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Lu X, Zhang Y, Xue J, Evert M, Calvisi D, Chen X, Wang X. MAD2L1 supports MYC-driven liver carcinogenesis in mice and predicts poor prognosis in human hepatocarcinoma. Toxicol Sci 2025; 203:41-51. [PMID: 39316419 DOI: 10.1093/toxsci/kfae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
Mitotic arrest-deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint implicated in cancer cell proliferation and tumorigenesis. The functional role of MAD2L1 in hepatocellular carcinoma (HCC) has not been adequately investigated, especially in vivo. In the current manuscript, we sought to address the function of MAD2L1 in hepatocarcinogenesis. We found that MAD2L1 expression is upregulated in human HCCs, where its expression is associated with higher aggressive tumor grade, elevated proliferative activity, and poor prognosis. In human HCC cell lines, MAD2L1 knockdown led to decreased cell growth. Moreover, RNA-seq results demonstrated that MAD2L1 silencing induces the expression of genes associated with cell cycle, DNA replication, and various cancer-related pathways, supporting the critical role of MAD2L1 during HCC growth and differentiation. In a c-MYC-induced mouse HCC model, we revealed an increased expression of Mad2l1. Furthermore, Mad2l1 CRIPSR-mediated silencing prevented c-MYC-driven mouse liver development. Altogether, our study suggests that MAD2L1 plays a crucial role in hepatocarcinogenesis, and that its suppression could be a promising therapeutic strategy for treating human HCC. MAD2L1 plays a critical role in liver cancer development, silencing MAD2L1 reduced cell growth in vitro and inhibited c-MYC-driven liver cancer development in vivo. MAD2L1 suppression might be a promising therapeutic approach for treating human liver cancer.
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Affiliation(s)
- Xinjun Lu
- Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Ya Zhang
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
| | - Jiahao Xue
- Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Diego Calvisi
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Xin Chen
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
| | - Xue Wang
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
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Li D, Bao Q, Ren S, Ding H, Guo C, Gao K, Wan J, Wang Y, Zhu M, Xiong Y. Comprehensive Analysis of the Mechanism of Anoikis in Hepatocellular Carcinoma. Genet Res (Camb) 2024; 2024:8217215. [PMID: 39297018 PMCID: PMC11410409 DOI: 10.1155/2024/8217215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/25/2024] [Accepted: 08/10/2024] [Indexed: 09/21/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC), ranking as the second-leading cause of global mortality among malignancies, poses a substantial burden on public health worldwide. Anoikis, a type of programmed cell death, serves as a barrier against the dissemination of cancer cells to distant organs, thereby constraining the progression of cancer. Nevertheless, the mechanism of genes related to anoikis in HCC is yet to be elucidated. Methods This paper's data (TCGA-HCC) were retrieved from the database of the Cancer Genome Atlas (TCGA). Differential gene expression with prognostic implications for anoikis was identified by performing both the univariate Cox and differential expression analyses. Through unsupervised cluster analysis, we clustered the samples according to these DEGs. By employing the least absolute shrinkage and selection operator Cox regression analysis (CRA), a clinical predictive gene signature was generated from the DEGs. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of immune cell types. The external validation data (GSE76427) were procured from Gene Expression Omnibus (GEO) to verify the performance of the clinical prognosis gene signature. Western blotting and immunohistochemistry (IHC) analysis confirmed the expression of risk genes. Results In total, 23 prognostic DEGs were identified. Based on these 23 DEGs, the samples were categorized into four distinct subgroups (clusters 1, 2, 3, and 4). In addition, a clinical predictive gene signature was constructed utilizing ETV4, PBK, and SLC2A1. The gene signature efficiently distinguished individuals into two risk groups, specifically low and high, demonstrating markedly higher survival rates in the former group. Significant correlations were observed between the expression of these risk genes and a variety of immune cells. Moreover, the outcomes from the validation cohort analysis aligned consistently with those obtained from the training cohort analysis. The results of Western blotting and IHC showed that ETV4, PBK, and SLC2A1 were upregulated in HCC samples. Conclusion The outcomes of this paper underscore the effectiveness of the clinical prognostic gene signature, established utilizing anoikis-related genes, in accurately stratifying patients. This signature holds promise in advancing the development of personalized therapy for HCC.
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Affiliation(s)
- Dongqian Li
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Qian Bao
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Shiqi Ren
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Haoxiang Ding
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Chengfeng Guo
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Kai Gao
- Nantong University Medical School, Nantong 226001, Jiangsu, China
| | - Jian Wan
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Yao Wang
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - MingYan Zhu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Yicheng Xiong
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Nantong University Medical School of Nantong University, Nantong 226001, Jiangsu, China
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Hernández-Magaña A, Bensussen A, Martínez-García JC, Álvarez-Buylla ER. A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence. NPJ Syst Biol Appl 2024; 10:99. [PMID: 39223160 PMCID: PMC11369243 DOI: 10.1038/s41540-024-00422-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the gene expression profile of hepatocytes and mesenchymal cells in senescent, quiescent, proliferative, and stem-like states. The epigenetic landscape associated with the regulatory network was analyzed. We observed that the loss of p53, p16, RB, or the constitutive activation of β-catenin and YAP1 increases the robustness of the proliferative stem-like phenotypes. Additionally, we found that p53 inactivation facilitates the transition of proliferative hepatocytes into stem-like mesenchymal phenotype. Thus, phenotypic plasticity may be altered, and stem-like phenotypes related to CSCs may be easier to attain following the mutation acquisition.
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Affiliation(s)
- Alexis Hernández-Magaña
- Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Antonio Bensussen
- Departamento de Control Automático, Cinvestav-IPN, Ciudad de México, México
| | | | - Elena R Álvarez-Buylla
- Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México.
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, México.
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Liu Y, Pang Z, Wang J, Wang J, Ji B, Xu Y, He J, Zhang L, Han Y, Shen L, Xu W, Ren M. Multi-omics comprehensive analysis reveals the predictive value of N6-methyladenosine- related genes in prognosis and immune escape of bladder cancer. Cancer Biomark 2024; 40:79-94. [PMID: 38517777 PMCID: PMC11307005 DOI: 10.3233/cbm-230286] [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: 07/03/2023] [Accepted: 12/18/2023] [Indexed: 03/24/2024]
Abstract
BACKGROUND N6-methyladenosine (m6A) is the most frequent RNA modification in mammals, and its role in bladder cancer (BC) remains rarely revealed. OBJECTIVE To predict the value of m6A-related genes in prognosis and immunity in BC. METHODS We performed multiple omics analysis of 618 TCGA and GEO patients and used principal component analysis (PCA) to calculate the m6A score for BC patients. RESULTS We described the multiple omics status of 23 m6A methylation-related genes (MRGs), and four m6A clusters were identified, which showed significant differences in immune infiltration and biological pathways. Next, we intersected the differential genes among m6A clusters, and 11 survival-related genes were identified, which were used to calculate the m6A score for the patients. We found that the high-score (HS) group showed lower tumor mutation burden (TMB) and TP53 mutations and better prognosis than the low-score (LS) group. Lower immune infiltration, higher expression of PD-L1, PD-1, and CTLA4, and higher immune dysfunction and immune exclusion scores were identified in the LS group, suggesting a higher possibility of immune escape. Finally, the experimental verification shows that the m6A related genes, such as IGFBP1, plays an important role in the growth and metastasis of bladder cancer. CONCLUSIONS These findings revealed the important roles of m6A MRGs in predicting prognosis, TMB status, TP53 mutation, immune functions and immunotherapeutic response in BC.
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Affiliation(s)
- Yang Liu
- Department of Urology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zhongqi Pang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jianshe Wang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jinfeng Wang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Bo Ji
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yidan Xu
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jiaxin He
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lu Zhang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yansong Han
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Linkun Shen
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Wanhai Xu
- Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Minghua Ren
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Ho YF, Yajit NLM, Shiau JY, Malek SNA, Shyur LF, Karsani SA. Changes in the Proteome Profile of A549 Cells Following Helichrysetin-Induced Apoptosis Suggest the Involvement of DNA Damage Response and Cell Cycle Arrest-Associated Proteins. Appl Biochem Biotechnol 2023; 195:6867-6880. [PMID: 36947367 DOI: 10.1007/s12010-023-04384-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 03/23/2023]
Abstract
Our previous findings demonstrated that Helichrysetin possessed promising anti-cancer activity. It was able to induce apoptosis in the A549 cell line. However, its mechanism of action is unknown. The present study aimed to unravel possible underlying molecular mechanisms of helichrysetin-induced apoptosis in A549 (human lung carcinoma) cells using comparative quantitative proteomics (iTRAQ labeled), followed by an exhaustive bioinformatics analysis. Our results suggested that DNA damage response (DDR) and cell cycle arrest were responsible for lung cancer cell death with helichrysetin treatment. Among proteins that changed in abundance were Nrf2 and HMOX1. They are oxidative stress-related proteins and were increased in abundance. BRAT1 was also increased in abundance, suggesting an increase in DNA damage repair, indicating the occurrence of DNA damage due to oxidative stress. However, several essential DDR downstream proteins such as p-ATM, BRCA1, FANCD2, and Rb1 that would further increase DNA damage were found to be dramatically decreased in relative abundance. Cell cycle-related proteins, p53, p21, and cyclin D1, were increased while cyclin A, cyclin E, and cdk2 were decreased. This is predicted to facilitate S-phase arrest. Furthermore, excessive DNA damage and prolonged arrest would in turn result in the induction of mitochondrial-mediated apoptosis. Based on these observations, we postulate that the effects of helichrysetin were in part via the suppression of DNA damage response which led to DNA damage and prolonged cell cycle arrest. Subsequently, this event initiated mitochondrial-mediated apoptosis in A549 lung cancer cells.
