, and then involved in the tumor cell invasion via activation of p38/AKT/ERK/EMT pathway.
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46
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Wang P, Xu J, Hou Z, Wang F, Song Y, Wang J, Zhu H, Jin H. miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA. Cell Prolif 2016; 49:484-93. [PMID: 27302634 DOI: 10.1111/cpr.12265] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/07/2016] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Pulmonary arterial hypertension (PAH) is a fast progressing vascular disease characterized by uncontrolled cell proliferation of pulmonary artery smooth muscle cells (PASMCs). Some studies have suggested that PAH and cancers share an apoptosis-resistant state, featuring excessive cell proliferation. The miR-34 family consists of tumour-suppressive miRNAs, and its reduced expression has been reported in numerous cancers; however, its role in hypoxia-induced PAH has not been previously studied. MATERIALS AND METHODS miR-34 family expression was evaluated in a rat model with hypoxia and in cultured hypoxic PASMCs, using real-time quantitative PCR (RT-qPCR). Function of miR-34 family was assessed by transfecting miR-34 mimics and inhibitors. Dual luciferase reporter gene assays, RT-qPCR and Western blotting were performed to validate target genes of miR-34. RESULTS Significant down-regulation of miR-34a in hypoxic lung tissue, pulmonary artery and PASMCs was identified and then effects of miR-34a in modulating cell proliferation in human pulmonary artery smooth muscle cells (hPASMCs) was investigated in vitro. Reduction of miR-34a levels in hPASMCs caused increased proliferation and these effects were reversed by overexpression of miR-34a. miR-34a overexpression down-regulated platelet-derived growth factor receptor alpha (PDGFRA) expression, which is a key factor in PAH development. These results suggest that miR-34a is a potential regulator of proliferation in PASMCs, and that it could be used as a novel treatment strategy in PAH.
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Affiliation(s)
- Peng Wang
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.,Department of Physiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, China
| | - Jie Xu
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Zhiling Hou
- Department of Emergency Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Fangfang Wang
- Department of Pathophysiology, College of Basic Medical Sciences, Jiamusi University, Jiamusi, China
| | - Yingli Song
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Jiao Wang
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Hui Zhu
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Hongbo Jin
- Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China
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Hu PH, Pan LH, Wong PTY, Chen WH, Yang YQ, Wang H, Xiang JJ, Xu M. 125I-labeled anti-bFGF monoclonal antibody inhibits growth of hepatocellular carcinoma. World J Gastroenterol 2016; 22:5033-5041. [PMID: 27275095 PMCID: PMC4886378 DOI: 10.3748/wjg.v22.i21.5033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/14/2016] [Accepted: 03/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory efficacy of 125I-labeled anti-basic fibroblast growth factor (bFGF) monoclonal antibody (mAb) in hepatocellular carcinoma (HCC).
METHODS: bFGF mAb was prepared by using the 1G9B9 hybridoma cell line with hybridization technology and extracted from ascites fluid through a Protein G Sepharose affinity column. After labeling with 125I through the chloramine-T method, bFGF mAb was further purified by a Sephadex G-25 column. Gamma radiation counter GC-1200 detected radioactivity of 125I-bFGF mAb. The murine H22 HCC xenograft model was established and randomized to interventions with control (phosphate-buffered saline), 125I-bFGF mAb, 125I plus bFGF mAb, bFGF mAb, or 125I. The ratios of tumor inhibition were then calculated. Expression of bFGF, fibroblast growth factor receptor (FGFR), platelet-derived growth factor, and vascular endothelial growth factor (VEGF) mRNA was determined by quantitative reverse transcriptase real-time polymerase chain reaction.
RESULTS: The purified bFGF mAb solution was 8.145 mg/mL with a titer of 1:2560000 and was stored at -20 °C. After coupling, 125I-bFGF mAb was used at a 1: 1280000 dilution, stored at 4 °C, and its specific radioactivity was 37 MBq/mg. The corresponding tumor weight in the control, 125I, bFGF mAb, 125I plus bFGF mAb, and 125I-bFGF mAb groups was 1.88 ± 0.25, 1.625 ± 0.21, 1.5 ± 0.18, 1.41 ± 0.16, and 0.98 ± 0.11 g, respectively. The tumor inhibition ratio in the 125I, bFGF mAb, 125I plus bFGF mAb, and 125I-bFGF mAb groups was 13.6%, 20.2%, 25.1%, and 47.9%, respectively. Growth of HCC xenografts was inhibited significantly more in the 125I-bFGF mAb group than in the other groups (P < 0.05). Expression of bFGF and FGFR mRNA in the 125I-bFGF mAb group was significantly decreased in comparison with other groups (P < 0.05). Groups under interventions revealed increased expression of VEGF mRNA (except for 125I group) compared with the control group.
CONCLUSION: 125I-bFGF mAb inhibits growth of HCC xenografts. The coupling effect of 125I-bFGF mAb is more effective than the concomitant use of 125I and bFGF mAb.
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MESH Headings
- Animals
- Antibodies, Monoclonal/metabolism
- Antibodies, Monoclonal/pharmacology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/radiotherapy
- Cell Line, Tumor
- Cell Proliferation/radiation effects
- Fibroblast Growth Factor 2/immunology
- Fibroblast Growth Factor 2/metabolism
- Gene Expression Regulation, Neoplastic
- Hybridomas
- Iodine Radioisotopes/pharmacology
- Liver Neoplasms, Experimental/immunology
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/radiotherapy
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Platelet-Derived Growth Factor/genetics
- Platelet-Derived Growth Factor/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Radioimmunotherapy/methods
- Radiopharmaceuticals/pharmacology
- Real-Time Polymerase Chain Reaction
- Receptors, Fibroblast Growth Factor/genetics
- Receptors, Fibroblast Growth Factor/metabolism
- Receptors, Vascular Endothelial Growth Factor/genetics
- Receptors, Vascular Endothelial Growth Factor/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Burden/radiation effects
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Liang C, Li Y, Luo J. A Novel Method to Detect Functional microRNA Regulatory Modules by Bicliques Merging. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2016; 13:549-556. [PMID: 27295638 DOI: 10.1109/tcbb.2015.2462370] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
UNLABELLED MicroRNAs (miRNAs) are post-transcriptional regulators that repress the expression of their targets. They are known to work cooperatively with genes and play important roles in numerous cellular processes. Identification of miRNA regulatory modules (MRMs) would aid deciphering the combinatorial effects derived from the many-to-many regulatory relationships in complex cellular systems. Here, we develop an effective method called BiCliques Merging (BCM) to predict MRMs based on bicliques merging. By integrating the miRNA/mRNA expression profiles from The Cancer Genome Atlas (TCGA) with the computational target predictions, we construct a weighted miRNA regulatory network for module discovery. The maximal bicliques detected in the network are statistically evaluated and filtered accordingly. We then employed a greedy-based strategy to iteratively merge the remaining bicliques according to their overlaps together with edge weights and the gene-gene interactions. Comparing with existing methods on two cancer datasets from TCGA, we showed that the modules identified by our method are more densely connected and functionally enriched. Moreover, our predicted modules are more enriched for miRNA families and the miRNA-mRNA pairs within the modules are more negatively correlated. Finally, several potential prognostic modules are revealed by Kaplan-Meier survival analysis and breast cancer subtype analysis. AVAILABILITY BCM is implemented in Java and available for download in the supplementary materials, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/ TCBB.2015.2462370.
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