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Yang T, Zou M, Xie Y, Zhang Y, Wang K, Jiang S, Zou Q. STEAP4 with copper reductase activity suppresses tumorigenesis by regulating the cell cycle in hepatocellular carcinoma cells. Cell Div 2024; 19:35. [PMID: 39719623 DOI: 10.1186/s13008-024-00140-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND Abnormal expression of six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). However, the biological role and regulatory mechanisms of STEAP4 in HCC remain unclear. METHODS AND RESULTS Here, we analyzed STEAP4 expression levels and differentially expressed genes (DEGs) between STEAP4 high- and low-expression groups using multiple databases. Proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) assays, propidium iodide (PI) flow cytometry, and colony formation assays were conducted to assess the effects of STEAP4 on HCC cell proliferation, cell cycle progression, and clonogenic capacity. STEAP4 was downregulated in HCC tumor tissues, with lower expression associated with poorer overall survival (OS) and disease-free survival (DFS) in patients. Functional network analysis suggested that STEAP4 regulates cell cycle signaling, with tumor sections showing a negative correlation between STEAP4 and cell cycle proteins. Overexpression of STEAP4, combined with non-cytotoxic copper exposure in the HepG2 cell line, reduced proliferation and clonogenicity, induced cell cycle arrest, and downregulated the mRNA and protein levels of cell cycle-regulating genes. A predictive model based on STEAP4 and cell cycle gene demonstrated prognostic value in HCC patients. CONCLUSIONS Our results lay a foundation for further study of the cell cycle regulatory role of STEAP4 with Cu2+ reductase activity in HCC, indicating that STEAP4 may be a promising therapeutic target for HCC.
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Affiliation(s)
- Ting Yang
- Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China
| | - Minhong Zou
- Department of Ultrasonic Diagnosis, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China
| | - Yujie Xie
- Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China
| | - Yong Zhang
- Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China.
| | - Kun Wang
- Department of Joint Surgery and Orthopedic Trauma, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China.
| | - Shihai Jiang
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103, Leipzig, Germany.
| | - Qiong Zou
- Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China.
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Zhou W, Wang J, Tian F, Liu P, Li M, Song C, Zhang Y, Yang X, Nie X, Shi Y. High PLK3 levels are linked with less tumor invasion, lower FIGO stage and better prognosis of endometrial cancer. Biomark Med 2024; 18:523-533. [PMID: 39082977 PMCID: PMC11364079 DOI: 10.1080/17520363.2024.2347192] [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: 07/02/2023] [Accepted: 04/03/2024] [Indexed: 08/30/2024] Open
Abstract
Aim: To evaluate correlations of tumor PLK3 with clinical features and prognosis of resectable endometrial cancer (EC) patients.Methods: Tumor tissues from 200 EC patients receiving surgical resections and adjacent tissues from 50 of them were collected for PLK3 determination using immunohistochemistry.Results: Tumor PLK3 negatively linked with myometrial invasion ≥50%, lymphovascular invasion, stromal cervical invasion, and International Federation of Gynecology and Obstetrics stage (all p < 0.050). High tumor PLK3 independently related to longer disease-free survival (DFS) (p = 0.044) and overall survival (OS) (p = 0.049). Its prognostic value was also validated by time-dependent receiver operating characteristic analyses (area under curve at most timepoints was >0.700).Conclusion: Tumor PLK3 potentially reflects prolonged DFS and OS in EC patients undergoing surgical resections.
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Affiliation(s)
- Weiyue Zhou
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Jurong Wang
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Fen Tian
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Ping Liu
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Meiyan Li
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Chunli Song
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Yixin Zhang
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Xiaoming Yang
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Xiaohuan Nie
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
| | - Yuanyuan Shi
- Department of Gynecology, HanDan Central Hospital, Handan, 056000, China
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3
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Xu M, Deng X, Xiang N, Zhang Z, Yang M, Liu Q. Plk3 Enhances Cisplatin Sensitivity of Nonsmall-Cell Lung Cancer Cells through Inhibition of the PI3K/AKT Pathway via Stabilizing PTEN. ACS OMEGA 2024; 9:8995-9002. [PMID: 38434880 PMCID: PMC10905570 DOI: 10.1021/acsomega.3c07271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/05/2024] [Accepted: 01/26/2024] [Indexed: 03/05/2024]
Abstract
Polo-like kinase 3 (Plk3) is involved in tumor development with a tumor suppressive function. However, the effect of Plk3 on the chemoresistance remains unclear. It has been documented that activation of the PI3K/AKT signaling pathway by PTEN loss significantly enhances chemoresistance in nonsmall-cell lung cancer (NSCLC). This study aims to evaluate the PTEN regulation by Plk3 and identify targets and underlying mechanisms that could be used to relieve chemoresistance. Our results showed that silencing Plk3 reduced PTEN expression and activated PI3K/AKT signaling by dephosphorylating and destabilizing PTEN in NSCLC cells. Reducing Plk3 expression promoted drug resistance to cisplatin (DDP), while overexpressing Plk3 promoted DDP sensitivity. However, these effects were attenuated when MK2206, a PI3K/AKT inhibitor, was applied. In conclusion, upregulation of Plk3 sensitized NSCLC cells toward DDP, which provides a potential target to restore DDP chemoresponse. We provided novel evidence that the PTEN/PI3K/AKT signaling pathway could be regulated by Plk3 through phosphorylation of PTEN and highlighted the critical role of Plk3 in the DDP resistance of NSCLC.