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Affiliation(s)
- Yen Fong Ho
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Noor Liana Mat Yajit
- University of Malaya Centre for Proteomics Research (UMCPR), Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Jeng-Yuan Shiau
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115, Taiwan
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan
| | - Sri Nurestri Abd Malek
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Lie-Fen Shyur
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115, Taiwan.
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan.
| | - Saiful Anuar Karsani
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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Song Z, Zhang J, Sun Y, Jiang Z, Liu X. Establishment and validation of an immune infiltration predictive model for ovarian cancer. BMC Med Genomics 2023; 16:227. [PMID: 37759229 PMCID: PMC10538244 DOI: 10.1186/s12920-023-01657-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The most prevalent mutation in ovarian cancer is the TP53 mutation, which impacts the development and prognosis of the disease. We looked at how the TP53 mutation associates the immunophenotype of ovarian cancer and the prognosis of the disease. METHODS We investigated the state of TP53 mutations and expression profiles in culturally diverse groups and datasets and developed an immune infiltration predictive model relying on immune-associated genes differently expressed between TP53 WT and TP53 MUT ovarian cancer cases. We aimed to construct an immune infiltration predictive model (IPM) to enhance the prognosis of ovarian cancer and investigate the impact of the IPM on the immunological microenvironment. RESULTS TP53 mutagenesis affected the expression of seventy-seven immune response-associated genes. An IPM was implemented and evaluated on ovarian cancer patients to distinguish individuals with low- and high-IPM subgroups of poor survival. For diagnostic and therapeutic use, a nomogram is thus created. According to pathway enrichment analysis, the pathways of the human immune response and immune function abnormalities were the most associated functions and pathways with the IPM genes. Furthermore, patients in the high-risk group showed low proportions of macrophages M1, activated NK cells, CD8+ T cells, and higher CTLA-4, PD-1, PD-L1, and TIM-3 than patients in the low-risk group. CONCLUSIONS The IPM model may identify high-risk patients and integrate other clinical parameters to predict their overall survival, suggesting it is a potential methodology for optimizing ovarian cancer prognosis.
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Affiliation(s)
- Zhenxia Song
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Jingwen Zhang
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Yue Sun
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China
| | - Zhongmin Jiang
- Department of Pathology, Tian Jin Fifth's Central Hospital, #41 Zhejiang Road, Binhai District, Tianjin, 300450, P. R. China
| | - Xiaoning Liu
- Department of Obstetrics, Qingdao women and childeren's hospital, #6 Tongfu Road, Shibei District, Qingdao, Shandong, 266000, P. R. China.
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Liu L, Wang Q, Wu L, Zhang L, Huang Y, Yang H, Guo L, Fang Z, Wang X. Overexpression of POLA2 in hepatocellular carcinoma is involved in immune infiltration and predicts a poor prognosis. Cancer Cell Int 2023; 23:138. [PMID: 37452331 PMCID: PMC10349470 DOI: 10.1186/s12935-023-02949-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/16/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second malignancy worldwide. POLA2 initiates DNA replication, regulates cell cycle and gene repair that promote tumorigenesis and disease progression. However, the prognostic and biological function roles of POLA2 in HCC had not been conclusively determined. METHODS The expression levels and prognosis role of POLA1 and POLA2 in HCC were analyzed based on TCGA-LIHC database and recruited 24 HCC patients. Gene mutations were analyzed using "maftools" package. POLA2 and immune cells correlations were analyzed by TIMER. POLA2 co-expressed genes functional enrichment were evaluated using Metascape. The mRNA and protein level of POLA2 was detected in HCC cells and tissues. Cell migration, invasion, proliferation, cell cycle and HCC cell lines derived xenograft model were performed to investigate POLA2 biological function. RESULTS POLA2 was significantly high expressed in HCC than in normal liver tissue in both TCGA-LIHC and our collected HCC samples. In validation cohort, POLA2 significantly related to tumor differentiation, tumor size and Ki-67 (p < 0.05). In TCGA-LIHC cohort, overexpression of POLA2 predicted a low OS and associated with different clinical stages. Multivariate Cox regression showed overexpression of POLA2 effectively distinguished the prognosis at different T, N, M, stages and grades of HCC. POLA2 expression correlated with mutation burden, immune cells infiltration and immune-associated genes expression of HCC. Functional enrichment revealed that POLA2 co-expressed genes were linked to cellular activity, plasma membrane protein complex and leukocyte activity, immune response-regulated cell surface receptor signaling pathway, and immune response-regulated signaling pathway. Moreover, POLA2 was also positively co-expressed with some immune checkpoints (CD274, CTL-4, HAVCR2, PDCD1, PDCD1LG2, TIGIT, and LAG3) (p < 0.001). Gene knockdown revealed that POLA2 promoted proliferation, migration, invasion, and cell cycle of SMMC-7721 and HepG2. The HCC xenograft tumor model also demonstrated remarkably tumor size inhibition, tumor proliferation inhibtion and tumor necrosis promotion when POLA2 knockdown. CONCLUSIONS POLA2 influenced immune microenvironment and tumor progression of HCC indicated that it might be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.
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Affiliation(s)
- Long Liu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, 317000, Zhejiang, China
| | - Qi Wang
- Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, Zhejiang, China
| | - Linjun Wu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, 317000, Zhejiang, China
- Taizhou Hospital Library, Wenzhou Medical University, Linhai, 317000, Zhejiang, China
| | - Lele Zhang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Yuxi Huang
- Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, Zhejiang, China
| | - Haihua Yang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province, Linhai, 317000, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive, System Tumor of Zhejiang Province, Zhejiang, China
| | - Le Guo
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, 317000, Zhejiang, China.
- Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, Zhejiang, China.
| | - Xuequan Wang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province, Linhai, 317000, Zhejiang, China.
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive, System Tumor of Zhejiang Province, Zhejiang, China.
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Kopystecka A, Patryn R, Leśniewska M, Budzyńska J, Kozioł I. The Use of ctDNA in the Diagnosis and Monitoring of Hepatocellular Carcinoma-Literature Review. Int J Mol Sci 2023; 24:ijms24119342. [PMID: 37298294 DOI: 10.3390/ijms24119342] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/18/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important limitations, especially in very small nodules and those which show atypical imaging features. In recent years, liquid biopsy and molecular analysis of tumor breakdown products have become an attractive source of new biomarkers. Patients with liver and biliary malignancies, including hepatocellular carcinoma (HCC), may greatly benefit from ctDNA testing. These patients are often diagnosed at an advanced stage of the disease, and relapses are common. Molecular analysis may indicate the best cancer treatment tailored to particular patients with specific tumor DNA mutations. Liquid biopsy is a minimally invasive technique that facilitates the early detection of cancer. This review summarizes the knowledge of ctDNA in liquid biopsy as an indicator for early diagnosis and monitoring of hepatocellular cancer.
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Affiliation(s)
- Agnieszka Kopystecka
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Rafał Patryn
- Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Magdalena Leśniewska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Julia Budzyńska
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ilona Kozioł
- Students' Scientific Circle on Medical Law, Department of Humanities and Social Medicine, Medical University of Lublin, 20-093 Lublin, Poland
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Li D, Lei L, Wang J, Tang B, Wang J, Dong R, Shi W, Liu G, Zhao T, Wu Y, Zhang Y. Prognosis and personalized medicine prediction by integrated whole exome and transcriptome sequencing of hepatocellular carcinoma. Front Genet 2023; 14:1075347. [PMID: 36816040 PMCID: PMC9932713 DOI: 10.3389/fgene.2023.1075347] [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: 10/20/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a clinically and genetically heterogeneous disease. To better describe the clinical value of the main driver gene mutations of HCC, we analyzed the whole exome sequencing data of 125 patients, and combined with the mutation data in the public database, 14 main mutant genes were identified. And we explored the correlation between the main mutation genes and clinical features. Consistent with the results of previous data, we found that TP53 and LRP1B mutations were related to the prognosis of our patients by WES data analysis. And we further explored the associated characteristics of TP53 and LRP1B mutations. However, it is of great clinical significance to tailor a unique prediction method and treatment plan for HCC patients according to the mutation of TP53. For TP53 wild-type HCC patients, we proposed a prognostic risk model based on 11 genes for better predictive value. According to the median risk score of the model, HCC patients with wild-type TP53 were divided into high-risk and low-risk groups. We found significant transcriptome changes in the enrichment of metabolic-related pathways and immunological characteristics between the two groups, suggesting the predictability of HCC immunotherapy by using this model. Through the CMap database, we found that AM580 had potential therapeutic significance for high-risk TP53 wild-type HCC patients.
