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Godizzi F, Armando F, Boracchi P, Avallone G, Stefanello D, Ferrari R, Chiti LE, Cappelleri A, Zamboni C, Dell'Aere S, Corradi A, Roccabianca P. Survivin, β-catenin, and ki-67 immunohistochemical expression in canine perivascular wall tumors: Preliminary assessment of prognostic significance. Vet Pathol 2024; 61:912-927. [PMID: 38727195 DOI: 10.1177/03009858241246981] [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: 11/05/2024]
Abstract
High survivin expression has been correlated with poor outcomes in several canine tumors but not in soft tissue tumors (STTs). Survivin is a target gene of the Wnt/β-catenin pathway, which is involved in human STT oncogenesis. Immunohistochemistry for survivin, β-catenin, and Ki-67 was performed on 41 canine perivascular wall tumors (cPWTs), and statistical associations of protein expression and histopathologic and clinical variables with clinical outcomes were investigated. Immunohistochemically, there was nuclear positivity (0.9%-12.2% of tumor cells) for survivin in 41/41 (100%), cytoplasmic positivity (0 to > 75% of tumor cells) for survivin in 31/41 (76%), nuclear positivity (2.9%-67.2% of tumor cells) for β-catenin in 24/41 (59%), and cytoplasmic positivity (0% to > 75% of tumor cells) for β-catenin in 23/41 (56%) of cPWTs. All tumors expressed nuclear Ki-67 (2.2%-23.5%). In univariate analysis and multivariate analysis (UA and MA, respectively), every 1% increase of nuclear survivin was associated with an increase of the instantaneous death risk by a factor of 1.15 [hazard ratio (HR) = 1.15; P = .007]. Higher nuclear survivin was associated with grade II/III neoplasms (P = .043). Expression of cytoplasmic survivin, nuclear and cytoplasmic β-catenin, and nuclear Ki-67 were not significantly associated with prognosis in UA nor MA. Tumor size was a significant prognostic factor for local recurrence in UA [subdistribution HR (SDHR) = 1.19; P = .02] and for reduced overall survival time in MA. According to UA and MA, a unitary increase of mitotic count was associated with an increase of the instantaneous death risk by a factor of 1.05 (HR = 1.05; P = .014). Nuclear survivin, mitotic count, and tumor size seem to be potential prognostic factors for cPWTs. In addition, survivin and β-catenin may represent promising therapeutic targets for cPWTs.
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Affiliation(s)
- Francesco Godizzi
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine, Foundation, Hannover, Germany
| | - Patrizia Boracchi
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Giancarlo Avallone
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Italy
| | - Damiano Stefanello
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Roberta Ferrari
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Lavinia E Chiti
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Andrea Cappelleri
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
- Mouse and Animal Pathology Laboratory (MAPLab), Fondazione UniMi, Milan, Italy
| | - Clarissa Zamboni
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Silvia Dell'Aere
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Attilio Corradi
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Paola Roccabianca
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
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Liu N, Li Y, Luo G, Jiang M, Liu C, Zhang Y, Zhang L. SIRT6 suppresses colon cancer growth by inducing apoptosis and autophagy through transcriptionally down-regulating Survivin. Mitochondrion 2024; 78:101932. [PMID: 38986922 DOI: 10.1016/j.mito.2024.101932] [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: 08/30/2023] [Revised: 06/28/2024] [Accepted: 07/07/2024] [Indexed: 07/12/2024]
Abstract
SIRT6, an evolutionarily conserved histone deacetylase, has been identified as a novel direct downstream target of Akt/FoxO3a and a tumor suppressor in colon cancer in our previous research. Nevertheless, the precise mechanisms through which SIRT6 hinders tumor development remain unclear. To ascertain whether SIRT6 directly impacts Survivin transcription, a ChIP assay was conducted using an anti-SIRT6 antibody to isolate DNA. YM155 was synthesized to explore Survivin's role in mitochondrial apoptosis, autophagy and tumor progression. Our investigation into the regulation of Survivin involved real-time fluorescence imaging in living cells, real-time PCR, immunohistochemistry, flow cytometry, and xenograft mouse assays. In this current study, we delved into the role of SIRT6 in colon cancer and established that activated SIRT6 triggers mitochondrial apoptosis by reducing Survivin expression. Subsequent examinations revealed that SIRT6 directly binds to the Survivin promoter, impeding its transcription. Notably, direct inhibition of Survivin significantly impeded colon cancer proliferation by inducing mitochondrial apoptosis and autophagy both in vitro and in vivo. More interestingly, Survivin inhibition reactivated the Akt/FoxO3a pathway and elevated SIRT6 levels, establishing a positive feedback loop. Our results identify Survivin as a novel downstream transcriptional target of SIRT6 that fosters tumor growth and holds promise as a prospective target for colon cancer therapy.
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Affiliation(s)
- Nannan Liu
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China; School of Biomedical Sciences, Hunan University, Changsha, China
| | - Yanqiu Li
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Guang Luo
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Meimei Jiang
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Chun Liu
- Department of Respirology & Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yingjie Zhang
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China; School of Biomedical Sciences, Hunan University, Changsha, China
| | - Lingling Zhang
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
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Li Q, Liu H, Wang H, Xiong W, Dai L, Zhang X, Wang P, Ye H, Shi J, Fang Z, Wang K. Anti-BIRC5 autoantibody serves as a valuable biomarker for diagnosing AFP-negative hepatocellular carcinoma. PeerJ 2024; 12:e17494. [PMID: 38832035 PMCID: PMC11146321 DOI: 10.7717/peerj.17494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/09/2024] [Indexed: 06/05/2024] Open
Abstract
Background Autoantibodies targeting tumor-associated antigens (TAAbs) have emerged as promising biomarkers for early cancer detection. This research aimed to assess the diagnostic capacity of anti-BIRC5 autoantibody in detecting AFP-negative hepatocellular carcinoma (ANHCC). Methods This research was carried out in three stages (discovery phase, validation phase, and evaluation phase) and included a total of 744 participants. Firstly, the anti-BIRC5 autoantibody was discovered using protein microarray, exhibiting a higher positive rate in ANHCC samples (ANHCCs) compared to normal control samples (NCs). Secondly, the anti-BIRC5 autoantibody was validated through enzyme-linked immunosorbent assay (ELISA) in 85 ANHCCs and 85 NCs from two clinical centers (Zhengzhou and Nanchang). Lastly, the diagnostic usefulness of the anti-BIRC5 autoantibody for hepatocellular carcinoma (HCC) was evaluated by ELISA in a cohort consisting of an additional 149 AFP-positive hepatocellular carcinoma samples (APHCCs), 95 ANHCCs and 244 NCs. The association of elevated autoantibody to high expression of BIRC5 in HCC was further explored by the database from prognosis, immune infiltration, DNA methylation, and gene mutation level. Results In the validation phase, the area under the ROC curve (AUC) of anti-BIRC5 autoantibody to distinguish ANHCCs from NCs in Zhengzhou and Nanchang centers was 0.733 and 0.745, respectively. In the evaluation phase, the AUCs of anti-BIRC5 autoantibody for identifying ANHCCs and HCCs from NCs were 0.738 and 0.726, respectively. Furthermore, when combined with AFP, the AUC for identifying HCCs from NCs increased to 0.914 with a sensitivity of 77.5% and specificity of 91.8%. High expression of BIRC5 gene is not only correlated with poor prognosis of HCCs, but also significantly associated with infiltration of immune cells, DNA methylation, and gene mutation. Conclusion The findings suggest that the anti-BIRC5 autoantibody could serve as a potential biomarker for ANHCC, in addition to its supplementary role alongside AFP in the diagnosis of HCC. Next, we can carry out specific verification and explore the function of anti-BIRC5 autoantibody in the occurrence and development of HCC.
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Affiliation(s)
- Qing Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Haiyan Liu
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Han Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenzhuo Xiong
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Liping Dai
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Xiuzhi Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
- Department of Pathology, Henan Medical College, Zhengzhou, Henan, China
| | - Peng Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Ye
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jianxiang Shi
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Zhihao Fang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Keyan Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
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Biber JC, Sullivan A, Brazzo JA, Heo Y, Tumenbayar BI, Krajnik A, Poppenberg KE, Tutino VM, Heo SJ, Kolega J, Lee K, Bae Y. Survivin as a mediator of stiffness-induced cell cycle progression and proliferation of vascular smooth muscle cells. APL Bioeng 2023; 7:046108. [PMID: 37915752 PMCID: PMC10618027 DOI: 10.1063/5.0150532] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 10/05/2023] [Indexed: 11/03/2023] Open
Abstract
Stiffened arteries are a pathology of atherosclerosis, hypertension, and coronary artery disease and a key risk factor for cardiovascular disease events. The increased stiffness of arteries triggers a phenotypic switch, hypermigration, and hyperproliferation of vascular smooth muscle cells (VSMCs), leading to neointimal hyperplasia and accelerated neointima formation. However, the mechanism underlying this trigger remains unknown. Our analyses of whole-transcriptome microarray data from mouse VSMCs cultured on stiff hydrogels simulating arterial pathology identified 623 genes that were significantly and differentially expressed (360 upregulated and 263 downregulated) relative to expression in VSMCs cultured on soft hydrogels. Functional enrichment and gene network analyses revealed that these stiffness-sensitive genes are linked to cell cycle progression and proliferation. Importantly, we found that survivin, an inhibitor of apoptosis protein, mediates stiffness-dependent cell cycle progression and proliferation as determined by gene network and pathway analyses, RT-qPCR, immunoblotting, and cell proliferation assays. Furthermore, we found that inhibition of cell cycle progression did not reduce survivin expression, suggesting that survivin functions as an upstream regulator of cell cycle progression and proliferation in response to ECM stiffness. Mechanistically, we found that the stiffness signal is mechanotransduced via the FAK-E2F1 signaling axis to regulate survivin expression, establishing a regulatory pathway for how the stiffness of the cellular microenvironment affects VSMC behaviors. Overall, our findings indicate that survivin is necessary for VSMC cycling and proliferation and plays a role in regulating stiffness-responsive phenotypes.
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Affiliation(s)
- John C. Biber
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA
| | - Andra Sullivan
- Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, New York 14260, USA
| | - Joseph A. Brazzo
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA
| | | | - Bat-Ider Tumenbayar
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA
| | - Amanda Krajnik
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA
| | | | | | - Su-Jin Heo
- Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - John Kolega
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA
| | - Kwonmoo Lee
- Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Yongho Bae
- Author to whom correspondence should be addressed:
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Liu Y, Chen X, Luo W, Zhao Y, Nashan B, Huang L, Yuan X. Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid-derived suppressor cells in hepatocellular carcinoma. Cancer Med 2023; 12:16370-16385. [PMID: 37326143 PMCID: PMC10469657 DOI: 10.1002/cam4.6271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Preclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC). METHOD AND RESULTS Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC. CONCLUSION Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.