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Affiliation(s)
- Mengshan Xu
- Breast
Tumor Center, Hainan Provincial Tumor Hospital, Haikou 570312, Hainan, China
| | - Xiaoyun Deng
- Department
of Medical Oncology, Hainan Provincial Tumor
Hospital, Haikou 570312, Hainan, China
| | - Nana Xiang
- Department
of Medical Oncology, Luoyang Central Hospital, Luoyang 471001, Henan, China
| | - Zhao Zhang
- Breast
Tumor Center, Hainan Provincial Tumor Hospital, Haikou 570312, Hainan, China
| | - Min Yang
- Department
of Medical Oncology, Hainan Provincial Tumor
Hospital, Haikou 570312, Hainan, China
| | - Qinxiang Liu
- Department
of Medical Oncology, Hainan Provincial Tumor
Hospital, Haikou 570312, Hainan, China
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El-Khobar KE, Tay E, Diefenbach E, Gloss BS, George J, Douglas MW. Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer. Life Sci Alliance 2023; 6:e202201630. [PMID: 37648284 PMCID: PMC10468647 DOI: 10.26508/lsa.202201630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/04/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Polo-like kinase 1 (PLK1) is a regulator of cell mitosis and cytoskeletal dynamics. PLK1 overexpression in liver cancer is associated with tumour progression, metastasis, and vascular invasion. Hepatitis C virus (HCV) NS5A protein stimulates PLK1-mediated phosphorylation of host proteins, so we hypothesised that HCV-PLK1 interactions might be a mechanism for HCV-induced liver cancer. We used a HCV cell-culture model (Jc1) to investigate the effects of virus infection on the cytoskeleton. In HCV-infected cells, a novel posttranslational modification in β-actin was observed with phosphorylation at Ser239. Using in silico and in vitro approaches, we identified PLK1 as the mediating kinase. In functional experiments with a phosphomimetic mutant form of β-actin, Ser239 phosphorylation influences β-actin polymerization and distribution, resulting in increased cell motility. The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC.
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Affiliation(s)
- Korri E El-Khobar
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
- Eijkman Institute for Molecular Biology, Jakarta, Indonesia
| | - Enoch Tay
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Eve Diefenbach
- Protein Core Facility, Westmead Institute for Medical Research, Westmead, Australia
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Westmead, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Mark W Douglas
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
- Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, University of Sydney at Westmead Hospital, Westmead, Australia
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Kim DE, Byeon HE, Kim DH, Kim SG, Yim H. Plk2-mediated phosphorylation and translocalization of Nrf2 activates anti-inflammation through p53/Plk2/p21 cip1 signaling in acute kidney injury. Cell Biol Toxicol 2023; 39:1509-1529. [PMID: 35842499 PMCID: PMC10425522 DOI: 10.1007/s10565-022-09741-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/29/2022] [Indexed: 11/30/2022]
Abstract
The Plk2 is a cellular stress-responsive factor that is induced in response to oxidative stress. However, the roles of Plk2 in acute kidney injury (AKI) have not been clarified. We previously found that Plk2 is an interacting factor of Nrf2 in response to cellular stress, since Plk2 is upregulated in the Nrf2-dependent network. Here, we show that the levels of p53, Plk2, p21cip1, and chromatin-bound Nrf2 were all upregulated in kidney tissues of mice or NRK52E cells treated with either cisplatin or methotrexate. Upregulation of Plk2 by p53 led to an increase of Nrf2 in both soluble and chromatin fractions in cisplatin-treated NRK52E cells. Consistently, depletion of Plk2 suppressed the levels of Nrf2. Of note, Plk2 directly phosphorylated Nrf2 at Ser40, which facilitated its interaction with p21cip1 and translocation into the nuclei for the activation of anti-oxidative and anti-inflammatory factors in response to AKI. Together, these findings suggest that Plk2 may serve as an anti-oxidative and anti-inflammatory regulator through the phosphorylation and activation of Nrf2 to protect kidney cells from kidney toxicants and that Plk2 and Nrf2 therefore work cooperatively for the protection and survival of kidney cells from harmful stresses.