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Affiliation(s)
- Debao Li
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong, China,Chongqing International Institute for Immunology, Chongqing, China,Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Lei Lei
- Department of Ophthalmology, Airforce Hospital, Chengdu, Sichuan, China
| | - Jinsong Wang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Bo Tang
- Chongqing International Institute for Immunology, Chongqing, China
| | - Jiuling Wang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Rui Dong
- Chongqing International Institute for Immunology, Chongqing, China
| | - Wenjiong Shi
- Chongqing International Institute for Immunology, Chongqing, China
| | - Guo Liu
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Sichuan, China
| | - Tingting Zhao
- Chongqing International Institute for Immunology, Chongqing, China,School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Yuzhang Wu
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong, China,Chongqing International Institute for Immunology, Chongqing, China,Institute of Immunology, PLA, Army Medical University, Chongqing, China,*Correspondence: Yi Zhang, ; Yuzhang Wu,
| | - Yi Zhang
- Chongqing International Institute for Immunology, Chongqing, China,School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China,*Correspondence: Yi Zhang, ; Yuzhang Wu,
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11
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Lu D, Liao J, Cheng H, Ma Q, Wu F, Xie F, He Y. Construction and systematic evaluation of a machine learning-based cuproptosis-related lncRNA score signature to predict the response to immunotherapy in hepatocellular carcinoma. Front Immunol 2023; 14:1097075. [PMID: 36761763 PMCID: PMC9905126 DOI: 10.3389/fimmu.2023.1097075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a common malignant cancer with a poor prognosis. Cuproptosis and associated lncRNAs are connected with cancer progression. However, the information on the prognostic value of cuproptosis-related lncRNAs is still limited in HCC. Methods We isolated the transcriptome and clinical information of HCC from TCGA and ICGC databases. Ten cuproptosis-related genes were obtained and related lncRNAs were correlated by Pearson's correlation. By performing lasso regression, we created a cuproptosis-related lncRNA prognostic model based on the cuproptosis-related lncRNA score (CLS). Comprehensive analyses were performed, including the fields of function, immunity, mutation and clinical application, by various R packages. Results Ten cuproptosis-related genes were selected, and 13 correlated prognostic lncRNAs were collected for model construction. CLS was positively or negatively correlated with cancer-related pathways. In addition, cell cycle and immune related pathways were enriched. By performing tumor microenvironment (TME) analysis, we determined that T-cells were activated. High CLS had more tumor characteristics and may lead to higher invasiveness and treatment resistance. Three genes (TP53, CSMD1 and RB1) were found in high CLS samples with more mutational frequency. More amplification and deletion were detected in high CLS samples. In clinical application, a CLS-based nomogram was constructed. 5-Fluorouracil, gemcitabine and doxorubicin had better sensitivity in patients with high CLS. However, patients with low CLS had better immunotherapeutic sensitivity. Conclusion We created a prognostic CLS signature by machine learning, and we comprehensively analyzed the signature in the fields of function, immunity, mutation and clinical application.
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Affiliation(s)
- Dingyu Lu
- Oncology Department, Deyang People’s Hospital, Deyang, China
| | - Jian Liao
- Intensive care Unit, Deyang People’s Hospital, Deyang, China
| | - Hao Cheng
- Oncology Department, Deyang People’s Hospital, Deyang, China
| | - Qian Ma
- Oncology Department, Deyang People’s Hospital, Deyang, China
| | - Fei Wu
- Oncology Department, Deyang People’s Hospital, Deyang, China
| | - Fei Xie
- Oncology Department, Deyang People’s Hospital, Deyang, China
| | - Yingying He
- Oncology Department, Deyang People’s Hospital, Deyang, China
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12
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Luo L, Liu H, Yan F. Dynamic behavior of P53-Mdm2-Wip1 gene regulatory network under the influence of time delay and noise. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:2321-2347. [PMID: 36899536 DOI: 10.3934/mbe.2023109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The tumor suppressor protein P53 can regulate the cell cycle, thereby preventing cell abnormalities. In this paper, we study the dynamic characteristics of the P53 network under the influence of time delay and noise, including stability and bifurcation. In order to study the influence of several factors on the concentration of P53, bifurcation analysis on several important parameters is conducted; the results show that the important parameters could induce P53 oscillations within an appropriate range. Then we study the stability of the system and the existing conditions of Hopf bifurcation by using Hopf bifurcation theory with time delays as the bifurcation parameter. It is found that time delay plays a key role in inducing Hopf bifurcation and regulating the period and amplitude of system oscillation. Meanwhile, the combination of time delays can not only promote the oscillation of the system but it also provides good robustness. Changing the parameter values appropriately can change the bifurcation critical point and even the stable state of the system. In addition, due to the low copy number of the molecules and the environmental fluctuations, the influence of noise on the system is also considered. Through numerical simulation, it is found that noise not only promotes system oscillation but it also induces system state switching. The above results may help us to further understand the regulation mechanism of the P53-Mdm2-Wip1 network in the cell cycle.
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Affiliation(s)
- LanJiang Luo
- Department of Mathematics, Yunnan Normal University, Kunming 650500, China
- Key Laboratory of Complex System Modeling and Application for Universities in Yunnan, Kunming 650500, China
| | - Haihong Liu
- Department of Mathematics, Yunnan Normal University, Kunming 650500, China
- Key Laboratory of Complex System Modeling and Application for Universities in Yunnan, Kunming 650500, China
| | - Fang Yan
- Department of Mathematics, Yunnan Normal University, Kunming 650500, China
- Key Laboratory of Complex System Modeling and Application for Universities in Yunnan, Kunming 650500, China
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Abdul Razak AR, Bauer S, Suarez C, Lin CC, Quek R, Hütter-Krönke ML, Cubedo R, Ferretti S, Guerreiro N, Jullion A, Orlando EJ, Clementi G, Sand Dejmek J, Halilovic E, Fabre C, Blay JY, Italiano A. Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results From a Proof-of-Concept, Phase Ib Study. Clin Cancer Res 2021; 28:1087-1097. [PMID: 34921024 DOI: 10.1158/1078-0432.ccr-21-1291] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy. METHODS In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A (4-week cycle: siremadlin once daily [QD] and ribociclib QD, [2 weeks on, 2 weeks off]); Regimen B (3-week cycle: siremadlin once every 3 weeks; ribociclib QD [2 weeks on, 1 week off]); Regimen C (4-week cycle: siremadlin once every 4 weeks; ribociclib QD [2 weeks on, 2 weeks off]). The primary objective was to determine the maximum tolerated dose and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens. RESULTS As of 16 October 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity. CONCLUSION Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
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Affiliation(s)
| | - Sebastian Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany; DKTK partner site Essen and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Cristina Suarez
- Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO)
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital
| | | | | | - Ricardo Cubedo
- Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda
| | | | | | | | | | - Giorgia Clementi
- Translational Clinical Oncology, Novartis Institutes for BioMedical Research
| | | | | | | | - Jean-Yves Blay
- Medecine, Centre Leon Bérard, Univ Claude Bernard, Unicancer
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14
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Ravichandran A, Clegg J, Adams MN, Hampson M, Fielding A, Bray LJ. 3D Breast Tumor Models for Radiobiology Applications. Cancers (Basel) 2021; 13:5714. [PMID: 34830869 PMCID: PMC8616164 DOI: 10.3390/cancers13225714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/28/2021] [Accepted: 11/07/2021] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is a leading cause of cancer-associated death in women. The clinical management of breast cancers is normally carried out using a combination of chemotherapy, surgery and radiation therapy. The majority of research investigating breast cancer therapy until now has mainly utilized two-dimensional (2D) in vitro cultures or murine models of disease. However, there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers over the past decade, highlighting a complimentary model for studies of radiotherapy, especially in conjunction with chemotherapy. In this review, we underline the effects of radiation therapy on normal and malignant breast cells and tissues, and explore the emerging opportunities that pre-clinical 3D models offer in improving our understanding of this treatment modality.
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Affiliation(s)
- Akhilandeshwari Ravichandran
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia; (A.R.); (J.C.); (M.H.)
- ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia;
| | - Julien Clegg
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia; (A.R.); (J.C.); (M.H.)
- ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia;
| | - Mark N. Adams
- ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia;
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia
| | - Madison Hampson
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia; (A.R.); (J.C.); (M.H.)
| | - Andrew Fielding
- School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, Australia;
| | - Laura J. Bray
- School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia; (A.R.); (J.C.); (M.H.)
- ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia;
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Zhang Z, Papa Akuetteh PD, Lin L, Wu Y, Li Y, Huang W, Ni H, Lv H, Zhang Q. Development and validation of a ferroptosis-related model for three digestive tract tumors based on a pan-cancer analysis. Epigenomics 2021; 13:1497-1514. [PMID: 34581636 DOI: 10.2217/epi-2021-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aims: To develop a ferroptosis gene-based survival-predictor model for predicting the prognosis of patients with digestive tract tumors, a pan-caner analysis was performed. Materials & methods: Based on unsupervised clustering and the expression levels of ferroptosis genes, patients with cancer were divided into two clusters. The least absolute shrinkage and selection operator method Cox regression analysis was used to establish the survival-predictor model. Results: Based on the pan-cancer analysis, a 20 gene-based survival-predictor model for predicting survival rates was developed, which was validated in patients with hepatocellular carcinoma. Conclusion: The survival-predictor model accurately predicted the prognosis of patients with digestive tract tumors.