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Affiliation(s)
- Yun Liu
- Department of Radiation Oncology, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Xi Chen
- Department of Gastrointestinal Oncology Surgery, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Wenwu Luo
- Department of PathologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Yufei Zhao
- Department of Radiation Oncology, Anhui Provincial Cancer HospitalThe First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Björn Nashan
- Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTCDivision of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
| | - Lei Huang
- Department of OncologyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Medical Center on Aging of Ruijin Hospital, MCARJH, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Xiaodong Yuan
- Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTCDivision of Life Sciences and Medicine, University of Science and Technology of ChinaHefeiChina
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Demirci NS, Çavdar E, Erdem GU, Hatipoglu E, Celik E, Sezer S, Yolcu A, Dogan M, Seber ES. Is the serum level of survivin, an antiapoptotic protein, a potential predictive and prognostic biomarker in metastatic pancreatic cancer? Medicine (Baltimore) 2023; 102:e34014. [PMID: 37352081 PMCID: PMC10289789 DOI: 10.1097/md.0000000000034014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/15/2023] [Accepted: 05/25/2023] [Indexed: 06/25/2023] Open
Abstract
In the present study, we aimed to assess the association between the serum survivin level and overall survival and treatment response rates in metastatic pancreatic cancer (MPC). Serum samples were prospectively collected from 41 patients with newly diagnosed MPC patients and 41 healthy individuals (control group) to assess the survivin levels. The median survivin level was 136.2 ng/mL in patients with MPC and 52 ng/mL in healthy individuals (P = .028). Patients were divided into low- and high-survivin groups according to the baseline median survivin level. Patients with a high serum survivin level compared with a low serum survivin level had shorter median progression-free survival (2.39 vs 7.06 months; P = .008, respectively) and overall survival (3.74 vs 9.52 months; P = .026, respectively). Patients with higher serum survivin levels had significantly worse response rates (P = .007). The baseline high level of serum survivin in patients with MPC may be associated with treatment resistance and poor prognosis. A confirmation will be needed for these results in future large multicenter prospective studies.
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Affiliation(s)
- Nebi Serkan Demirci
- Department of Medical Oncology, Faculty of Medicine, Istanbul University-Cerrahpasa Cerrahpasa, Turkey
| | - Eyyüp Çavdar
- Department of Oncology, Faculty of Medicine, Tekirdag Namik Kemal University, Turkey
| | - Gokmen Umut Erdem
- Department of Medical Oncology, Başakşehir Çam and Sakura City Hospital, Turkey
| | - Engin Hatipoglu
- Department of General Surgery, Faculty of Medicine, Istanbul University-Cerrahpasa Cerrahpasa, Turkey
| | - Emir Celik
- Department of Medical Oncology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences, Turkey
| | - Sevilay Sezer
- Department of Biochemistry, Ministry of Health Ankara City Hospital, Turkey
| | - Ahmet Yolcu
- Department of Radiation Oncology, Tekirdag Namik Kemal University Faculty of Medicine, Turkey
| | - Mutlu Dogan
- Department of Medical Oncology, Ankara Oncology Training and Research Hospital, Turkey
| | - Erdogan Selcuk Seber
- Department of Oncology, Faculty of Medicine, Tekirdag Namik Kemal University, Turkey
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Yesupatham ST, Dayanand CD, Azeem Mohiyuddin SM, Harendra Kumar ML. An Insight into Survivin in Relevance to Hematological, Biochemical and Genetic Characteristics in Tobacco Chewers with Oral Squamous Cell Carcinoma. Cells 2023; 12:1444. [PMID: 37408277 PMCID: PMC10217417 DOI: 10.3390/cells12101444] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Survivin is an inhibitor of apoptosis protein (IAP), encoded by the Baculoviral IAP Repeat Containing 5 (BIRC5) gene located on q arm (25.3) on chromosome 17. It is expressed in various human cancers and involved in tumor resistance to radiation and chemotherapy. The genetic analysis of the BIRC5 gene and its protein survivin levels in buccal tissue related to oral squamous cell carcinoma (OSCC) in South Indian tobacco chewers has not been studied. Hence, the study was designed to quantify survivin in buccal tissue and its association with pretreatment hematological parameters and to analyze the BIRC5 gene sequence. METHOD In a single centric case control study, buccal tissue survivin levels were measured by ELISA. A total of 189 study subjects were categorized into Group 1 (n = 63) habitual tobacco chewers with OSCC, Group 2 (n = 63) habitual tobacco chewers without OSCC, and Group 3 (n = 63) healthy subjects as control. Retrospective hematological data were collected from Group 1 subjects and statistically analyzed. The BIRC5 gene was sequenced and data were analyzed using a bioinformatics tool. RESULTS Survivin protein mean ± SD in Group 1 was (1670.9 ± 796.21 pg/mL), in Group 2 it was (1096.02 ± 346.17 pg/mL), and in Group 3 it was (397.5 ± 96.1 pg/mL) with significance (p < 0.001). Survivin levels showed significance with cut-off levels of absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and lymphocyte/monocyte ratio (LMR) at (p = 0.001). The unique variants found only in OSCC patients were T → G in the promoter region, G → C in exon 3, C → A, A → G, G → T, T → G, A → C, G → A in exon 4, C → A, G → T, G → C in the exon 5 region. CONCLUSIONS The tissue survivin level increased in OSCC patients compared to controls; pretreatment AMC, LMR, and NLR may serve as add-on markers along with survivin to measure the progression of OSCC. Unique mutations in the promoter and exons 3-5 were observed in sequence analysis and were associated with survivin concentrations.
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Affiliation(s)
- Susanna Theophilus Yesupatham
- Department of Biochemistry, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India;
| | - C. D. Dayanand
- Allied Health and Basic Sciences, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - S. M. Azeem Mohiyuddin
- Department of Otorhinolaryngology and Head and Neck Surgery, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - M. L. Harendra Kumar
- Department of Pathology, Shridevi Institute of Medical Sciences and Research Hospital, Sira Road, Tumakuru 572106, Karnataka, India
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Wen K, Yang F, Hu L, Shi J, Mui S, Wang W, Liao H, Li H, Xiao Z, Yan Y. Analysis of the potential association between ferroptosis and immune in hepatocellular carcinoma and their relationship with prognosis. Front Oncol 2023; 12:1031156. [PMID: 36776357 PMCID: PMC9910086 DOI: 10.3389/fonc.2022.1031156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/20/2022] [Indexed: 01/27/2023] Open
Abstract
Background The development of targeted therapy and immunotherapy has enriched the treatment of hepatocellular carcinoma (HCC), however, have had poor or no reponse, or even no response. Previous research suggested that ferroptosis and tumor immune microenvironment (TIME) may have a fundamental impact on efficacy during HCC immunotherapy and targeted therapy. Therefore, there is a clinical need to develop a signature that categorizes HCC patients in order to make more accurate clinical decisions. Methods Clinical data and gene expression data of HCC patients were obtained from The Cancer Genome Atlas (TCGA) portal and International Cancer Genome Consortium (ICGC) portal. To identify ferroptosis-related immune-related genes (ferroptosis-related IRGs), Pearson correlation analysis was conducted. The ferroptosis-related IRGs prognostic signature (FIPS) was constructed using Univariate Cox and LASSO Cox algorithms. The predictive effectiveness of FIPS was evaluated using Receiver Operating Characteristic (ROC) curves and survivorship curve. The correlation ship between FIPS and TIME was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. The relationship between FIPS and immunotherapy responsiveness was evaluated using immunophenoscore. The expression level of 10 ferroptosis-related IRGs in normal liver tissues and HCC tissues was compared using immunohistochemistry. Finally, we established a nomogram (based on FIPS, TNM stage, and age) for clinical application. Results The FIPS was established with ten ferroptosis-related IRGs. The high-FIPS subgroup showed a poor clinical prognosis and an obviously higher proportion of HCC patients with advanced TNM stage, high WHO grade and high alpha fetoprotein(AFP) value. Analysis of TIME indicated that patients in the high-FIPS subgroup may be in immunosuppressed state. Meanwhile, we found that ferroptosis may be inhibited in the high-FIPS subgroup and this subgroup may be impervious to immunotherapy and sorafenib. Conclusion We constructed a novel potential prognostic signature for HCC patients that predicts overall survival, ferroptosis and immune status, sorafenib sensitivity, and immunotherapy responsiveness.
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Affiliation(s)
- Kai Wen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Feng Yang
- Department of General Surgery, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, China
| | - Lei Hu
- Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Sintim Mui
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Weidong Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hao Liao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huoming Li
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China,*Correspondence: Zhiyu Xiao, ; Yongcong Yan,
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China,*Correspondence: Zhiyu Xiao, ; Yongcong Yan,
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Izquierdo AG, Carreira MC, Rodriguez-Carnero G, Perez-Lois R, Seoane LM, Casanueva FF, Crujeiras AB. Gender Dimorphism in Hepatic Carcinogenesis-Related Gene Expression Associated with Obesity as a Low-Grade Chronic Inflammatory Disease. Int J Mol Sci 2022; 23:ijms232315002. [PMID: 36499327 PMCID: PMC9739425 DOI: 10.3390/ijms232315002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/23/2022] [Accepted: 11/26/2022] [Indexed: 12/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) show clear evidence of sexual dimorphism, with a significantly higher incidence in males. Among the determining factors that could explain this sex-based difference, the specific distribution of fat by sex has been suggested as a primary candidate, since obesity is a relevant risk factor. In this context, obesity, considered a low-grade chronic inflammatory pathology and responsible for the promotion of liver disease, could lead to sexual dimorphism in the expression profile of genes related to tumor development. When we compared the expression levels of genes associated with the early stages of carcinogenesis in the liver between male and female diet-induced obesity (DIO) rats, we observed that the expression pattern was similar in obese male and female animals. Interestingly, the SURVIVIN/BIRC5 oncogene showed a higher expression in male DIO rats than in female DIO and lean rats. This trend related to sexual dimorphism was observed in leukocytes from patients with obesity, although the difference was not statistically significant. In conclusion, this study evidenced a similar pattern in the expression of most carcinogenesis-related genes in the liver, except SUVIVIN/BIRC5, which could be a predictive biomarker of liver carcinogenesis predisposition in male patients with obesity.