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Affiliation(s)
- Da-Eun Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, Gyeonggi-do, Korea
| | - Hye Eun Byeon
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, Gyeonggi-do, Korea
| | - Dae-Hoon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, Gyeonggi-do, Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, 10326, Gyeonggi-Do, Korea.
- College of Pharmacy, Seoul National University, Gwanakro 599, Seoul, 08826, Korea.
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, Gyeonggi-do, Korea.
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6
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Luo L, Zhang XY, Zhen YW, Guo GC, Peng DZ, Wei C, Pei DL, Yu B, Ji YC, Liu XZ, Han L, Zhang ZY. Polo-like kinase 1 is related with malignant characteristics and inhibits macrophages infiltration in glioma. Front Immunol 2022; 13:1058036. [PMID: 36618405 PMCID: PMC9811677 DOI: 10.3389/fimmu.2022.1058036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Tumor immune microenvironment (TIM) plays a critical role in tumorigenesis and progression. Recently, therapies based on modulating TIM have made great breakthroughs in cancer treatment. Polo-like kinase 1 (PLK1) is a crucial regulatory factor of the cell cycle process and its dysregulations often cause various pathological processes including tumorigenesis. However, the detailed mechanisms surrounding the regulation of PLK1 on glioma immune microenvironment remain undefined. METHODS Public databases and online datasets were used to extract data of PLK1 expression, clinical features, genetic alterations, and biological functions. The EdU, flow cytometry, and macrophage infiltration assays as well as xenograft animal experiments were performed to determine the relationship between PLK1 and glioma immune microenvironment in vivo and in vitro. RESULTS PLK1 is always highly expressed in multiple cancers especially in glioma. Univariable and Multivariate proportional hazard Cox analysis showed that PLK1 was a prognostic biomarker for glioma. Simultaneously, highly expressed PLK1 is significantly related to prognosis, histological and genetic features in glioma by analyzing public databases. In addition, the enrichment analysis suggested that PLK1 might related to "immune response", "cell cycle", "DNA replication", and "mismatch repair" in glioma. Immune infiltration analysis demonstrated that highly expressed PLK1 inhibited M1 macrophages infiltration to glioblastoma immune microenvironment by Quantiseq and Xcell databases and negatively related to some chemokines and marker genes of M1 macrophages in glioblastoma. Subsequent experiments confirmed that PLK1 knockdown inhibited the proliferation of glioma cells but increased the M1 macrophages infiltration and polarization. Furthermore, in glioma xenograft mouse models, we showed that inhibiting PLK1 blocked tumor proliferation and increased the M1 macrophages infiltration. Finally, PLK1 methylation analysis and lncRNA-miRNA network revealed the potential mechanism of abnormal PLK1 expression in glioma. CONCLUSIONS PLK1 inhibits M1 macrophages infiltration into glioma immune microenvironment and is a potential biomarker for glioma.
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Affiliation(s)
- Lin Luo
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiao-Yang Zhang
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Ying-Wei Zhen
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Gao-Chao Guo
- Department of Neurosurgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Da-Zhao Peng
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng Wei
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Dong-Ling Pei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bin Yu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yu-Chen Ji
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xian-Zhi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhen-Yu Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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PLK4 Is a Potential Biomarker for Abnormal Tumor Proliferation, Immune Infiltration, and Prognosis in ccRCC. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:6302234. [PMID: 36176741 PMCID: PMC9514917 DOI: 10.1155/2022/6302234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/12/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022]
Abstract
Background PLK4 is highly expressed and associated with poor prognosis in various malignancies. However, the role of PLK4 in clear cell renal cell carcinoma (ccRCC) is still unclear. This study is aimed at analyzing the expression, the potential regulating mechanism, and the role of PLK4 in the ccRCC by bioinformatics. Methods PLK4 mRNA expression data and methylation levels in ccRCC were examined using TIMER, UALCAN, MethSurv, NCBI-GEO, and UCSC databases. Quantitative real-time PCR verifies the regulatory relationship between PLK4 and has-miR-214-3p. The GEPIA2 and STRING databases were used to find similar genes of PLK4 and then enriched with R language to analyze their similar genes. Correlations between PLK4 and tumor-infiltrating immune cells and cytokines exerting immunosuppression were analyzed using the TIMER database and the TISIDB databases. Results PLK4 mRNA expression levels were significantly higher in ccRCC tissues than in paracancerous tissues. ccRCC tissues had lower DNA methylation levels of PLK4 than normal tissues. Importantly, the high PLK4 expression was associated with poor prognosis in ccRCC patients. The has-miR-214-3p negatively regulates the expression of PLK4. GO and KEGG pathway analysis showed that PLK4 coexpressed genes were mainly associated with multiple immune-related pathways, including cytokinesis, sister chromatid adhesions, and mitotic nuclear division. Our data suggest that the PLK4 expression is closely related to the level of immune infiltration and the cytokines that exert immune suppression, and IPS was significantly higher in the PLK4 low expression group. Conclusion The PLK4 expression is associated with the prognosis of ccRCC patients and affects the immune microenvironment of ccRCC, and PLK4 is expected to be a new target for the diagnosis and treatment of ccRCC.