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Affiliation(s)
- Zhongjing Zhang
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
| | - Percy David Papa Akuetteh
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
| | - Leilei Lin
- First school of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Yiyang Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yimeng Li
- Key Laboratory of Diagnosis & Treatment of Severe Hepato-Pancreatic Diseases, The First Affiliated Hospital, Wenzhou Medical University, 325015, Zhejiang Province, China
| | - Weiguo Huang
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
| | - Haizhen Ni
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
| | - Heping Lv
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
| | - Qiyu Zhang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang Province, China
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Duan X, Cai Y, He T, Shi X, Zhao J, Zhang H, Shen Y, Zhang H, Zhang H, Duan W, Jiang B, Mao X. The effect of the TP53 and RB1 mutations on the survival of hepatocellular carcinoma patients with different racial backgrounds. J Gastrointest Oncol 2021; 12:1786-1796. [PMID: 34532128 DOI: 10.21037/jgo-21-312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/02/2021] [Indexed: 12/18/2022] Open
Abstract
Background Racial disparities in the survival of patients with hepatocellular carcinoma (HCC) exist. Gene mutations have a profound effect on carcinogenesis, are easily affected by environment and etiology factors, and may result in survival divergences among patients with different racial backgrounds. This report explores the effects of gene mutations on the survival of American Caucasians and Asian patients. Methods The sequencing and clinical data of 336 HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. The sequencing data was subject to gene mutation profiling, and an analysis of immune cell infiltration was conducted. A multivariate analysis was performed to assess the independent effects of gene mutations on patients' overall survival (OS) and disease-free survival (DFS). Results Asian HCC patients had a significantly higher level of TP53 mutation frequency than Caucasian HCC patients (Asian vs. Caucasian, 39% vs. 23%; P=0.003). The TP53 mutation was associated with shorter OS [hazard ratio (HR), 2.33; 95% confidence interval (CI), 1.36-3.97; P=0.002] and DFS (HR, 2.2; 95% CI, 1.38-3.51; P<0.001) in Caucasian HCC patients, but had no effect on Asian HCC patients' survival. Compared to Asian HCC patients, Caucasian HCC patients with the TP53 mutation had a decreased proportion of infiltrating M2 macrophages and activating natural killer (NK) cells, and an increased proportion of follicular helper T cells. The RB1 mutation was associated with shorter OS (HR, 3.37; 95% CI, 1.73-6.57; P<0.001) in Asian HCC patients, and shorter DFS (HR, 2.11; 95% CI, 1.15-3.88; P=0.017) in Caucasian HCC patients. Asian HCC patients with the RB1 mutation had a decreased proportion of infiltrating CD8 T cells. Conclusions The effects of the TP53 and RB1 mutations on survival differ among Asian and Caucasian HCC patients.
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Affiliation(s)
- Xiaohui Duan
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yi Cai
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | | | | | | | - Hui Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yao Shen
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Hongjian Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Heng Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Wenbin Duan
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Bo Jiang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Xianhai Mao
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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Huo J, Wu L, Zang Y. Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma. Front Oncol 2021; 11:618976. [PMID: 34178618 PMCID: PMC8222811 DOI: 10.3389/fonc.2021.618976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/14/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood. MATERIAL AND APPROACH This study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan-Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis. RESULTS A prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression. CONCLUSION Our study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.
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Affiliation(s)
- Junyu Huo
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqun Wu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yunjin Zang
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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Radomska D, Czarnomysy R, Radomski D, Bielawska A, Bielawski K. Selenium as a Bioactive Micronutrient in the Human Diet and Its Cancer Chemopreventive Activity. Nutrients 2021; 13:1649. [PMID: 34068374 PMCID: PMC8153312 DOI: 10.3390/nu13051649] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/15/2022] Open
Abstract
This review answers the question of why selenium is such an important trace element in the human diet. Daily dietary intake of selenium and its content in various food products is discussed in this paper, as well as the effects of its deficiency and excess in the body. Moreover, the biological activity of selenium, which it performs mainly through selenoproteins, is discussed. These specific proteins are responsible for thyroid hormone management, fertility, the aging process, and immunity, but their key role is to maintain a redox balance in cells. Furthermore, taking into account world news and the current SARS-CoV-2 virus pandemic, the impact of selenium on the course of COVID-19 is also discussed. Another worldwide problem is the number of new cancer cases and cancer-related mortality. Thus, the last part of the article discusses the impact of selenium on cancer risk based on clinical trials (including NPC and SELECT), systematic reviews, and meta-analyses. Additionally, this review discusses the possible mechanisms of selenium action that prevent cancer development.
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Affiliation(s)
- Dominika Radomska
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (D.R.); (D.R.); (K.B.)
| | - Robert Czarnomysy
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (D.R.); (D.R.); (K.B.)
| | - Dominik Radomski
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (D.R.); (D.R.); (K.B.)
| | - Anna Bielawska
- Department of Biotechnology, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland;
| | - Krzysztof Bielawski
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland; (D.R.); (D.R.); (K.B.)
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Aragoneses-Cazorla G, Serrano-Lopez J, Martinez-Alfonzo I, Vallet-Regí M, González B, Luque-Garcia JL. A novel hemocompatible core@shell nanosystem for selective targeting and apoptosis induction in cancer cells. Inorg Chem Front 2021. [DOI: 10.1039/d1qi00143d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Synthesis, characterization and evaluation of transferrin-decorated mesoporous silica-coated silver nanoparticles as a novel hemocompatible core@shell nanosystem for selective targeting and apoptosis induction in cancer cells.
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Affiliation(s)
| | | | | | - María Vallet-Regí
- Department of Chemistry in Pharmaceutical Sciences
- Faculty of Pharmacy
- Complutense University of Madrid
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12)
- Madrid
| | - Blanca González
- Department of Chemistry in Pharmaceutical Sciences
- Faculty of Pharmacy
- Complutense University of Madrid
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12)
- Madrid
| | - Jose L. Luque-Garcia
- Department of Analytical Chemistry
- Faculty of Chemical Sciences
- Complutense University of Madrid
- Madrid
- Spain
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Wu X, Lv D, Cai C, Zhao Z, Wang M, Chen W, Liu Y. A TP53-Associated Immune Prognostic Signature for the Prediction of Overall Survival and Therapeutic Responses in Muscle-Invasive Bladder Cancer. Front Immunol 2020; 11:590618. [PMID: 33391264 PMCID: PMC7774015 DOI: 10.3389/fimmu.2020.590618] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background TP53 gene mutation is one of the most common mutations in human bladder cancer (BC) and has been implicated in the progression and prognosis of BC. Methods RNA sequencing data and TP53 mutation data in different populations and platforms were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database to determine and validate a TP53-associated immune prognostic signature (TIPS) based on differentially expressed immune-related genes (DEIGs) between muscle-invasive bladder cancer (MIBC) patients with and without TP53 mutations. Results A total of 99 DEIGs were identified based on TP53 mutation status. TIPS including ORM1, PTHLH, and CTSE were developed and validated to identify high-risk prognostic group who had a poorer prognosis than low-risk prognostic group in TCGA and GEO database. The high-risk prognostic group were characterized by a higher abundance of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages than the low-risk prognostic group. Moreover, they exhibited a lower abundance of CD56bright NK cells, higher expression of CTLA4, LAG3, PDCD1, TIGIT, and HAVCR2, as well as being more likely to respond to anti–PD-1, and neoadjuvant chemotherapy than the low-risk prognostic group. Based on TIPS and other clinical characteristics, a nomogram was constructed for clinical use. Conclusion TIPS derived from TP53 mutation status is a potential prognostic signature or therapeutic target but additional prospective studies are necessary to confirm this potential.
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Affiliation(s)
- Xiangkun Wu
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Daojun Lv
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Chao Cai
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Zhijian Zhao
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Ming Wang
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Wenzhe Chen
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
| | - Yongda Liu
- Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, China
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Go YY, Kim SR, Kim DY, Chae SW, Song JJ. Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep 2020; 10:20622. [PMID: 33244087 PMCID: PMC7692486 DOI: 10.1038/s41598-020-77674-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 11/11/2020] [Indexed: 12/16/2022] Open
Abstract
Cannabidiol (CBD) has anti-tumorigenic activity. However, the anti-cancer effect of CBD on head and neck squamous cell carcinoma (HNSCC) remains unclear. The cytotoxicity of CBD on HNSCC was analyzed using cell survival and colony-forming assays in vitro. RNA-seq was used for determining the mechanism underlying CBD-induced cell death. Xenograft mouse models were used to determine CBD’s effects in vivo. CBD treatment significantly reduced migration/invasion and viability of HNSCC cells in a dose- and time-dependent manner. HNSCC mouse xenograft models revealed anti-tumor effects of CBD. Furthermore, combinational treatment with CBD enhanced the efficacy of chemotherapy drugs. Apoptosis and autophagy processes were involved in CBD-induced cytotoxicity of HNSCCs. RNA-seq identified decreased expression of genes associated with DNA repair, cell division, and cell proliferation, which were involved in CBD-mediated cytotoxicity toward HNSCCs. We identified CBD as a new potential anti-cancer compound for single or combination therapy of HNSCC.
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Affiliation(s)
- Yoon Young Go
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul, 08308, South Korea.,Institute for Health Care Convergence Center, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Su Ra Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul, 08308, South Korea
| | - Do Yeon Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul, 08308, South Korea
| | - Sung-Won Chae
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul, 08308, South Korea
| | - Jae-Jun Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Guro Hospital, 80 Guro-dong, Guro-gu, Seoul, 08308, South Korea. .,Institute for Health Care Convergence Center, Korea University Guro Hospital, Seoul, Republic of Korea.