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Affiliation(s)
- Andrea G. Izquierdo
- Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Marcos C. Carreira
- CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
- Molecular Endocrinology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Gemma Rodriguez-Carnero
- Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Raquel Perez-Lois
- Endocrine Physiopathology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Luisa M. Seoane
- CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
- Endocrine Physiopathology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Felipe F. Casanueva
- CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
- Molecular Endocrinology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Ana B. Crujeiras
- Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
- CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
- Correspondence: or ; Tel.: +34-981-955-710
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10
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Sartorius K, Antwi SO, Chuturgoon A, Roberts LR, Kramvis A. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality? Front Oncol 2022; 12:891812. [PMID: 35600358 PMCID: PMC9115561 DOI: 10.3389/fonc.2022.891812] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Department of Surgery, KZN Kwazulu-Natal (UKZN) Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Samuel O Antwi
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Lewis R Roberts
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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11
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Zhao Y, Li C, Zhang Y, Li Z. CircTMTC1 contributes to nasopharyngeal carcinoma progression through targeting miR-495-MET-eIF4G1 translational regulation axis. Cell Death Dis 2022; 13:250. [PMID: 35301291 PMCID: PMC8930977 DOI: 10.1038/s41419-022-04686-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/20/2021] [Accepted: 02/24/2022] [Indexed: 02/07/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is the most common primary malignancy arising from the epithelial cells of nasopharynx. CircTMTC1 is upregulated in NPC patients, but its role and molecular mechanism in NPC are unknown. Normal nasopharyngeal epithelium and tumor tissues were collected. The expression of circTMTC1, miR-495, MET/eIF4G1 pathway-related molecules were examined. Colony formation and transwell assays were used to assess cell proliferation, migration, and invasion. Cell apoptosis was analyzed by annexin V and propidium iodide (PI) staining. Gene interaction was examined by RNA immunoprecipitation (RIP) and luciferase activity assays. Subcutaneous and intravenous xenograft mouse models were established to analyze NPC growth and metastasis in vivo. CircTMTC1 was highly expressed and miR-495 was downregulated in NPC, which were associated with poor prognosis of NPC. Both circTMTC1 knockdown and miR-495 overexpression inhibited NPC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) and promoted cell apoptosis. CircTMTC1 directly targeted miR-495 to promote the expression of its downstream target gene MET. miR-495 knockdown enhanced the expression of c-Myc, Cyclin D1, and survivin and accelerated NPC cell proliferation, migration, invasion, and EMT through targeting MET and activating the MET-eIF4G1 axis. CircTMTC1 silence inhibited NPC growth and lung metastasis by targeting the miR-495-MET-eIF4G1 translational regulation axis in vivo. CircTMTC1 accelerates NPC progression through targeting miR-495 and consequently activating the MET-eIF4G1 translational regulation axis, suggesting potential therapeutic targets for NPC treatment.
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Affiliation(s)
- Yajie Zhao
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China
| | - Chao Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China
| | - Yan Zhang
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, Henan Province, P. R. China
| | - Zhanzhan Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China.
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12
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Kim CH, Kim OH, Park JH, Kim SJ. A novel strategy to promote liver regeneration: utilization of secretome obtained from survivin-overexpressing adipose-derived stem cells. Ann Surg Treat Res 2021; 101:322-331. [PMID: 34934759 PMCID: PMC8651986 DOI: 10.4174/astr.2021.101.6.322] [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: 08/02/2021] [Revised: 09/01/2021] [Accepted: 10/19/2021] [Indexed: 12/02/2022] Open
Abstract
Purpose Survivin is a typical antiapoptotic protein. It is copiously expressed during human fetal development but is infrequently present in adult tissues. In this experiment, we researched the treatment effect of the secretome that adipose-derived stem cells (ASCs) transfected with survivin. Methods First of all, we generated survivin-overexpressing ASCs transfected with a plasmid comprising a gene encoding survivin. The secreted substances released from survivin-overexpressing ASCs (survivin-secretome) were collected, and were determined their in vitro and in vivo therapeutic potential, especially in the model of liver impairment. Results In vitro, the survivin-secretome significantly increased cell viability and promoted the expression of proliferation-related markers (proliferating cell nuclear antigen [PCNA], phospho-signal transducer and activator of transcription 3 (p-STAT3), hepatocyte growth factor [HGF], vascular endothelial growth factor [VEGF]) and anti-apoptosis-related markers (myeloid cell leukemia-1 [Mcl-1] and survivin) (P < 0.05). In vivo using 70% hepatectomy mice, the survivin-secretome group exhibited the lowest serum levels of interleukin-6, tumor necrosis factor-α (P < 0.05). The serum levels of liver transaminases (alanine aminotransferase and aspartate aminotransferase) were also the lowest in the survivin-secretome group (P < 0.05). The survivin-secretome group also exhibited the highest liver regeneration on the 7th day after 70% partial hepatectomy (P < 0.05). In the subsequent liver specimen analysis, the specimens of survivin-secretome exhibited the highest expression of p-STAT3, HGF, VEGF, PCNA, and Mcl-1 and the lowest expression of bcl-2-like protein 4 (P < 0.05). Conclusion Taken together, secretome secreted by survivin-overexpressing ASCs could be an effective way to improve liver regeneration and repair for liver injury treatment.
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Affiliation(s)
- Cho-Hee Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ok-Hee Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Park
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Say-June Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul, Korea
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13
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Arista-Romero M, Cascante A, Fornaguera C, Borrós S. Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy. Pharmaceutics 2021; 13:pharmaceutics13111959. [PMID: 34834374 PMCID: PMC8618611 DOI: 10.3390/pharmaceutics13111959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/17/2021] [Accepted: 11/04/2021] [Indexed: 12/21/2022] Open
Abstract
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies.
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Affiliation(s)
- Maria Arista-Romero
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (M.A.-R.); (A.C.); (C.F.)
| | - Anna Cascante
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (M.A.-R.); (A.C.); (C.F.)
- Sagetis Biotech SL, Via Augusta 394, 08017 Barcelona, Spain
| | - Cristina Fornaguera
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (M.A.-R.); (A.C.); (C.F.)
- Sagetis Biotech SL, Via Augusta 394, 08017 Barcelona, Spain
| | - Salvador Borrós
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (M.A.-R.); (A.C.); (C.F.)
- Sagetis Biotech SL, Via Augusta 394, 08017 Barcelona, Spain
- Correspondence:
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14
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Qiao Y, Pei Y, Luo M, Rajasekaran M, Hui KM, Chen J. Cytokinesis regulators as potential diagnostic and therapeutic biomarkers for human hepatocellular carcinoma. Exp Biol Med (Maywood) 2021; 246:1343-1354. [PMID: 33899543 DOI: 10.1177/15353702211008380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers.
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Affiliation(s)
- Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China
| | - Yunxin Pei
- Pharmacy Institute and Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, The affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Collaborative Innovation Center of Traditional Chinese Medicines from Zhejiang Province, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China
| | - Miao Luo
- Pharmacy Institute and Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, The affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Collaborative Innovation Center of Traditional Chinese Medicines from Zhejiang Province, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China
| | - Muthukumar Rajasekaran
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore
| | - Kam M Hui
- Pharmacy Institute and Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, The affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Collaborative Innovation Center of Traditional Chinese Medicines from Zhejiang Province, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.,Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.,Duke-NUS Medical School, Singapore 169857, Singapore
| | - Jianxiang Chen
- Pharmacy Institute and Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, The affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Collaborative Innovation Center of Traditional Chinese Medicines from Zhejiang Province, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.,Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore
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15
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Zhu XQ, Yang H, Lin MH, Shang HX, Peng J, Chen WJ, Chen XZ, Lin JM. Qingjie Fuzheng Granules regulates cancer cell proliferation, apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via Sonic Hedgehog pathway. J Gastrointest Oncol 2021; 11:1123-1134. [PMID: 33456987 DOI: 10.21037/jgo-20-213] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Sonic Hedgehog (SHh) signaling pathway plays a critical role in cell proliferation, apoptosis, and tumor angiogenesis in various types of malignancies including colorectal cancer (CRC). Qingjie Fuzheng Granules (QFG) is a traditional Chinese medicinal formula, which has been clinically used in various cancer treatments, including CRC. In this study, we explored the potential molecular mechanisms of QFG treatment effects on CRC via the SHh pathway. Methods A CRC HCT-116 xenograft mouse model was utilized for all experiments. Mice were treated with intra-gastric administration of 1 g/kg of QFG or saline 6 days a week for 28 days (4 weeks). Body weight, length and shortest diameter of the tumor were measured every 3 days. At the end of the treatment, the tumor weight was measured. TUNEL staining assays were used to detect tumor apoptosis. Western blot and immunohistochemistry (IHC) assays were used to detect the expression of relative proteins. Results In our results, QFG inhibited the increase of tumor volume and weight, and exhibited no impact on mouse body weight. Furthermore, QFG significantly decreased the expression of SHh, Smo and Gli proteins, indicating the action of SHh signaling. Consequently, the expression of pro-proliferative survivin, Ki-67, Cyclin-D1 and CDK4 were decreased and expression of anti-proliferative p21 was increased. The pro-apoptotic Bax/Bcl-2 ratio, cle-caspase-3 and TUNEL-positive cell percentage in tumor tissues were increased. Meanwhile, the pro-angiogenic VEGF-A and VEGFR-2 expression was down-regulated. Conclusions QFG inhibited CRC cell proliferation and promoted CRC cell apoptosis and tumor angiogenesis in vivo through the suppression of SHh pathway, suggesting that QFG could be a potential therapeutic drug for CRC.
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Affiliation(s)
- Xiao-Qin Zhu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Hong Yang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Ming-He Lin
- Editorial Department of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Hai-Xia Shang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Wu-Jin Chen
- Department of Oncology, Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xu-Zheng Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
| | - Jiu-Mao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.,Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, China
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16
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The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21238894. [PMID: 33255318 PMCID: PMC7727670 DOI: 10.3390/ijms21238894] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/31/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.
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17
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Priyanga J, Sharan Kumar B, Mahalakshmi R, Nirekshana K, Vinoth P, Sridharan V, Bhakta-Guha D, Guha G. A novel indenone derivative selectively induces senescence in MDA-MB-231 (breast adenocarcinoma) cells. Chem Biol Interact 2020; 331:109250. [PMID: 32956706 DOI: 10.1016/j.cbi.2020.109250] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 07/27/2020] [Accepted: 08/28/2020] [Indexed: 11/15/2022]
Abstract
Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-MB-231). On 24 h treatment, the nID caused decline in the viability of MDA-MB-231 and MDA-MB-468 cells, but did not significantly (P < 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-MB-231 and MDA-MB-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21Cip1/WAF1 expression, on treatment with the nID. This ensued cell cycle arrest at G1 stage, which might have driven the MDA-MB-231 cells to senescence. We observed a selectivity of the nID to target MDA-MB-231 cells, whereas WRL-68 cells did not show any considerable effect. The results underscored that the nID has potential to be developed into a cancer therapeutic.
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Affiliation(s)
- J Priyanga
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - B Sharan Kumar
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - R Mahalakshmi
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - K Nirekshana
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - P Vinoth
- Department of Chemistry, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - Vellaisamy Sridharan
- Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), Samba, Jammu, India
| | - Dipita Bhakta-Guha
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India.
| | - Gunjan Guha
- Cellular Dyshomeostasis Laboratory, Department of Biotechnology, School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India.
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18
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Xiao H, Wang B, Xiong HX, Guan JF, Wang J, Tan T, Lin K, Zou SB, Hu ZG, Wang K. A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis. J Cell Physiol 2020; 236:2572-2591. [PMID: 32853412 DOI: 10.1002/jcp.30015] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/09/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023]
Abstract
Changes in immune responses to hepatocellular carcinoma (HCC) are closely related to the occurrence, development, and prognosis of this disease. Exploring the role of immune-related genes (IRGs) in HCC would provide insights into the mechanisms regulating this disease. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) provide a platform for such research, owing to a large number of HCC samples available for comprehensive and systematic immunogenomics analyses. We analyzed the IRGs expression profile and clinical information of patients with HCC based on the TCGA and ICGC database. Potential molecular mechanisms and properties of the screened IRGs were analyzed across multiple databases. And we analyzed the correlation between IRGs, single-nucleotide polymorphisms, and copy number variation. A novel prognostic index, based on IRGs, was developed using the LASSO Cox regression algorithm, followed by univariate and multivariate Cox regression analyses to analyze the prognostic index. Information in the ICGC database was used to verify the reliability of the prognostic index. A total of 54 differentially expressed IRGs were found to be significantly associated with HCC prognosis, and there is a significant correlation between their expression level and copy number variation. Functional enrichment analyses indicated that the genes play active roles in tumor and immune-related signaling pathways. In addition, five potential biomarkers namely IRG, MAPK3, HSP90AA1, HSP90AB1, HSPA4, and CDK4, were identified. Finally, a novel prognostic index, based on IRGs (PSMD14, FABP6, ISG20L2, HGF, BIRC5, IL17D, and STC2), was found useful as an independent prognostic factor, not only for prognosis but also to reflect levels of infiltration in a variety of immune cells. Our team conducted a genomics study of IRGs in HCC and screened several clinically significant IRGs, and our model provides an effective approach for stratification and characterization of patients using IRG-based immunolabeling tools to monitor the prognosis of HCC.