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22
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Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis. Cancers (Basel) 2020; 12:cancers12061694. [PMID: 32630560 PMCID: PMC7352625 DOI: 10.3390/cancers12061694] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 11/18/2022] Open
Abstract
Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development.
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Optimized doxycycline-loaded niosomal formulation for treatment of infection-associated prostate cancer: An in-vitro investigation. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101715] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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24
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Rodenak-Kladniew B, Castro A, Stärkel P, Galle M, Crespo R. 1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs. Life Sci 2020; 243:117271. [DOI: 10.1016/j.lfs.2020.117271] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/26/2019] [Accepted: 01/03/2020] [Indexed: 12/25/2022]
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25
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Riley AS, McKenzie GAG, Green V, Schettino G, England RJA, Greenman J. The effect of radioiodine treatment on the diseased thyroid gland. Int J Radiat Biol 2019; 95:1718-1727. [DOI: 10.1080/09553002.2019.1665206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
| | - Gordon A. G. McKenzie
- Hull and East, Yorkshire Hospitals NHS Trust, Cottingham, UK
- Hull York Medical School, Hull, UK
| | | | - Giuseppe Schettino
- Medical Radiation Sciences Group, National Physical Laboratory, University of Surrey, Teddington, UK
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Alvarez-Ortega N, Caballero-Gallardo K, Olivero-Verbel J. Toxicological effects in children exposed to lead: A cross-sectional study at the Colombian Caribbean coast. ENVIRONMENT INTERNATIONAL 2019; 130:104809. [PMID: 31302530 DOI: 10.1016/j.envint.2019.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/28/2019] [Accepted: 05/02/2019] [Indexed: 06/10/2023]
Abstract
Lead (Pb) is an environmental pollutant with a toxicity that is a serious public health problem. The aim of this research was to evaluate the associations between Pb exposure and morphometric, hematological and biochemical parameters, mRNA expression of the P53, SOD1, ALAD, TNF and INF-γ genes, ALAD polymorphisms (db SNP ID: rs1800435) and Intelligence Quotient (IQ) in children from the Colombian Caribbean. Blood lead levels (BLL) were determined in 554 participants between the ages of 5-16 years old, from different places of the Colombian Caribbean. A health survey was given to assess risk factors. Whole blood was used for hematology and plasma employed to analyze markers of hepatic toxicity. Gene expression was quantified from blood mRNA by RT-PCR. The ALAD polymorphism was characterized by PCR-RFLP, and the Kaufman's brief intelligence test was employed to estimate the IQ. The mean BLL was 3.5 ± 0.2 μg/dL. The site of greatest exposure to Pb was Tasajera, a poor fishing community, with an average of 8.9 ± 0.8 μg/dL. Breastfeeding was associated with high BLL. Morphometric characteristics and IQ were negatively correlated with BLL. The blood platelet count and the mean corpuscular hemoglobin concentration showed positive and negative correlations with BLL, respectively. Negative relationships with BLL were observed with the ratios Neutrophils/Eosinophils and Neutrophils/Basophils, whereas for BLL and Neutrophils/Monocytes the association was positive. The associations between morphometric and some hematological parameters with BLL were age- and gender-related. The expression of ALAD, SOD1, INF-γ and P53 mRNA was down-regulated according to the BLL, whereas TNF showed an opposite trend. In short, fishing communities are at a high risk of Pb exposure. This xenobiotic can affect physical development and IQ, as well as hematological parameters, even at low concentrations. In addition, it can regulate the transcription of genes associated with inflammation, apoptosis, cell cycle, heme synthesis, and oxidative stress.
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Affiliation(s)
- Neda Alvarez-Ortega
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia
| | - Karina Caballero-Gallardo
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia
| | - Jesus Olivero-Verbel
- Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, Zaragocilla Campus, University of Cartagena, Cartagena 130015, Colombia.
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Long J, Wang A, Bai Y, Lin J, Yang X, Wang D, Yang X, Jiang Y, Zhao H. Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. EBioMedicine 2019; 42:363-374. [PMID: 30885723 PMCID: PMC6491941 DOI: 10.1016/j.ebiom.2019.03.022] [Citation(s) in RCA: 243] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 03/07/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC. METHODS We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53WT and TP53MUT HCC samples. Then, the influence of the IPM on the immune microenvironment in HCC was comprehensively analysed. FINDINGS TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group. INTERPRETATION TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. FUND: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).
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Affiliation(s)
- Junyu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, China
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongxu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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28
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Pham MQ, Tran THV, Pham QL, Gairin JE. In silico analysis of the binding properties of solasonine to mortalin and p53, and in vitro pharmacological studies of its apoptotic and cytotoxic effects on human HepG2 and Hep3b hepatocellular carcinoma cells. Fundam Clin Pharmacol 2019; 33:385-396. [DOI: 10.1111/fcp.12447] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/30/2018] [Accepted: 01/07/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Minh Quan Pham
- UPS UMR 152 Pharma‐DEV Université Toulouse 3 Faculté des Sciences Pharmaceutiques Université de Toulouse 35 Chemin des Maraîchers F‐31062 Toulouse France
- Institute of Natural Products Chemistry Vietnam Academy of Science and Technology Building 1H, 18 Hoang Quoc Viet Hanoi Vietnam
| | - Thi Hoai Van Tran
- Institute of Natural Products Chemistry Vietnam Academy of Science and Technology Building 1H, 18 Hoang Quoc Viet Hanoi Vietnam
- Vietnam Academy of Science and Technology Graduate University of Science and Technology 18 Hoang Quoc Viet Hanoi Vietnam
- Vietnam University of Traditional Medicine Ministry of Health 2 Tran Phu Hanoi Vietnam
| | - Quoc Long Pham
- Institute of Natural Products Chemistry Vietnam Academy of Science and Technology Building 1H, 18 Hoang Quoc Viet Hanoi Vietnam
| | - Jean Edouard Gairin
- UPS UMR 152 Pharma‐DEV Université Toulouse 3 Faculté des Sciences Pharmaceutiques Université de Toulouse 35 Chemin des Maraîchers F‐31062 Toulouse France
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Valente J, Sousa A, Gaspar V, Queiroz J, Sousa F. The biological performance of purified supercoiled p53 plasmid DNA in different cancer cell lines. Process Biochem 2018. [DOI: 10.1016/j.procbio.2018.09.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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30
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Chong KH, Zhang X, Zheng J. Dynamical analysis of cellular ageing by modeling of gene regulatory network based attractor landscape. PLoS One 2018; 13:e0197838. [PMID: 29856751 PMCID: PMC5983441 DOI: 10.1371/journal.pone.0197838] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 05/09/2018] [Indexed: 01/29/2023] Open
Abstract
Ageing is a natural phenomenon that is inherently complex and remains a mystery. Conceptual model of cellular ageing landscape was proposed for computational studies of ageing. However, there is a lack of quantitative model of cellular ageing landscape. This study aims to investigate the mechanism of cellular ageing in a theoretical model using the framework of Waddington's epigenetic landscape. We construct an ageing gene regulatory network (GRN) consisting of the core cell cycle regulatory genes (including p53). A model parameter (activation rate) is used as a measure of the accumulation of DNA damage. Using the bifurcation diagrams to estimate the parameter values that lead to multi-stability, we obtained a conceptual model for capturing three distinct stable steady states (or attractors) corresponding to homeostasis, cell cycle arrest, and senescence or apoptosis. In addition, we applied a Monte Carlo computational method to quantify the potential landscape, which displays: I) one homeostasis attractor for low accumulation of DNA damage; II) two attractors for cell cycle arrest and senescence (or apoptosis) in response to high accumulation of DNA damage. Using the Waddington's epigenetic landscape framework, the process of ageing can be characterized by state transitions from landscape I to II. By in silico perturbations, we identified the potential landscape of a perturbed network (inactivation of p53), and thereby demonstrated the emergence of a cancer attractor. The simulated dynamics of the perturbed network displays a landscape with four basins of attraction: homeostasis, cell cycle arrest, senescence (or apoptosis) and cancer. Our analysis also showed that for the same perturbed network with low DNA damage, the landscape displays only the homeostasis attractor. The mechanistic model offers theoretical insights that can facilitate discovery of potential strategies for network medicine of ageing-related diseases such as cancer.
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Affiliation(s)
- Ket Hing Chong
- Biomedical Informatics Lab, School of Computer Science and Engineering, Nanyang Technological University, 639798, Singapore, Singapore
| | - Xiaomeng Zhang
- Biomedical Informatics Lab, School of Computer Science and Engineering, Nanyang Technological University, 639798, Singapore, Singapore
| | - Jie Zheng
- Biomedical Informatics Lab, School of Computer Science and Engineering, Nanyang Technological University, 639798, Singapore, Singapore
- Complexity Institute, Nanyang Technological University, 637723, Singapore, Singapore
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Posadas K, Ankola A, Yang Z, Yee NS. Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study. Biomedicines 2018; 6:46. [PMID: 29673151 PMCID: PMC6027424 DOI: 10.3390/biomedicines6020046] [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: 03/13/2018] [Revised: 04/07/2018] [Accepted: 04/09/2018] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS). Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1) genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC.