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Affiliation(s)
- Han Xiao
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Ben Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Hai-Xia Xiong
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Jia-Fu Guan
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Jian Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Tao Tan
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Kang Lin
- Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.,Gastrointestinal Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shu-Bing Zou
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Zhi-Gang Hu
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
| | - Kai Wang
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China
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19
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Kumar S, Fairmichael C, Longley DB, Turkington RC. The Multiple Roles of the IAP Super-family in cancer. Pharmacol Ther 2020; 214:107610. [PMID: 32585232 DOI: 10.1016/j.pharmthera.2020.107610] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/16/2020] [Accepted: 06/08/2020] [Indexed: 12/22/2022]
Abstract
The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes. IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor κB (NF-κB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.
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Affiliation(s)
- Swati Kumar
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Ciaran Fairmichael
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Daniel B Longley
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Richard C Turkington
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.
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20
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Subhan MA, Torchilin VP. siRNA based drug design, quality, delivery and clinical translation. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 29:102239. [PMID: 32544449 DOI: 10.1016/j.nano.2020.102239] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 01/20/2023]
Abstract
Gene silencing by RNA interference represents a promising therapeutic approach. The development of carriers, e.g., polymers, lipids, peptides, antibodies, aptamers, small molecules, exosome and red blood cells, is crucial for the systemic delivery of siRNA. Cell-specific targeting ligands in the nano-carriers can improve the pharmacokinetics, biodistribution, and selectivity of siRNA therapeutics. The safety, effectiveness, quality and prosperity of production and manufacturing are important considerations for selecting the appropriate siRNA carriers. Efficacy of systemic delivery of siRNA requires considerations of trafficking through the blood, off-target effects, innate immune response and endosomal escape avoiding lysosomal degradation for entering into RNAi process. Multifunctional nanocarriers with stimuli-responsive properties such as pH, magnetic and photo-sensitive segments can enhance the efficacy of siRNA delivery. The improved preclinical characterization of suitable siRNA drugs, good laboratory practice, that reduce the differences between in vitro and in vivo results may increase the success of siRNA drugs in clinical settings.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, ShahJalal University of Science and Technology, Sylhet, Bangladesh.
| | - V P Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA; Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
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21
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Efficient nanocarriers of siRNA therapeutics for cancer treatment. Transl Res 2019; 214:62-91. [PMID: 31369717 DOI: 10.1016/j.trsl.2019.07.006] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/01/2019] [Accepted: 07/15/2019] [Indexed: 02/02/2023]
Abstract
Nanocarriers as drug delivery systems are promising and becoming popular, especially for cancer treatment. In addition to improving the pharmacokinetics of poorly soluble hydrophobic drugs by solubilizing them in a hydrophobic core, nanocarriers allow cancer-specific combination drug deliveries by inherent passive targeting phenomena and adoption of active targeting strategies. Nanoparticle-drug formulations can enhance the safety, pharmacokinetic profiles, and bioavailability of locally or systemically administered drugs, leading to improved therapeutic efficacy. Gene silencing by RNA interference (RNAi) is rapidly developing as a personalized field of cancer treatment. Small interfering RNAs (siRNAs) can be used to switch off specific cancer genes, in effect, "silence the gene, silence the cancer." siRNA can be used to silence specific genes that produce harmful or abnormal proteins. The activity of siRNA can be used to harness cellular machinery to destroy a corresponding sequence of mRNA that encodes a disease-causing protein. At present, the main barrier to implementing siRNA therapies in clinical practice is the lack of an effective delivery system that protects the siRNA from nuclease degradation, delivers to it to cancer cells, and releases it into the cytoplasm of targeted cancer cells, without creating adverse effects. This review provides an overview of various nanocarrier formulations in both research and clinical applications with a focus on combinations of siRNA and chemotherapeutic drug delivery systems for the treatment of multidrug resistant cancer. The use of various nanoparticles for siRNA-drug delivery, including liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, exosomes, and red blood cells for targeted drug delivery in cancer is discussed.
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22
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Dong L, Xie L, Li M, Dai H, Wang X, Wang P, Zhang Q, Liu W, Hu X, Zhao M. Downregulation of B7-H4 suppresses tumor progression of hepatocellular carcinoma. Sci Rep 2019; 9:14854. [PMID: 31619714 PMCID: PMC6795893 DOI: 10.1038/s41598-019-51253-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 09/28/2019] [Indexed: 01/13/2023] Open
Abstract
B7-H4, as a member of the B7 superfamily, was overexpressed in various types of cancers. However, the effects of B7-H4 on the aggressiveness of HCC and the underlying mechanisms have not yet been fully explored. For this purpose, B7-H4 expression was detected by Flow cytometry and Western blotting, it was highly expressed in several HCC cell lines but not in normal LO2 cell line. Knockdown B7-H4 expression induced HCC cells apoptosis by flow cytometry and colony formation assays and increased several apoptosis-related proteins, including survivin, cleaved caspase-3, cleaved caspase-7, and Bax, while the pro-growth protein survivin was reduced. Then the proliferation and cell cycle were suppressed after treated by siB7-H4. Moreover, the level of B7-H4 was significantly correlated with cell migration. In vivo, intra-tumor injection of siRNA targeting B7-H4 can significantly inhibited the growth of HepG2 cells in nude mice. Finally, regions of interest were manually traced on T1WI, T2WI, DWI and ADC of MR images. ADC values were increased in HCC xenografts after B7-H4 siRNA treatment. These data indicated that downregulation of B7-H4 suppressed the proliferation and migration and promoted apoptosis in vitro and in vivo. Blocking the B7-H4 channel might be a potential therapeutic strategy for HCC.
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Affiliation(s)
- Lijie Dong
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China.,Department of Radiology, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Lulu Xie
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Minjing Li
- Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Hanhan Dai
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Xia Wang
- Department of Oral Pathology, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Peiyuan Wang
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Qiang Zhang
- Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Wei Liu
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Xuemei Hu
- Department of Immunology, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China.
| | - Mingdong Zhao
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China.
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Zheng ZH, Wu DM, Fan SH, Wen X, Han XR, Wang S, Wang YJ, Zhang ZF, Shan Q, Li MQ, Hu B, Zheng YL, Lu J. LncRNA AB209371 up-regulated Survivin gene by down-regulating miR-203 in ovarian carcinoma. J Ovarian Res 2019; 12:92. [PMID: 31601255 PMCID: PMC6785849 DOI: 10.1186/s13048-019-0559-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 08/27/2019] [Indexed: 11/10/2022] Open
Abstract
AB209371 gene has been characterized as an oncogenic lncRNA in liver cancer. However, its involvement in ovarian carcinoma (OC) is unknown. In the present study, we analyzed the roles of AB209371 in OC. We found that AB209371 gene and Survivin gene were up-regulated in OC and positively correlated with OC development. AB209371 over-expression led to up-regulated Survivin in OC cells, while Survivin over-expression failed to affect AB209371. In addition, AB209371 over-expression led to down-regulated miR-203. However, miR-203 over-expression failed to affect AB209371, but down-regulated the expression of Survivin. In addition, over-expressions of AB209371 and Survivin resulted in the increased proliferation rate of OC cells. Over-expression MiR-203 played the opposite role and attenuated the effects of AB209371 over-expression. Therefore, AB209371 may down-regulate miR-203 to up-regulate Survivin, thereby promoting OC cell proliferation. Our study provided novel insights into the pathogenesis of OC.
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Affiliation(s)
- Zi-Hui Zheng
- State Key Laboratory Cultivation Base For TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Xin Wen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Xin-Rui Han
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Shan Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Meng-Qiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China. .,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China.
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science; College of Health Sciences, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou, 221116, Jiangsu Province, People's Republic of China. .,College of Health Sciences, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People's Republic of China.
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Survivin expression starts before hepatocellular cancer development in the liver of chronic hepatitis B patients: a pilot, cross-sectional study. GASTROENTEROLOGY REVIEW 2019; 15:138-143. [PMID: 32550946 PMCID: PMC7294976 DOI: 10.5114/pg.2019.87081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 07/15/2019] [Indexed: 11/17/2022]
Abstract
Introduction Survivin expression is well known feature of hepatocellular carcinoma (HCC); however, there is no information about survivin expression in chronic hepatitis B (CHB). Aim Investigating survivin expression in the liver of CHB patients. Material and methods This is a single-centre, cross-sectional study. Seventy-five CHB patients and eight control patients were enrolled into the study between 2008 and 2018. Immunohistochemical study was performed by using anti-survivin antibody to evaluate survivin immunoreactivity. Results Survivin immunoreactivity was significantly higher in CHB patients compared to controls (p = 0.008). Also, the degree of survivin immunoreactivity was significantly higher in CHB patients (p = 0.027). Between the anti-survivin-positive and anti-survivin-negative groups, baseline laboratory parameters and initial pathology features were not significantly different. Conclusions This is the first study evaluating survivin expression in CHB patients. Understanding the possible relationship between survivin expression and HCC development in this population can promote new studies in terms of new therapies and treatment timing.
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25
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Chen W, Dong W, Wang J, Wen Z, Hao X. Elevated Expressions of Survivin and Endoglin in Patients with Hepatic Carcinoma. Cancer Biother Radiopharm 2019; 34:7-12. [PMID: 30730204 DOI: 10.1089/cbr.2018.2539] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE To investigate expression profiles of survivin and endoglin in patients with hepatic carcinoma. MATERIALS AND METHODS Cancerous tissues (hepatic carcinoma group) of 48 patients with hepatic carcinoma and adjacent noncancerous hepatic tissues (control group) were used as objects of study. Histopathological staining [hematoxylin & eosin (H&E) staining] was used to study the pathological differences in hepatic tissues between hepatic carcinoma group and control group. Moreover, survivin and endoglin protein expressions in hepatic tissues in hepatic carcinoma group and control group were detected via western blotting. Finally, Statistical Product and Service Solutions 17.0 statistical software was used to analyze the differences in survivin and endoglin expressions in hepatic tissues between hepatic carcinoma group and control group. RESULTS H&E staining showed that histopathological features in hepatic carcinoma group were significantly different from those in control group. Compared with those in control group, the cell structure in hepatic carcinoma group was damaged, karyopyknosis was obvious, and the hepatic injury was serious. Reverse transcription-polymerase chain reaction showed that survivin and endoglin mRNA expression levels in hepatic carcinoma group were significantly increased compared with those in control group. Besides, immunofluorescence method and western blotting revealed the low expressions of survivin and endoglin proteins in tissues in control group, which were obviously lower than those in hepatic tissues in hepatic carcinoma group. Results of analyses of variance showed that the expressions of survivin and endoglin in normal hepatic tissues and cancerous tissues had statistically significant differences (p < 0.01). Furthermore, expressions of survivin and endoglin were significantly associated with histological grade, tumor size, and tumor, node, metastasis (TNM) stage. CONCLUSION Elevated expressions of survivin and endoglin are associated with histological grade, tumor size, and TNM stage in patients with hepatic carcinoma, indicating that survivin and endoglin might be involved in the pathogenesis of hepatic carcinoma and therapeutic targeting them might be a novel approach for the treatment of hepatic carcinoma.
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Affiliation(s)
- Wenmei Chen
- 1 Department of Liver Disease Area 9, Qingdao No.6 People's Hospital, Qingdao, China
| | - Wenjing Dong
- 2 Department of Liver Disease Area 7, Qingdao No.6 People's Hospital, Qingdao, China
| | - Jintai Wang
- 3 Department of Orthopedic, Qingdao No.8 People's Hospital, Qingdao, China
| | - Zirong Wen
- 1 Department of Liver Disease Area 9, Qingdao No.6 People's Hospital, Qingdao, China
| | - Xinjie Hao
- 2 Department of Liver Disease Area 7, Qingdao No.6 People's Hospital, Qingdao, China
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Wu B, Liu R. PAQR4 promotes cell proliferation and metastasis through the CDK4-pRB-E2F1 pathway in non-small-cell lung cancer. Onco Targets Ther 2019; 12:3625-3633. [PMID: 31190865 PMCID: PMC6521844 DOI: 10.2147/ott.s181432] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background It is reported that progestin and adipoQ receptor 4 (PAQR4) has a tumorigenic effect on human breast cancer, but the role of PAQR4 in non-small-cell lung cancer (NSCLC) is unknown. The aim of this study was to investigate the role of PAQR4 in NSCLC. Methods Quantitative real-time PCR (qRT-PCR) and immunohistchemical (IHC) staining were used to analyze the expression of PAQR4 in HCC tissues and adjacent normal tissues. MTT, colony formation assay, flow cytometry (FCM), wound healing assays and transwell invasion assays were used to investigate the effects of PAQR4 on cell proliferation, colony formation, cell cycle, migration and invasion. Murine xenograft model assay was carried out to characterize the effects of PAQR4 knockdown on tumor growth in vivo. Results In this study, we found that the expression of PAQR4 was significantly upregulated in the NSCLC tissues of patients compared with that in the matched non-cancerous tissues. In addition, we found that PAQR4 was also significantly up-regulated in the NSCLC cell lines compared with normal human lung epithelial cells. Besides, we found that the over-expression of PAQR4 promoted promoted proliferation, colony formation, migration and invasion of the NSCLC cells, whereas the knockdown of PAQR4 inhibited proliferation, colony formation, migration and invasion of the NSCLC cells. Furthermore, mechanistic studies showed that the CDK4-pRB-E2F1 pathway was involved in NSCLC. Conclusion Hence, these results suggest that PAQR4 may be used as a new target in NSCLC therapy.
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Affiliation(s)
- Bin Wu
- Department of Pulmonary and Critical Care Medicine, Baoan Central Hospital of Shenzhen, Shenzhen 518102, China
| | - Rongyu Liu
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China,
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27
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Chang YW, Singh KP. Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells. Toxicol Appl Pharmacol 2019; 374:65-76. [PMID: 31047982 DOI: 10.1016/j.taap.2019.04.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/09/2019] [Accepted: 04/26/2019] [Indexed: 01/03/2023]
Abstract
Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.
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Affiliation(s)
- Yu-Wei Chang
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, USA
| | - Kamaleshwar P Singh
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX, USA.
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Ragab HM, Maksoud NAE, Elaziz WA, Halim MH, Kamel A, Abdulla NA. Combination of Serum Survivin and AFP as a Potential Marker in HCC Associated with Hepatitis C Viral Infection. JOURNAL OF APPLIED SCIENCES 2019; 19:295-302. [DOI: 10.3923/jas.2019.295.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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29
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A novel approach for assessment of prostate cancer aggressiveness using survivin-driven tumour-activatable minicircles. Gene Ther 2019; 26:177-186. [PMID: 30867586 DOI: 10.1038/s41434-019-0067-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 01/15/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022]
Abstract
Early and accurate detection of cancer is essential to optimising patient outcomes. Of particular importance to prostate cancer is the ability to determine the aggressiveness of a primary tumour, which allows for effective management of patient care. In this work, we propose using gene vectors called tumour-activatable minicircles which deliver an exogenously encoded reporter gene into cancer cells, forcing them to produce a unique and sensitive biomarker. These minicircles express a blood reporter protein called secreted embryonic alkaline phosphatase mediated by the tumour-specific survivin promoter, which exhibits activity graded to prostate cancer aggressiveness. Together, these components underlie a detection system where levels of blood reporter are indicative of not only the presence, but also the metastatic potential of a tumour. Our goal was to assess the ability of tumour-activatable minicircles to detect and characterise primary prostate lesions. Our minicircles produced reporter levels related to survivin expression across a range of prostate cancer cell lines. When survivin-driven minicircles were administered intratumourally into mice, reporter levels in blood samples were significantly higher (p < 0.05) in mice carrying prostate tumours of high versus low-aggressiveness. Continued development of this gene-based system could provide clinicians with a powerful tool to evaluate prostate cancer aggressiveness using a sensitive and affordable blood assay.
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Pandey A, Tripathi SC, Shukla S, Mahata S, Vishnoi K, Misra SP, Misra V, Mitra S, Dwivedi M, Bharti AC. Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori. Cancer Rep (Hoboken) 2018; 1:e1004. [PMID: 32729225 DOI: 10.1002/cnr2.1004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/15/2018] [Accepted: 03/30/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Localization and differential expression of STAT3 and survivin in cancer cells are often related to distinct cellular functions. The involvement of survivin and STAT3 in gastric cancer has been reported in separate studies but without clear understanding of their kinetics in cancer progression. METHODS We examined intracellular distribution of STAT3 and survivin in gastric adenocarcinoma and compared it with normal and precancer tissues using immunoblotting and immunohistochemistry. RESULTS Analysis of a total of 156 gastric samples comprising 61 histologically normal, 30 precancerous tissues (comprising intestinal metaplasia and dysplasia), and 65 adenocarcinomas, collected as endoscopic biopsies from treatment naïve study participants, revealed a significant (P < .001) increase in overall protein levels. Survivin expression was detectable in both cytoplasmic (90.8%) and nuclear (87.7%) compartments in gastric adenocarcinomas lesions. Precancerous dysplastic gastric lesions exhibited a moderate survivin expression (56.7%) localized in cytoplasmic compartment. Similarly, STAT3 and pSTAT3 expression was detected at high level in gastric cancer lesions. The levels of compartmentalized expression of survivin and STAT3/pSTAT3 correlated in precancerous and adenocarcinoma lesions. Although overexpression of these proteins was found associated with the tobacco use and alcohol consumption, their expression invariably and strongly correlated with concurrent Helicobacter pylori infection. Receiver operating characteristic analysis of nuclear survivin, STAT3, and pSTAT3 in different study groups showed acceptable positive and negative predictive values with area under the curve above 0.8 (P < .001). CONCLUSION Overall, our results suggest that overall increase in survivin and STAT3 and their subcellular localization are key determinants of gastric cancer progression, which can be collectively used as potential disease biomarkers and therapeutic targets for gastric cancer.
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Affiliation(s)
- Arvind Pandey
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.,Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India
| | | | - Shirish Shukla
- Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, USA
| | - Sutapa Mahata
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Division of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India
| | - Kanchan Vishnoi
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Sri Prakash Misra
- Department of Gastroenterology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Vatsala Misra
- Department of Pathology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Sankar Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA
| | - Manisha Dwivedi
- Department of Gastroenterology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Alok C Bharti
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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Huang YH, Lin KH, Yu JS, Wu TJ, Lee WC, Chao CCK, Pan TL, Yeh CT. Targeting HSP60 by subcutaneous injections of jetPEI/HSP60-shRNA destabilizes cytoplasmic survivin and inhibits hepatocellular carcinoma growth. Mol Carcinog 2018; 57:1087-1101. [PMID: 29672920 DOI: 10.1002/mc.22827] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 03/28/2018] [Accepted: 04/17/2018] [Indexed: 01/14/2023]
Abstract
Heat shock protein 60 (HSP60) overexpresses in various types of cancer, but its expression levels and functions in hepatocellular carcinoma (HCC) are still in dispute. We aim to clarify this issue and examine whether HSP60 could be a therapeutic target for HCC. We found drastically enhanced cell apoptosis and suppressed cell proliferation in two HCC cell lines with HSP60-silencing, and also indicated survivin was involved in this regulatory process in vitro and in vivo. However, HSP60-silencing in normal human hepatocytes only resulted in a minimal reduction of cell proliferation but without effects on cell apoptosis. We also showed HSP60 interacted with cytosolic but not mitochondrial survivin by immunoprecipitation assay. A rigorous method was used to standardize quantification from immunoblot assay to obtain more precise expression levels of HSP60 and survivin. The expression of HSP60 and survivin positively correlated in both cancerous and non-cancerous liver tissues (P < 0.001) after analyzing 145 surgically removed HCC tissues. A total of 56.6% of HCC patients overexpressed HSP60 in cancerous tissues, and 40.0% under-expressed HSP60. Higher expression of HSP60 and survivin in non-cancerous tissues both correlated with shorter overall survival (P = 0.029 and P < 0.001, respectively). Finally, we evaluated the therapeutic potential of HSP60 using extraneous delivery of jetPEI/shHSP60 complexes. The treatment results showed significant reduction of tumor weight by 44.3% (P < 0.05), accompanied by under-expression of survivin. These studies suggested that HSP60 not only served as a prognostic marker but also served as a novel therapeutic target for HCC.