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Affiliation(s)
- Kristine Posadas
- Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
| | - Anita Ankola
- Department of Radiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
| | - Zhaohai Yang
- Department of Pathology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
| | - Nelson S Yee
- Division of Hematology-Oncology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center; Experimental Therapeutics Program, Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma. PLoS One 2018; 13:e0191683. [PMID: 29381751 PMCID: PMC5790278 DOI: 10.1371/journal.pone.0191683] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 01/09/2018] [Indexed: 12/18/2022] Open
Abstract
Background Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells. Methods In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting. Results We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt. Conclusion This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.
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Ohbayashi I, Sugiyama M. Plant Nucleolar Stress Response, a New Face in the NAC-Dependent Cellular Stress Responses. FRONTIERS IN PLANT SCIENCE 2018; 8:2247. [PMID: 29375613 PMCID: PMC5767325 DOI: 10.3389/fpls.2017.02247] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 12/21/2017] [Indexed: 05/24/2023]
Abstract
The nucleolus is the most prominent nuclear domain, where the core processes of ribosome biogenesis occur vigorously. All these processes are finely orchestrated by many nucleolar factors to build precisely ribosome particles. In animal cells, perturbations of ribosome biogenesis, mostly accompanied by structural disorders of the nucleolus, cause a kind of cellular stress to induce cell cycle arrest, senescence, or apoptosis, which is called nucleolar stress response. The best-characterized pathway of this stress response involves p53 and MDM2 as key players. p53 is a crucial transcription factor that functions in response to not only nucleolar stress but also other cellular stresses such as DNA damage stress. These cellular stresses release p53 from the inhibition by MDM2, an E3 ubiquitin ligase targeting p53, in various ways, which leads to p53-dependent activation of a set of genes. In plants, genetic impairments of ribosome biogenesis factors or ribosome components have been shown to cause characteristic phenotypes, including a narrow and pointed leaf shape, implying a common signaling pathway connecting ribosomal perturbations and certain aspects of growth and development. Unlike animals, however, plants have neither p53 nor MDM2 family proteins. Then the question arises whether plant cells have a nucleolar stress response pathway. In recent years, it has been reported that several members of the plant-specific transcription factor family NAC play critical roles in the pathways responsive to various cellular stresses. In this mini review, we outline the plant cellular stress response pathways involving NAC transcription factors with reference to the p53-MDM2-dependent pathways of animal cells, and discuss the possible involvement of a plant-unique, NAC-mediated pathway in the nucleolar stress response in plants.
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Affiliation(s)
- Iwai Ohbayashi
- FAFU-UCR Joint Center and Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Munetaka Sugiyama
- Botanical Gardens, Graduate School of Science, The University of Tokyo, Tokyo, Japan
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Xing Y, Liqi Z, Jian L, Qinghua Y, Qian Y. Doxycycline Induces Mitophagy and Suppresses Production of Interferon-β in IPEC-J2 Cells. Front Cell Infect Microbiol 2017; 7:21. [PMID: 28203548 PMCID: PMC5285722 DOI: 10.3389/fcimb.2017.00021] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 01/16/2017] [Indexed: 01/03/2023] Open
Abstract
Previous reports have demonstrated that the second-generation tetracycline derivative doxycycline (DOX) interrupts mitochondrial proteostasis and physiology, inhibits proliferation of many cell types, and induces apoptosis. However, the effects of DOX, which is widely used in porcine husbandry by feed, on the porcine intestinal epithelium are unclear. In this study, we demonstrated that DOX damaged mitochondrial morphology and induced the co-localization of mitochondria with autophagosomes, suggesting that DOX induces mitophagy in IPEC-J2 cells. We also found evidence that DOX increased intracellular levels of reactive oxygen species (ROS) or mitochondrial-specific ROS in a dose dependent manner. Moreover, 50 μg/ml DOX significantly decreased production of interferon-β and facilitated replication of transmissible gastroenteritis coronavirus in IPEC-J2 cells. These results demonstrated that DOX induced mitophagy and ROS production, which damaged the intestinal epithelium. As DOX is used extensively in pig husbandry, uncontrolled application poses a significant threat of viral infection, so stricter policies on its usage should be required.
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Affiliation(s)
- Yang Xing
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University Nanjing, China
| | - Zhu Liqi
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University Nanjing, China
| | - Lin Jian
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University Nanjing, China
| | - Yu Qinghua
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University Nanjing, China
| | - Yang Qian
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University Nanjing, China
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Qi R, Qiao T, Zhuang X. Small interfering RNA targeting S100A4 sensitizes non-small-cell lung cancer cells (A549) to radiation treatment. Onco Targets Ther 2016; 9:3753-62. [PMID: 27382312 PMCID: PMC4922784 DOI: 10.2147/ott.s106557] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Objective This study aimed to investigate the impact of S100A4-small interfering RNA (S100A4-siRNA) on apoptosis and enhanced radiosensitivity in non-small-cell lung cancer (A549) cells. We also explored the mechanisms of radiosensitization and identified a new target to enhance radiosensitivity and gene therapy for non-small-cell lung cancer. Methods RNA interference is a powerful tool for gene silencing. In this study, we constructed an effective siRNA to knock down S100A4. A549 cells were randomly divided into three groups: blank, negative control, and S100A4-siRNA. To investigate the effect of S100A4-siRNA, the expression of S100A4, E-cadherin, and p53 proteins and their messenger RNA (mRNA) was detected by Western blot and quantitative real-time polymerase chain reaction. Transwell chambers were used to assess cell invasion. Cell cycle and apoptosis were analyzed by flow cytometry. Radiosensitivity was determined by colony formation ability. Results Our results demonstrate that S100A4-siRNA effectively silenced the S100A4 gene. When siRNA against S100A4 was used, S100A4 protein expression was downregulated, whereas the expressions of E-cadherin and p53 were upregulated. In addition, a clear reduction in S100A4 mRNA levels was noted compared with the blank and negative control groups, whereas E-cadherin and p53 mRNA levels increased. Transfection with S100A4-siRNA significantly reduced the invasiveness of A549 cells. S100A4 silencing induced immediate G2/M arrest in cell cycle studies and increased apoptosis rates in A549 cells. In clonogenic assays, we used a multitarget, single-hit model to detect radiosensitivity after S100A4 knockdown. All parameters (D0, Dq, α, β) indicated that the downregulation of S100A4 enhanced radiosensitivity in A549 cells. Furthermore, S100A4-siRNA upregulated p53 expression, suggesting that S100A4 may promote A549 cell proliferation, invasion, and metastasis by regulating the expression of other proteins. Therefore, siRNA-directed S100A4 knockdown may represent a viable clinical therapy for lung cancer. Conclusion S100A4 downregulation potentially enhances the sensitivity of human A549 cells to radiotherapy.
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Affiliation(s)
- Ruixue Qi
- Department of Oncology, Affiliated Jinshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Tiankui Qiao
- Department of Oncology, Affiliated Jinshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xibing Zhuang
- Department of Oncology, Affiliated Jinshan Hospital, Fudan University, Shanghai, People's Republic of China
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Rai P, He F, Kwang J, Engelward BP, Chow VTK. Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest. Sci Rep 2016; 6:22972. [PMID: 27026501 PMCID: PMC4812240 DOI: 10.1038/srep22972] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 02/22/2016] [Indexed: 01/24/2023] Open
Abstract
Streptococcus pneumoniae produces pneumolysin toxin as a key virulence factor against host cells. Pneumolysin is a cholesterol-dependent cytolysin (CDC) toxin that forms lytic pores in host membranes and mediates pneumococcal disease pathogenesis by modulating inflammatory responses. Here, we show that pneumolysin, which is released during bacterial lysis, induces DNA double strand breaks (DSBs), as indicated by ataxia telangiectasia mutated (ATM)-mediated H2AX phosphorylation (γH2AX). Pneumolysin-induced γH2AX foci recruit mediator of DNA damage checkpoint 1 (MDC1) and p53 binding protein 1 (53BP1), to sites of DSBs. Importantly, results show that toxin-induced DNA damage precedes cell cycle arrest and causes apoptosis when DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining is inhibited. Further, we observe that cells that were undergoing DNA replication harbored DSBs in greater frequency during pneumolysin treatment. This observation raises the possibility that DSBs might be arising as a result of replication fork breakdown. Additionally, neutralizing the oligomerization domain of pneumolysin with monoclonal antibody suppresses DNA damage and also cell cycle arrest, indicating that pneumolysin oligomerization is important for causing DNA damage. Taken together, this study reveals a previously unidentified ability of pneumolysin to induce cytotoxicity via DNA damage, with implications in the pathophysiology of S. pneumoniae infection.
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Affiliation(s)
- Prashant Rai
- Infectious Diseases Group, Singapore-MIT Alliance for Research &Technology, Singapore 138602.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545
| | - Fang He
- Animal Health Biotechnology, Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604
| | - Jimmy Kwang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545.,Animal Health Biotechnology, Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604
| | - Bevin P Engelward
- Infectious Diseases Group, Singapore-MIT Alliance for Research &Technology, Singapore 138602.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Vincent T K Chow
- Infectious Diseases Group, Singapore-MIT Alliance for Research &Technology, Singapore 138602.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545
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Kumazawa T, Nishimura K, Katagiri N, Hashimoto S, Hayashi Y, Kimura K. Gradual reduction in rRNA transcription triggers p53 acetylation and apoptosis via MYBBP1A. Sci Rep 2015; 5:10854. [PMID: 26044764 PMCID: PMC4456663 DOI: 10.1038/srep10854] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 05/05/2015] [Indexed: 12/19/2022] Open
Abstract
The nucleolus, whose primary function is ribosome biogenesis, plays an essential role in p53 activation. Ribosome biogenesis is inhibited in response to cellular stress and several nucleolar proteins translocate from the nucleolus to the nucleoplasm, where they activate p53. In this study, we analysed precisely how impaired ribosome biogenesis regulates the activation of p53 by depleting nucleolar factors involved in rRNA transcription or rRNA processing. Nucleolar RNA content decreased when rRNA transcription was inhibited. In parallel with the reduced levels of nucleolar RNA content, the nucleolar protein Myb-binding protein 1 A (MYBBP1A) translocated to the nucleoplasm and increased p53 acetylation. The acetylated p53 enhanced p21 and BAX expression and induced apoptosis. In contrast, when rRNA processing was inhibited, MYBBP1A remained in the nucleolus and nonacetylated p53 accumulated, causing cell cycle arrest at the G1 phase by inducing p21 but not BAX. We propose that the nucleolus functions as a stress sensor to modulate p53 protein levels and its acetylation status, determining cell fate between cell cycle arrest and apoptosis by regulating MYBBP1A translocation.
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Affiliation(s)
- Takuya Kumazawa
- 1] Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan [2] First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho Kashihara, Nara 634-8522, Japan
| | - Kazuho Nishimura
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan
| | - Naohiro Katagiri
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan
| | - Sayaka Hashimoto
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan
| | - Yuki Hayashi
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan
| | - Keiji Kimura
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennnoudai, Tsukuba 305-8577, Japan
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Induction of S phase arrest and apoptosis by ethyl acetate extract from Tetrastigma hemsleyanum in human hepatoma HepG2 cells. Tumour Biol 2015; 36:2541-50. [DOI: 10.1007/s13277-014-2869-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/18/2014] [Indexed: 10/24/2022] Open
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Chong KH, Samarasinghe S, Kulasiri D. Mathematical modelling of p53 basal dynamics and DNA damage response. Math Biosci 2015; 259:27-42. [DOI: 10.1016/j.mbs.2014.10.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 10/23/2014] [Accepted: 10/31/2014] [Indexed: 02/06/2023]
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Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Front Mol Biosci 2014; 1:24. [PMID: 25988165 PMCID: PMC4429645 DOI: 10.3389/fmolb.2014.00024] [Citation(s) in RCA: 384] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 10/31/2014] [Indexed: 12/15/2022] Open
Abstract
Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body. In recent years, remarkable progress has been made toward the understanding of proposed hallmarks of cancer development, care, and treatment modalities. Radiation therapy or radiotherapy is an important and integral component of cancer management, mostly conferring a survival benefit. Radiation therapy destroys cancer by depositing high-energy radiation on the cancer tissues. Over the years, radiation therapy has been driven by constant technological advances and approximately 50% of all patients with localized malignant tumors are treated with radiation at some point in the course of their disease. In radiation oncology, research and development in the last three decades has led to considerable improvement in our understanding of the differential responses of normal and cancer cells. The biological effectiveness of radiation depends on the linear energy transfer (LET), total dose, number of fractions and radiosensitivity of the targeted cells or tissues. Radiation can either directly or indirectly (by producing free radicals) damages the genome of the cell. This has been challenged in recent years by a newly identified phenomenon known as radiation induced bystander effect (RIBE). In RIBE, the non-irradiated cells adjacent to or located far from the irradiated cells/tissues demonstrate similar responses to that of the directly irradiated cells. Understanding the cancer cell responses during the fractions or after the course of irradiation will lead to improvements in therapeutic efficacy and potentially, benefitting a significant proportion of cancer patients. In this review, the clinical implications of radiation induced direct and bystander effects on the cancer cell are discussed.
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Affiliation(s)
- Rajamanickam Baskar
- Division of Cellular and Molecular Research, Department of Radiation Oncology, National Cancer Centre Singapore, Singapore
| | - Jiawen Dai
- Division of Cellular and Molecular Research, Department of Radiation Oncology, National Cancer Centre Singapore, Singapore
| | - Nei Wenlong
- Division of Cellular and Molecular Research, Department of Radiation Oncology, National Cancer Centre Singapore, Singapore
| | - Richard Yeo
- Division of Cellular and Molecular Research, Department of Radiation Oncology, National Cancer Centre Singapore, Singapore
| | - Kheng-Wei Yeoh
- Division of Cellular and Molecular Research, Department of Radiation Oncology, National Cancer Centre Singapore, Singapore
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Findlay JM, Middleton MR, Tomlinson I. A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage. Ann Oncol 2014; 26:624-644. [PMID: 25214541 PMCID: PMC4374384 DOI: 10.1093/annonc/mdu449] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Recent advances in next generation sequencing reinforce the potential for DNA sequence markers to guide esophageal cancer management. We report the first systematic review and meta-analysis, identifying 94 markers of outcome and 41 of stage. Overall, evidence was poor. Meta-analyses demonstrated outcome associations for 6 tumor and 9 germline variants: priorities for prospective evaluation. Introduction There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage. Methods A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study. Results Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded. Conclusions Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.
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Affiliation(s)
- J M Findlay
- Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Oxford OesophagoGastric Centre
| | - M R Middleton
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - I Tomlinson
- Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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Ji YN, Wang Q, Xue J. TP53 immunohistochemical expression is associated with the poor outcome for hepatocellular carcinoma: evidence from a meta-analysis. Tumour Biol 2014; 35:1653-9. [PMID: 24078450 DOI: 10.1007/s13277-013-1228-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 09/17/2013] [Indexed: 12/12/2022] Open
Abstract
Various studies examined the relationship between p53 expression with the clinical outcome in patients with hepatocellular carcinoma (HCC), but yielded conflicting results. Electronic databases updated to July 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between p53 expression and survival of patients with HCC. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 24 studies that evaluated the correlation between p53 expression and survival in patients with HCC. Combined hazard ratios suggested that p53 expression had an unfavorable impact on overall survival (OS) (HR (hazard ratio) = 1.55, 95 % CI (confidence interval) 1.36-1.74) and disease-free survival (DFS) (HR = 1.54, 95 % CI 1.21-1.88) in patients with HCC. No significant heterogeneity was observed among 20 studies for OS (P = 0.786) and among 11 studies for DFS (P = 0.698). P53 expression indicates a poor prognosis for patients with hepatocellular carcinoma.
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Apoptotic effects of dipyrido [3,2-a:2',3'-c] phenazine (dppz) Au(III) complex against diethylnitrosamine/phenobarbital induced experimental hepatocarcinogenesis in rats. Mol Biol Rep 2014; 41:5109-21. [PMID: 24756331 DOI: 10.1007/s11033-014-3376-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 04/11/2014] [Indexed: 01/26/2023]
Abstract
We evaluated the effects of dipyrido [3,2-a:2',3'-c] phenazine (dppz) Au(III) complex ([Au(dppz)Cl2]Cl) on apoptosis during chemically induced hepatocellular carcinoma. 48 male Spraque-Dawley rats were divided into six groups; group I (control), group II [Dimethyl sulfoxide (DMSO)], group III ([Au(dppz)Cl2]Cl), group IV [diethylnitrosamine + Phenobabital (DEN + PB)], group V (DEN + PB + [Au(dppz)Cl2]Cl (2nd week)), and group VI (DEN + PB + [Au(dppz)Cl2]Cl (7th week). The rats in groups IV through VI were administrated with DEN in a single dose of intraperitoneal 175 mg/kg. After 2 weeks of DEN administration, these groups of rats were given daily PB in a dose of 500 ppm. In group V, after two weeks of DEN administration, [Au(dppz)Cl2]Cl complex (2 mg/kg) was given once a week by intraperitoneal injection. In the group VI, the rats were given a dose of 2 mg/kg [Au(dppz)Cl2]Cl complex once a week, 7 weeks after DEN administration. At the end of the study, blood and tissue samples were collected from the rats to determine levels of serum AST, ALT, and LDH, and caspase 3, p53, Bax, Bcl-2 and DNA fragmentation in liver. AST, ALT, LDH, and Bcl-2 levels were higher in group IV, compared to group I, but caspase 3 and p53 levels were lower. In group V, caspase 3, p53, Bax, and DNA fragmentation levels were higher than those of group IV. Caspase 3 and p53 levels increased in group VI compared with group IV. In conclusion, [Au(dppz)Cl2]Cl complex induced apoptosis by elevating levels of caspase 3, p53, Bax, and DNA fragmentation.