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Affiliation(s)
- Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Kwang-Huei Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Jau-Song Yu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Molecular Medicine Research Center, Chang-Gung University, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Chen Lee
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chuck C-K Chao
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Tai-Long Pan
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,School of Traditional Chinese Medicine, Chang-Gung University, Taoyuan, Taiwan.,Research Center of Industry of Human Ecology, Chang-Gung University of Science and Technology, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Molecular Medicine Research Center, Chang-Gung University, Taoyuan, Taiwan
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Han S, Pang MF, Nelson CM. Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1. J Cell Sci 2018; 131:jcs.210476. [PMID: 29588395 DOI: 10.1242/jcs.210476] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 02/27/2018] [Indexed: 12/14/2022] Open
Abstract
The Wnt/β-catenin pathway controls a variety of cellular behaviors, aberrant activation of which are associated with tumor progression in several types of cancer. The same cellular behaviors are also affected by the mechanical properties of the extracellular matrix (ECM) substratum, which induces signaling through integrins and integrin-linked kinase (ILK). Here, we examined the role of substratum stiffness in the regulation of cell proliferation downstream of Wnt3a. We found that treatment with Wnt3a increased proliferation of cells cultured on stiff substrata, with compliances characteristic of breast tumors, but not of cells on soft substrata, with compliances comparable to that of normal mammary tissue. Depleting ILK rendered cells unresponsive to Wnt3a on both substrata. Ectopic expression of ILK permitted Wnt3a to induce proliferation of cells on both microenvironments, although proliferation on soft substrata remained lower than that on stiff substrata. We further showed that ILK regulates expression of the Wnt receptor frizzled-1 (Fzd1), suggesting the presence of a positive feedback loop between Wnt3a, ILK and Fzd1. These findings suggest that tissue mechanics regulates the cellular response to Wnt under physiological and pathological microenvironmental conditions.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Siyang Han
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Mei-Fong Pang
- Department of Chemical & Biological Engineering, Princeton University, Princeton, NJ 08544, USA
| | - Celeste M Nelson
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA .,Department of Chemical & Biological Engineering, Princeton University, Princeton, NJ 08544, USA
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Yin H, Que R, Liu C, Ji W, Sun B, Lin X, Zhang Q, Zhao X, Peng Z, Zhang X, Qian H, Chen L, Yao Y, Su C. Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma. Cancer Lett 2018; 425:54-64. [PMID: 29608986 DOI: 10.1016/j.canlet.2018.03.044] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P-EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3'-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives. WM-127 was demonstrated to be a strong Survivin inhibitor that inhibited cell proliferation, induced cell cycle arrest and apoptosis of HCC cells, and suppressed the growth of HCC xenografted tumors in nude mice, suggesting that WM-127 might be a promising drug for HCC treatment. WM-127 exhibited less cytotoxicity in normal cells. Mechanistic studies showed that WM-127 suppressed the activity of Survivin/β-catenin pathway and the expression of Bax to induce cell cycle arrest and apoptosis. Taken together, we constructed an economical, practical, efficient and convenient cell platform for screening the Survivin-targeted drugs from the enormous diversity of chemicals or factors, which would be a potential tool for antitumor drug research and development.
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Affiliation(s)
- Haisen Yin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China; Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Risheng Que
- Department of Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Chunying Liu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Weidan Ji
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Qin Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xinying Zhao
- Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Zhangxiao Peng
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xiaofeng Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Haihua Qian
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Lei Chen
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Yonggang Yao
- Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, 221002, Jiangsu, China.
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Wang Y, Mo Y, Wang L, Su P, Xie Y. Let-7b contributes to hepatocellular cancer progression through Wnt/β-catenin signaling. Saudi J Biol Sci 2018; 25:953-958. [PMID: 30108446 PMCID: PMC6087813 DOI: 10.1016/j.sjbs.2018.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 03/01/2018] [Accepted: 03/05/2018] [Indexed: 12/11/2022] Open
Abstract
Elevated evidences show that microRNAs (miRNAs) play vital roles in tumor progression regulation. However, the functional role of let-7b in hepatocellular carcinoma (HCC) is still largely unknown. In this study, we try to investigate the biological activity of let-7b in human HCC cells and try to find the potential regulatory signaling pathway. Our results indicate that let- 7b was remarkably down-regulated in human HCC tissues by qRT-PCR. In addition, let-7b overexpression decreased the expression of β-catenin and c-Myc, while upregulated E-cadherin expression in HCC cells which was verified by quantitative real-time PCR (qRT-PCR) and western blotting. Furthermore, Wnt/β-catenin was involved in let-7b biological activity which was revealed by luciferase assay. Moreover, Wnt/β-catenin signaling inhibitor blocks HCC cell proliferation which is as the same pattern as let-7b overexpression inhibits in HCC cells proliferation. In conclusion, down-regulated let-7b promotes HCC cell proliferation through Wnt/β-catenin signaling in HCC cells. These results suggested that appropriate manipulation of let-7b might be a new treatment of human HCC in the future.
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Affiliation(s)
- Yiwei Wang
- North China University of Science and Technology Affiliated Hospital, Tangshan 063000, PR China
| | - Yanbo Mo
- North China University of Science and Technology Affiliated Hospital, Tangshan 063000, PR China
| | - Lin Wang
- North China University of Science and Technology Affiliated Hospital, Tangshan 063000, PR China
| | - Peng Su
- North China University of Technology, Tangshan 063000, PR China
| | - Yuxi Xie
- North China University of Science and Technology Affiliated Hospital, Tangshan 063000, PR China
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Zarei N, Fazeli M, Mohammadi M, Nejatollahi F. Cell growth inhibition and apoptosis in breast cancer cells induced by anti-FZD7 scFvs: involvement of bioinformatics-based design of novel epitopes. Breast Cancer Res Treat 2018; 169:427-436. [DOI: 10.1007/s10549-017-4641-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 12/23/2017] [Indexed: 02/06/2023]
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Sokołowska J, Urbańska K. Survivin expression in correlation with apoptotic activity in canine lymphomas. Pol J Vet Sci 2017; 20:329-338. [PMID: 28865215 DOI: 10.1515/pjvs-2017-0040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Survivin regulates cell cycle and mitosis and has antiapoptotic properties. Because of its dual function survivin has been the subject of much research focusing on its role in tumorigenesis and the relationship between survivin expression and apoptotic and/or proliferative activity in many types of human tumor including non-Hodgkin's Lymphomas. Such studies have not been conducted in canine lymphomas. The aim of this study was to evaluate the expression of survivin in canine lymphomas of low (5/25) and high (20/25) grades in relation to apoptotic markers (apoptotic index and index of caspase-3). Survivin was found in all examined lymphomas. Most tumors (18/25) showed survivin expression in 10%-25% of positive cells. Only in single cases was lower (0-10% positive cells, 1/25) or higher (25%-50% and >50% positive cells, 5/25 and 1/25, respectively) survivin expression. No significant differences between mean values of either index of survivin or apoptotic index was found between low and high grade lymphomas. However, such a difference among lymphoma grades was shown regarding the caspase-3 index. No correlation between the survivin index and either the apoptotic index or caspase-3 index was found, irrespective of the method of quantification: in whole specimens or in areas of low and high survivin expression. Positive correlation was consistently noted only between both apoptotic markers. The results indicate that survivin is commonly expressed in canine lymphomas. It seems that survivin does not exhibit anti-apoptotic activity in canine lymphomas. Lack of correlation between survivin expression and apoptotic markers could indicate its potential role in cell cycle activation in lymphoma cells.
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Matsumoto A, Takahashi Y, Nishikawa M, Sano K, Morishita M, Charoenviriyakul C, Saji H, Takakura Y. Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells. Cancer Sci 2017; 108:1803-1810. [PMID: 28667694 PMCID: PMC5581513 DOI: 10.1111/cas.13310] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 06/20/2017] [Accepted: 06/28/2017] [Indexed: 12/21/2022] Open
Abstract
Exosomes are extracellular vesicles released by various cell types and play roles in cell-cell communication. Several studies indicate that cancer cell-derived exosomes play important pathophysiological roles in tumor progression. Biodistribution of cancer cell-derived exosomes in tumor tissue is an important factor for determining their role in tumor proliferation; however, limited studies have assessed the biodistribution of exosomes in tumor tissues. In the present study, we examined the effect of cancer-cell derived exosomes on tumor growth by analyzing their biodistribution. Murine melanoma B16BL6-derived exosomes increased the proliferation and inhibited the apoptosis of B16BL6 cells, which was associated with an increase and decrease in the levels of proliferation- and apoptosis-related proteins, respectively. GW4869-induced inhibition of exosome secretion decreased the proliferation of B16BL6 cells, and treatment of GW4869-treated cells with B16BL6-derived exosomes restored their proliferation. Next, we treated B16BL6 tumors in mice with B16BL6-derived exosomes and examined the biodistribution and cellular uptake of these exosomes. After the intratumoral injection of radiolabeled B16BL6-derived exosomes, most radioactivity was detected within the tumor tissues of mice. Fractionation of cells present in the tumor tissue showed that fluorescently labeled exosomes were mainly taken up by B16BL6 cells. Moreover, intratumoral injection of B16BL6-derived exosomes promoted tumor growth, whereas intratumoral injection of GW4869 suppressed tumor growth. These results indicate that B16BL6 cells secrete and take up their own exosomes to induce their proliferation and inhibit their apoptosis, which promotes tumor progression.
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Affiliation(s)
- Akihiro Matsumoto
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Kohei Sano
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Masaki Morishita
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Chonlada Charoenviriyakul
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Hideo Saji
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
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Tiwari A, Loughner CL, Swamynathan S, Swamynathan SK. KLF4 Plays an Essential Role in Corneal Epithelial Homeostasis by Promoting Epithelial Cell Fate and Suppressing Epithelial-Mesenchymal Transition. Invest Ophthalmol Vis Sci 2017; 58:2785-2795. [PMID: 28549095 PMCID: PMC5455171 DOI: 10.1167/iovs.17-21826] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose The purpose of this study was to test the hypothesis that KLF4 promotes corneal epithelial (CE) cell fate by suppressing the epithelial–mesenchymal transition (EMT), using spatiotemporally regulated CE-specific ablation of Klf4 in Klf4Δ/ΔCE (Klf4LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre) mice. Methods CE-specific ablation of Klf4 was achieved by feeding Klf4Δ/ΔCE mice with doxycycline chow. The wild-type (WT; normal chow-fed littermates) and the Klf4Δ/ΔCE histology was compared by hematoxylin and eosin–stained sections; EMT marker expression was quantified by quantitative PCR, immunoblots, and immunofluorescent staining; and wound healing rate was measured by CE debridement using Algerbrush. KLF4 and EMT markers were quantified in human corneal limbal epithelial (HCLE) cells undergoing TGF-β1–induced EMT by quantitative PCR, immunoblots, and immunofluorescent staining. Results The epithelial markers E-cadherin, Krt12, claudin-3, and claudin-4 were down-regulated, whereas the mesenchymal markers vimentin, β-catenin, survivin, and cyclin-D1 and the EMT transcription factors Snail, Slug, Twist1, Twist2, Zeb1, and Zeb2 were up-regulated in the Klf4Δ/ΔCE corneas. The Klf4Δ/ΔCE cells migrated faster, filling 93% of the debrided area within 16 hours compared with 61% in the WT. After 7 days of wounding, the Klf4Δ/ΔCE cells that filled the gap failed to regain epithelial characteristics, as they displayed abnormal stratification; down-regulation of E-cadherin and Krt12; up-regulation of β-catenin, survivin, and cyclin-D1; and a 2.5-fold increase in the number of proliferative Ki67+ cells. WT CE cells at the migrating edge and the HCLE cells undergoing TGF-β1–induced EMT displayed significant down-regulation of KLF4. Conclusions Collectively, these results reveal that KLF4 plays an essential role in CE homeostasis by promoting epithelial cell fate and suppressing EMT.
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Affiliation(s)
- Anil Tiwari
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Chelsea L Loughner
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Sudha Swamynathan
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Shivalingappa K Swamynathan
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States 2McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States 3Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States 4Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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Zheng H, Zou AE, Saad MA, Wang XQ, Kwok JG, Korrapati A, Li P, Kisseleva T, Wang-Rodriguez J, Ongkeko WM. Alcohol-dysregulated microRNAs in hepatitis B virus-related hepatocellular carcinoma. PLoS One 2017; 12:e0178547. [PMID: 28562643 PMCID: PMC5451132 DOI: 10.1371/journal.pone.0178547] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 05/15/2017] [Indexed: 12/17/2022] Open
Abstract
Alcohol consumption and chronic hepatitis B virus (HBV) infection are two well-established risk factors for Hepatocellular carcinoma (HCC); however, there remains a limited understanding of the molecular pathway behind the pathogenesis and progression behind HCC, and how alcohol promotes carcinogenesis in the context of HBV+ HCC. Using next-generation sequencing data from 130 HCC patients and 50 normal liver tissues, we identified a panel of microRNAs that are significantly dysregulated by alcohol consumption in HBV+ patients. In particular, two microRNAs, miR-944 and miR-223-3p, showed remarkable correlation with clinical indication and genomic alterations. We confirmed the dysregulation of these two microRNAs in liver cell lines treated by alcohol and acetaldehyde, and showed that manipulation of miR-223-3p and miR-944 expression induces significant changes in cellular proliferation, sensitivity to doxorubicin, and the expression of both direct-binding and downstream mRNA targets. Together, the results of this study suggest that alcohol consumption in HBV+ HCCs regulates microRNAs that likely play previously uncharacterized roles in the alcohol-associated carcinogenesis of HCC, and future studies of these microRNAs may be valuable for furthering the understanding and treatment of alcohol and HBV-associated HCC.
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Affiliation(s)
- Hao Zheng
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Angela E. Zou
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Maarouf A. Saad
- School of medicine, Yale University, New Haven, Connecticut, United States of America
| | - Xiao Qi Wang
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - James G. Kwok
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Avinaash Korrapati
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Pinxue Li
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
| | - Jessica Wang-Rodriguez
- Department of Pathology, Veterans Administration Medical Center, San Diego, La Jolla, California, United States of America
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
| | - Weg M. Ongkeko
- Department of Surgery, University of California, San Diego, La Jolla, California, United States of America
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Magnetic Cationic Amylose Nanoparticles Used to Deliver Survivin-Small Interfering RNA for Gene Therapy of Hepatocellular Carcinoma In Vitro. NANOMATERIALS 2017; 7:nano7050110. [PMID: 28492491 PMCID: PMC5449991 DOI: 10.3390/nano7050110] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 05/07/2017] [Accepted: 05/09/2017] [Indexed: 12/12/2022]
Abstract
Amylose is a promising nanocarrier for gene delivery in terms of its good biocompatibility and high transfection efficiency. Small interfering RNA against survivin (survivin-siRNA) can cause tumor apoptosis by silencing a hepatocellular carcinoma (HCC)-specific gene at the messenger RNA level. In this study, we developed a new class of folate-functionalized, superparamagnetic iron oxide (SPIO)-loaded cationic amylose nanoparticles to deliver survivin-siRNA to HCC cells. The cellular uptake of nanocomplexes, cytotoxicity, cell apoptosis, and gene suppression mediated by siRNA-complexed nanoparticles were tested. The results demonstrated that folate-functionalized, SPIO-loaded cationic amylose nanoparticles can mediate a specific and safe cellular uptake of survivin-siRNA with high transfection efficiency, resulting in a robust survivin gene downregulation in HCC cells. The biocompatible complex of cationic amylose could be used as an efficient, rapid, and safe gene delivery vector. Upon SPIO loading, it holds a great promise as a theranostic carrier for gene therapy of HCC.
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Han Y, Wu Y, Yang C, Huang J, Guo Y, Liu L, Chen P, Wu D, Liu J, Li J, Zhou X, Hou J. Dynamic and specific immune responses against multiple tumor antigens were elicited in patients with hepatocellular carcinoma after cell-based immunotherapy. J Transl Med 2017; 15:64. [PMID: 28330473 PMCID: PMC5363021 DOI: 10.1186/s12967-017-1165-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 03/15/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers in China and frequently occurs with chronic hepatitis B virus infection. To investigate whether cell-based cancer immunotherapy induces tumor specific immune responses in patients with HCC and provides clinical benefits, as well as to elucidate the most immunogenic tumor associated antigens (TAAs), multiple antigen stimulating cellular therapy (MASCT) was applied in addition to standard of care. METHODS Mature dendritic cells (DCs) and activated T cells prepared for MASCT were generated from autologous peripheral blood mononuclear cells (PBMCs). DCs were loaded with a peptide pool of multiple HCC-related tumor antigens, and T cells were stimulated by these DCs. RESULTS Thirteen patients with HCC received repeated MASCT after tumor resection during which their immune responses were examined. After three courses of MASCT, the frequency of regulatory T cells in the patients' PBMCs significantly decreased (p < 0.001), while the antigen peptide pool-triggered T cell proliferation (p < 0.001) and IFNγ production (p = 0.001) were significantly enhanced. The specific T cell responses against each antigen in the pool were detected in 11 patients, but with individualized distinct patterns. The most immunogenic TAAs for HCC are survivin, CCND1, and RGS5. Moreover, the antigen-specific immune responses observed in tumor-free patients' PBMCs were significantly stronger than that in the patients with recurrence (p = 0.037). CONCLUSIONS Our study demonstrates that MASCT is well-tolerated by patients with HCC and elicits strong and dynamic immune responses specifically against multiple tumor associated antigens, which may correlate with clinical outcomes.
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Affiliation(s)
- Yanyan Han
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,HRYZ Biotech Co., Shenzhen, China
| | - Yeting Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yabing Guo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | | | | | - Jin Li
- HRYZ Biotech Co., Shenzhen, China
| | | | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Liu Z, Wang T, Zhang Z, Tang S, Feng S, Yue M, Hu M, Xuan L, Chen Y. Survivin downregulation using siRNA nanoliposomes inhibits cell proliferation and promotes the apoptosis of MHCC-97H hepatic cancer cells: An in vitro and in vivo study. Oncol Lett 2017; 13:2723-2730. [PMID: 28454458 PMCID: PMC5403348 DOI: 10.3892/ol.2017.5754] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/25/2016] [Indexed: 12/29/2022] Open
Abstract
At present, survivin is one of the most cancer-specific proteins that has been identified. The present study aimed to investigate the antitumor effects of novel survivin small interfering RNA (siRNA) nanoliposomes targeting survivin in human hepatocellular carcinoma MHCC-97H cells and xenograft mouse models. Survivin-targeted siRNA nanoliposomes were prepared and transfected into MHCC-97H cells and MHCC-97H-bearing nude mice. Survivin expression was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell viability was analyzed using an MTT assay and apoptosis was evaluated using Hoechst and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tumor growth in MHCC-97H-bearing mice was monitored following treatment and tumor samples were obtained for survivin expression analysis using RT-qPCR, western blotting and immunohistochemistry staining. Survivin expression levels were significantly downregulated by nanoliposome-mediated survivin siRNA delivery and this was associated with a significant inhibition of cell growth and an increase in the apoptosis of MHCC-97H cells. Downregulation of survivin expression using survivin siRNA nanoliposomes inhibited tumor growth in the MHCC-97H xenograft models without significant treatment-associated toxicity. Therefore, a cationic nanoliposome-based survivin siRNA delivery system was constructed and demonstrated to be efficient for survivin siRNA delivery in in vitro and in vivo studies. These results demonstrate that survivin downregulation was able to significantly attenuate cell proliferation and induce the apoptosis of MHCC-97H cells, as well as inhibit tumor cell growth in MHCC-97H xenograft models, indicating that survivin suppression using siRNA may contribute to the inhibition of tumor development by suppressing cell proliferation and promoting apoptosis.
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Affiliation(s)
- Ziqin Liu
- Department of Pediatrics, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Tianyou Wang
- Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, Xicheng, Beijing 100045, P.R. China
| | - Zhaoxia Zhang
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Suoqin Tang
- Department of Pediatrics, People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Shunqiao Feng
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Mei Yue
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Mengze Hu
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Litian Xuan
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
| | - Yanfei Chen
- Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China
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Yue L, Li L, Li D, Yang Z, Han S, Chen M, Lan S, Xu X, Hui L. High-throughput screening for Survivin and Borealin interaction inhibitors in hepatocellular carcinoma. Biochem Biophys Res Commun 2017; 484:642-647. [PMID: 28153734 DOI: 10.1016/j.bbrc.2017.01.160] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 01/29/2017] [Indexed: 10/20/2022]
Abstract
Survivin, a key member of the chromatin passenger complex (CPC), is often highly expressed in human cancers, making it a promising target for cancer treatment. Out of the numerous reported Survivin inhibitors, YM155 is only one entering clinical trial, but was recently failed in the Phase II trial. It is important to develop Survivin inhibitors with new strategies. We recently reported that both Survivin and its binding protein Borealin in the CPC complex are essential for the development of hepatocellular carcinoma, suggesting that disrupting the interaction between Survivin and Borealin would be a promising strategy. Here, we developed a high-throughput screening method based on bimolecular fluorescence complementation (BiFC) technology in cultured cells, which allowed the identification of small chemical inhibitors specifically blocking the Survivin and Borealin interaction. Primary hits from BiFC were further validated in an in vitro AlphaScreen system, which detects the direct interactions of Survivin and Borealin. Etoposide was identified as one of the effective hits. Direct interaction between Survivin and Etoposide was confirmed by surface plasmon resonance assay, and molecular docking analysis suggested the structural information on how Etoposide inhibits the Survivin and Borealin interaction. These results demonstrate a screening system to identify small molecule chemicals inhibiting Survivin and Borealin interaction. In future, an even larger scale screening may lead to identification of better Survivin and Borealin inhibitors.
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Affiliation(s)
- Liyun Yue
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Lu Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Dan Li
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, 10065, USA
| | - Zhuo Yang
- Chemical Biology Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shuai Han
- Chemical Biology Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ming Chen
- Chemical Biology Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shujue Lan
- Chemical Biology Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Xiaojun Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
| | - Lijian Hui
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
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Shintani M, Tashiro A, Sangawa A, Yamao N, Kamoshida S. Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma. Oncol Lett 2017; 12:4630-4634. [PMID: 28105170 DOI: 10.3892/ol.2016.5220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 04/22/2016] [Indexed: 11/06/2022] Open
Abstract
Survivin, a member of the inhibitor of apoptosis protein family, is a potential prognostic marker and molecular target for anticancer therapies. Chromosomal regional maintenance protein-1 (CRM-1) mediates the nuclear export of proteins such as survivin. The aims of the present study were to compare the expression and subcellular localization of CRM-1 in human gastric and colorectal carcinomas and to assess the association between CRM-1 and survivin expression in these tumor types. The nuclear and cytoplasmic CRM-1 expression rates in gastric carcinoma were 61% (42/69) and 29% (20/69), respectively, while the nuclear and cytoplasmic CRM-1 expression rates in colorectal carcinoma were 55% (43/78) and 37% (29/78), respectively. Nuclear and cytoplasmic CRM-1 expression was found to be significantly correlated with nuclear and cytoplasmic survivin expression in colorectal carcinoma, but not gastric carcinoma. These results indicate that CRM-1 expression patterns differ between gastric and colorectal carcinomas and thus, we hypothesize that CRM-1-mediated nuclear export of survivin may be deregulated in gastric carcinoma. Therefore, CRM-1 may exhibit different functions in gastric and colorectal carcinoma.