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44
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Zhan P, Ji YN. Prognostic significance of TP53 expression for patients with hepatocellular carcinoma: a meta-analysis. Hepatobiliary Surg Nutr 2014; 3:11-7. [PMID: 24696834 DOI: 10.3978/j.issn.2304-3881.2014.01.03] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 01/24/2014] [Indexed: 01/01/2023]
Abstract
BACKGROUND Various studies evaluated the relationship between p53 expression and the clinical outcome in patients with hepatocellular carcinoma (HCC), but yielded conflicting results. METHODS Electronic databases updated to Dec 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between p53 expression and survival of patients with HCC. Survival data were aggregated and quantitatively analyzed. RESULTS We performed a meta-analysis of 24 studies that evaluated the correlation between p53 expression and survival in patients with HCC. Combined hazard ratios (HRs) suggested that p53 expression had an unfavorable impact on overall survival (OS) [HR =1.64, 95% confidence interval (CI): 1.40-1.85], and disease free survival (DFS) (HR =1.57, 95% CI: 1.26-1.87) in patients with HCC. CONCLUSIONS p53 expression indicates a poor prognosis for patients with HCC.
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Affiliation(s)
- Ping Zhan
- 1 First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China ; 2 Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Ya-Nan Ji
- 1 First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China ; 2 Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, China
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Wu W, Yu LH, Ma B, Xu MJ. The inhibitory effect of doxycycline on cisplatin-sensitive and -resistant epithelial ovarian cancer. PLoS One 2014; 9:e89841. [PMID: 24598933 PMCID: PMC3943859 DOI: 10.1371/journal.pone.0089841] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 01/27/2014] [Indexed: 11/21/2022] Open
Abstract
Background Detecting a new effective and hypotoxic anticancer drug is an emerging new strategy for cancer chemotherapy. Doxycycline (DC) is a kind of antibiotics but also inhibits tumorigenesis. Methods MTT and cell invasion assay, flow cytometry, western-blot analysis and nude mice were used to investigate the effects and underlying mechanisms of doxycycline on epithelial ovarian cancer cells. Results Doxycycline inhibited the proliferation and invasion of SKOV3 and SKOV3/DDP; induced moderate apoptosis of SKOV3/DDP. CXCR4 expression at both mRNA and protein levels was downregulated in both cell lines when treated with doxycycline. Akt and ERK1/2 were involved in doxycycline effect on cell proliferation of SKOV3 but not of SKOV3/DDP. Akt and EKR1/2 phosphorylation were activated by SDF-1α, which was then inhibited by doxycycline in SKOV3. Pro-caspase-3 expression was significantly higher in SKOV3 than that in SKOV3/DDP which was upregulated when treated with doxycycline. In vivo, doxycycline inhibited peritoneal tumor xenograft and decreased malignant ascites. Conclusion Doxycycline not only has an inhibitory effect on ovarian cancer, but also can increase sensitivity to cisplatin. SDF-1α/CXCR4-regulated Akt and ERK 1/2 activations are probably involved in the antitumor effect of doxycycline on SKOV3 cells, while upregulation of pro-caspase-3 may be the main mechanism involved in SKOV3/DDP cells.
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Affiliation(s)
- Wei Wu
- Department of Gynecology and Obstetrics, Changhai Hospital, Second Military Medical University, Shanghai, P.R.China
- Department of Physiology, Second Military Medical University, Shanghai, P.R.China
| | - Li-hua Yu
- Department of Physiology, Second Military Medical University, Shanghai, P.R.China
| | - Bei Ma
- Department of Physiology, Second Military Medical University, Shanghai, P.R.China
- * E-mail: (BM); (MJX)
| | - Ming-juan Xu
- Department of Gynecology and Obstetrics, Changhai Hospital, Second Military Medical University, Shanghai, P.R.China
- * E-mail: (BM); (MJX)
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Zhan P, Ji YN, Yu LK. TP53 mutation is associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a meta-analysis. Hepatobiliary Surg Nutr 2014; 2:260-5. [PMID: 24570956 DOI: 10.3978/j.issn.2304-3881.2013.07.06] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 07/30/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND Various studies examined the relationship between p53 mutation with the clinical outcome in patients with hepatocellular carcinoma (HCC), but yielded conflicting results. METHODS Electronic databases updated to July 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between p53 mutation and survival of patients with HCC. Survival data were aggregated and quantitatively analyzed. RESULTS We performed a meta-analysis of 9 studies that evaluated the correlation between p53 mutation and survival in patients with HCC. Combined hazard ratios suggested that p53 mutation had an unfavorable impact on overall survival (OS) [hazard ratio (HR) =1.46, 95% confidence interval (CI): 1.15-1.76], and disease free survival (DFS) (HR =2.57, 95% CI: 1.46-3.68) in patients with HCC. The significant heterogeneity (P=0.035) was observed among 8 studies for OS, however no significant heterogeneity (P=0.597) was observed among 5 studies for DFS. CONCLUSIONS p53 mutation indicates a poor prognosis for patients with hepatocellular carcinoma.
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Affiliation(s)
- Ping Zhan
- First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China; ; The Collaborative Research (CORE) Group, Sydney, Australia
| | - Ya-Nan Ji
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Li-Ke Yu
- First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China
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Hu W, Ge Y, Ojcius DM, Sun D, Dong H, Yang XF, Yan J. p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species. Cell Microbiol 2013; 15:1642-59. [PMID: 23521874 DOI: 10.1111/cmi.12141] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 03/07/2013] [Accepted: 03/14/2013] [Indexed: 01/08/2023]
Abstract
Pathogenic Leptospira species, the causative agents of leptospirosis, have been shown to induce macrophage apoptosis through caspase-independent, mitochondrion-related apoptosis inducing factor (AIF) and endonuclease G (EndoG), but the signalling pathway leading to AIF/EndoG-based macrophage apoptosis remains unknown. Here we show that infection of Leptospira interrogans caused a rapid increase in reactive oxygen species (ROS), DNA damage, and intranuclear foci of 53BP1 and phosphorylation of H2AX (two DNAdamage indicators) in wild-type p53-containing mouse macrophages and p53-deficient human macrophages. Most leptospire-infected cells stayed at the G1 phase, whereas depletion or inhibition of p53 caused a decrease of the G1 -phase cells and the early apoptotic ratios. Infection with spirochaetes stimulated a persistent activation of p53 and an early activation of Akt through phosphorylation. The intranuclear translocation of p53, increased expression of p53-dependent p21(Cip) (1/) (WAF) (1) and pro-apoptotic Bcl-2 family proteins (Bax, Noxa and Puma), release of AIF and EndoG from mitochondria, and membrane translocation of Fas occurred during leptospire-induced macrophage apoptosis. Thus, our study demonstrated that ROS production and DNA damage-dependent p53-Bax/Noxa/Puma-AIF/EndoG signalling mediates the leptospire-induced cell cycle arrest and caspase-independent apoptosis of macrophages.
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Affiliation(s)
- Weilin Hu
- Division of Basic Medical Microbiology, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
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Savion S, Oserov G, Orenstein H, Torchinsky A, Fein A, Toder V. NF-κB-associated mechanisms underlying the response of embryonic cells to Doxorubicin. Toxicol In Vitro 2013; 27:804-11. [DOI: 10.1016/j.tiv.2012.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 11/23/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
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Cun Y, Dai N, Xiong C, Li M, Sui J, Qian C, Li Z, Wang D. Silencing of APE1 enhances sensitivity of human hepatocellular carcinoma cells to radiotherapy in vitro and in a xenograft model. PLoS One 2013; 8:e55313. [PMID: 23418439 PMCID: PMC3572126 DOI: 10.1371/journal.pone.0055313] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 12/21/2012] [Indexed: 01/08/2023] Open
Abstract
Resistance to radiotherapy is a key limitation for the treatment of human hepatocellular carcinoma (HCC). To overcome this problem, we investigated the correlation between radioresistance and the human apurinic/apyrimidinic endonuclease (APE1), a bifunctional protein, which plays an important role in DNA repair and redox regulation activity of transcription factors. In the present study, we examined the radiosensitivity profiles of three human HCC cell lines, HepG2, Hep3B, and MHCC97L, using the adenoviral vector Ad5/F35-mediated APE1 siRNA (Ad5/F35-siAPE1). The p53 mutant cell lines MHCC97L showed radioresistance, compared with HepG2 and Hep3B cells. APE1 was strongly expressed in MHCC97L cells and was induced by irradiation in a dose-dependent manner, and Ad5/F35-siAPE1 effectively inhibited irradiation-induced APE1 and p53 expression. Moreover, silencing of APE1 significantly potentiated the growth inhibition and apoptosis induction by irradiation in all tested human HCC cell lines. In addition, Ad5/F35-siAPE1 significantly enhanced inhibition of tumor growth and potentiated cell apoptosis by irradiation both in HepG2 and MHCC97L xenografts. In conclusion, down regulation of APE1 could enhance sensitivity of human HCC cells to radiotherapy in vitro and in vivo.
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Affiliation(s)
- Yanping Cun
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Nan Dai
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Chengjie Xiong
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China
| | - Mengxia Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Jiangdong Sui
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Chengyuan Qian
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Zheng Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
| | - Dong Wang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
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Molecular effects of doxycycline treatment on pterygium as revealed by massive transcriptome sequencing. PLoS One 2012; 7:e39359. [PMID: 22724003 PMCID: PMC3378547 DOI: 10.1371/journal.pone.0039359] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 05/21/2012] [Indexed: 11/19/2022] Open
Abstract
Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 µg/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina's massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results. Doxycycline significantly modified the expression of important cellular pathways in pterygium cells, in a way which is consistent with the observed efficacy of this antibiotic to reduce pterygium lesions in a mouse model. Clinical trials are under way to demonstrate whether there is a benefit for human patients.
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