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Affiliation(s)
- Michiko Shintani
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
| | - Akito Tashiro
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
| | - Akiko Sangawa
- Department of Diagnostic Pathology, Osaka Red Cross Hospital, Osaka 543-8555, Japan
| | - Naoki Yamao
- Department of Clinical Laboratory, Kuma Hospital, Kobe, Hyogo 650-0011, Japan
| | - Shingo Kamoshida
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
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45
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Cheng CW, Leong KW, Tse E. Understanding the role of PIN1 in hepatocellular carcinoma. World J Gastroenterol 2016; 22:9921-9932. [PMID: 28018099 PMCID: PMC5143759 DOI: 10.3748/wjg.v22.i45.9921] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 09/26/2016] [Accepted: 10/30/2016] [Indexed: 02/06/2023] Open
Abstract
PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, β-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in β-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.
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Assaf HA, Abdel-Maged WM, Elsadek BEM, Hassan MH, Adly MA, Ali SA. Survivin as a Novel Biomarker in the Pathogenesis of Acne Vulgaris and Its Correlation to Insulin-Like Growth Factor-I. DISEASE MARKERS 2016; 2016:7040312. [PMID: 27803511 PMCID: PMC5075610 DOI: 10.1155/2016/7040312] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 09/01/2016] [Accepted: 09/07/2016] [Indexed: 01/10/2023]
Abstract
Survivin, a member of the inhibitor of apoptosis protein family, has an important role in cell cycle regulation. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone with wide range of biologic effects including stimulation of lipogenesis in sebaceous glands. Their overexpression in some fibrotic disorders suggests a possible implication of both IGF-I and survivin in the pathogenesis of acne and/or acne scars. The current study aimed to assess and correlate serum levels of IGF-I and survivin in patients with active acne vulgaris and postinflammatory acne scars and to evaluate their lesional expressions in comparison to healthy controls. Serum IGF-I and survivin were estimated using commercially available ELISA kits and their tissues expressions were investigated using Western blotting. Our findings suggest that IGF-I and survivin could play potential roles in the pathogenesis of active acne vulgaris and more importantly in postinflammatory acne scars with significant positive correlation coefficient between serum levels of IGF-I and survivin which support IGF-I-/PI3K-/AKT-mediated downregulation of nuclear expression of FoxO transcription factors resulting in enhanced survivin expression.
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Affiliation(s)
- Hanan A. Assaf
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Wafaa M. Abdel-Maged
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Bakheet E. M. Elsadek
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, P.O. Box 71524, Assiut, Egypt
| | - Mohammed H. Hassan
- Department of Biochemistry and Molecular Biology, Qena Faculty of Medicine, South Valley University, P.O. Box 83523, Qena, Egypt
| | - Mohamed A. Adly
- Department of Zoology, Faculty of Science, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Soher A. Ali
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
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47
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Fong Y, Tang CC, Hu HT, Fang HY, Chen BH, Wu CY, Yuan SS, Wang HMD, Chen YC, Teng YN, Chiu CC. Inhibitory effect of trans-ferulic acid on proliferation and migration of human lung cancer cells accompanied with increased endogenous reactive oxygen species and β-catenin instability. Chin Med 2016; 11:45. [PMID: 27733866 PMCID: PMC5045596 DOI: 10.1186/s13020-016-0116-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 09/19/2016] [Indexed: 12/13/2022] Open
Abstract
Background Trans-ferulic (FA) acid exhibits antioxidant effects in vitro. However, the underlying mechanism of trans-FA activity in cellular physiology, especially cancer physiology, remains largely unknown. This study investigated the cellular physiological effects of trans-FA on the H1299 human lung cancer cell line. Methods The 2,2-diphenyl-1-picrylhydrazyl assay was used to determine free radical scavenging capability. Assessment of intracellular reactive oxygen species (ROS) was evaluated using oxidized 2ʹ,7ʹ-dichlorofluorescin diacetate and dihydroethidium staining. Trypan blue exclusion, colony formation, and anchorage-independent growth assays were used to determine cellular proliferation. Annexin V staining assay was used to assess cellular apoptosis by flow cytometry. Wound healing and Boyden’s well assays were used to detect the migration and invasion of cells. Gelatin zymography was used to detect matrix metalloproteinase (MMP-2 and MMP-9) activity. Western blotting was used to detect expression levels of various signaling pathway proteins. Results DPPH assay results indicated that trans-FA exerted potent antioxidant effects. However, trans-FA increased intracellular ROS levels, including hydrogen peroxide and superoxide anion, in H1299 cells. Trans-FA treatment inhibited cellular proliferation and induced moderate apoptotic cell death at the highest concentration used (0.6 mM). Furthermore, trans-FA moderately inhibited the migration of H1299 cells at the concentrations of 0.3 and 0.6 mM and attenuated MMP-2 and MMP-9 activity. Trans-FA caused the phosphorylation of β-catenin, resulting in proteasomal degradation of β-catenin. Conversely, trans-FA treatment increased the expression of pro-apoptotic factor Bax and decreased the expression of pro-survival factor survivin. Conclusion Various concentrations (0.06–0.6 mM) of trans-FA exert both anti-proliferation and anti-migration effects in the human lung cancer cell line H1299. Electronic supplementary material The online version of this article (doi:10.1186/s13020-016-0116-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yao Fong
- Department of Thoracic Surgery, Chi-Mei Medical Center, Tainan, 710 Taiwan
| | - Chia-Chun Tang
- Division of Chest, Ten Chan General Hospital, Chung-Li, 320 Taiwan, ROC
| | - Huei-Ting Hu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan
| | - Hsin-Yu Fang
- Department of Food Nutrition, Chung-Hwa University of Medical Technology, Tainan, 701 Taiwan
| | - Bing-Hung Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan.,The Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804 Taiwan
| | - Chang-Yi Wu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan.,Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804 Taiwan
| | - Shyng-Shiou Yuan
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807 Taiwan
| | - Hui-Min David Wang
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402 Taiwan
| | - Yen-Chun Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan
| | - Yen-Ni Teng
- Department of Biological Sciences and Technology, National University of Tainan, Tainan, 700 Taiwan
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan.,Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804 Taiwan.,Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807 Taiwan.,Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung, 807 Taiwan
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Lee SJ, Kim MJ, Kwon IC, Roberts TM. Delivery strategies and potential targets for siRNA in major cancer types. Adv Drug Deliv Rev 2016; 104:2-15. [PMID: 27259398 DOI: 10.1016/j.addr.2016.05.010] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 02/24/2016] [Accepted: 05/15/2016] [Indexed: 02/08/2023]
Abstract
Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types.
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49
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Ou D, Wu Y, Liu J, Lao X, Zhang S, Liao G. miRNA-335 and miRNA-182 affect the occurrence of tongue squamous cell carcinoma by targeting survivin. Oncol Lett 2016; 12:2531-2537. [PMID: 27698823 PMCID: PMC5038158 DOI: 10.3892/ol.2016.4938] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/15/2016] [Indexed: 12/17/2022] Open
Abstract
The aim of the present study was to characterize the roles of two microRNAs (miRs) that have been reported to be differentially expressed in tongue squamous cell carcinoma (TSCC), miR-335 and miR-182. In total, 20 tumor tissue samples and 20 corresponding adjacent non-cancerous samples were collected from patients with TSCC to measure the expression of miR-335 and miR-182 and the potential shared target of these miRs, survivin, using reverse transcription-quantitative polymerase chain reaction and western blotting. In the TSCC tissue samples, significantly decreased expression of the two miRs and increased expression of survivin were detected compared with adjacent non-cancerous controls. Subsequently, it was confirmed that survivin was the target gene of miR-335 and miR-182 using a luciferase assay in TSCC cells. In order to examine the function of miR-335 and miR-182 in the development of TSCC, TSCC cells were transiently transfected with the mimics of the two miRs, and it was confirmed that the introduction of miR-335 and miR-182 to cells suppressed the expression of survivin and markedly inhibited the proliferation of the TSCC cells. Furthermore, miR-335 and miR-182 were found to induce cell cycle arrest by suppressing the expression of survivin. The present study revealed a negative regulatory role of miR-335 and miR-182 in the proliferation of TSCC cells by targeting survivin, and miR-335 and miR-182 may be novel therapeutic targets for the treatment of TSCC.
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Affiliation(s)
- Deming Ou
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China; Department of Stomatology, Central Hospital of Panyu, Guangzhou, Guangdong 511400, P.R. China
| | - Ying Wu
- Department of Stomatology, Foshan Hospital of Chinese Traditional Medicine, Foshan, Guangdong 528000 P.R. China
| | - Jun Liu
- Department of Stomatology, Central Hospital of Panyu, Guangzhou, Guangdong 511400, P.R. China
| | - Xiaomei Lao
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Sien Zhang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Guiqing Liao
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, P.R. China
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50
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Youssef MM, Tolba MF, Badawy NN, Liu AW, El-Ahwany E, Khalifa AE, Zada S, Abdel-Naim AB. Novel combination of sorafenib and biochanin-A synergistically enhances the anti-proliferative and pro-apoptotic effects on hepatocellular carcinoma cells. Sci Rep 2016; 6:30717. [PMID: 27470322 PMCID: PMC4965826 DOI: 10.1038/srep30717] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 07/06/2016] [Indexed: 02/08/2023] Open
Abstract
Sorafenib (SOR) is the first-line treatment for hepatocellular carcinoma (HCC). However, its use is hindered by the recently expressed safety concerns. One approach for reducing SOR toxicity is to use lower doses in combination with other less toxic agents. Biochanin-A (Bio-A), a promising isoflavone, showed selective toxicity to liver cancer cells. We postulated that combining SOR and Bio-A could be synergistically toxic towards HCC cells. We further evaluated the underlying mechanism. Cytotoxicity assay was performed to determine the IC50 of Bio-A and SOR in HepG2, SNU-449 and Huh-7 cells. Then, combination index in HepG2 was evaluated using Calcusyn showing that the concurrent treatment with lower concentrations of SOR and Bio-A synergistically inhibited cell growth. Our combination induced significant arrest in pre-G and G0/G1 cell cycle phases and decrease in cyclin D1 protein level. Concomitantly, SOR/Bio-A reduced Bcl-2/Bax ratio. Furthermore, this co-treatment significantly increased caspase-3 & -9 apoptotic markers, while decreased anti-apoptotic and proliferative markers; survivin and Ki-67, respectively. Active caspase-3 in HepG2, SNU-449 and Huh-7 confirmed our synergism hypothesis. This study introduces a novel combination, where Bio-A synergistically enhanced the anti-proliferative and apoptotic effects of SOR in HCC cells, which could serve as a potential effective regimen for treatment.
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Affiliation(s)
- Mohieldin M Youssef
- The American University in Cairo, New Cairo, 11835 Egypt.,Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan
| | - Mai F Tolba
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
| | - Noha N Badawy
- The American University in Cairo, New Cairo, 11835 Egypt
| | - Andrew W Liu
- Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan
| | - Eman El-Ahwany
- Immunology Department, Theodor-Bilharz Research Institute (TBRI), Giza, 12411 Egypt
| | - Amani E Khalifa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
| | - Suher Zada
- The American University in Cairo, New Cairo, 11835 Egypt
| | - Ashraf B Abdel-Naim
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
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