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Cheng M, Yang Q, Liu Y, Zhao MJ, Du X, Sun J, Shu WJ, Huang Z, Bi J, Xu X, Du HN. SETD3 Methyltransferase Regulates PLK1 Expression to Promote In Situ Hepatic Carcinogenesis. Front Oncol 2022; 12:882202. [PMID: 35912180 PMCID: PMC9329778 DOI: 10.3389/fonc.2022.882202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundThe development of a new strategy to overcome chemoresistance to hepatocellular carcinoma (HCC) treatment is a long-standing issue. We have previously found that upregulated SETD3 levels are closely correlated with HCC. This study aims to explore the mechanism underlying how upregulation of SETD3 promotes liver carcinogenesis.MethodsRNA-Sequencing analysis was used to explore the correlation of SETD3 with regulatory targets. In vitro assays including cell proliferation and migration were performed to study the oncogenic roles of SETD3 and PLK1. Western blotting, immunohistochemical staining, and blood biochemical assays were performed to examine protein expression or pathological index in tumor tissues and mice liver tissues. Luciferase reporter system and chromatin immunoprecipitation assays were used to explore the mechanism.ResultsWe revealed that SETD3 regulates gene expression in subgroups, including cell division, cell proliferation, and cell cycle, in hepatocellular tumor cells. We found that SETD3 upregulation is associated with elevated PLK1 level in both hepatic tumor cells and clinical liver tissues. We further showed that overexpression of SETD3 promoted tumor cell proliferation and migration, whereas inhibition of PLK1 activity attenuated these phenotypes caused by SETD3. By taking advantage of the Sleep Beauty transposase system, we confirmed that upregulated mouse Setd3 promoted hepatic carcinogenesis in situ, but knockdown of mouse Plk1 mitigated Setd3-promoted tumorigenesis in mice. Mechanistically, we showed that SETD3 could be recruited to the promoter of PLK1 gene to facilitate PLK1 transcription.ConclusionsOur data demonstrate that elevated SETD3 may promote HCC by enhancing PLK1 expression, which suggests that SETD3 may act as a potential drug target combined with PLK1 inhibition to treat HCC.
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Affiliation(s)
- Meng Cheng
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Qingmiao Yang
- Cardiovascular Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yafei Liu
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Meng-Jie Zhao
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Xinyuan Du
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Jiaqi Sun
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Wen-Jie Shu
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zan Huang
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Jianping Bi
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hai-Ning Du, ; Jianping Bi, ; Ximing Xu,
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Hai-Ning Du, ; Jianping Bi, ; Ximing Xu,
| | - Hai-Ning Du
- Hubei Key Laboratory of Cell Homeostasis, RNA Institute, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
- *Correspondence: Hai-Ning Du, ; Jianping Bi, ; Ximing Xu,
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Zhang C, Ni C, Lu H. Polo-Like Kinase 2: From Principle to Practice. Front Oncol 2022; 12:956225. [PMID: 35898867 PMCID: PMC9309260 DOI: 10.3389/fonc.2022.956225] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/14/2022] [Indexed: 11/21/2022] Open
Abstract
Polo-like kinase (PLK) 2 is an evolutionarily conserved serine/threonine kinase that shares the n-terminal kinase catalytic domain and the C-terminal Polo Box Domain (PBD) with other members of the PLKs family. In the last two decades, mounting studies have focused on this and tried to clarify its role in many aspects. PLK2 is essential for mitotic centriole replication and meiotic chromatin pairing, synapsis, and crossing-over in the cell cycle; Loss of PLK2 function results in cell cycle disorders and developmental retardation. PLK2 is also involved in regulating cell differentiation and maintaining neural homeostasis. In the process of various stimuli-induced stress, including oxidative and endoplasmic reticulum, PLK2 may promote survival or apoptosis depending on the intensity of stimulation and the degree of cell damage. However, the role of PLK2 in immunity to viral infection has been studied far less than that of other family members. Because PLK2 is extensively and deeply involved in normal physiological functions and pathophysiological mechanisms of cells, its role in diseases is increasingly being paid attention to. The effect of PLK2 in inhibiting hematological tumors and fibrotic diseases, as well as participating in neurodegenerative diseases, has been gradually recognized. However, the research results in solid organ tumors show contradictory results. In addition, preliminary studies using PLK2 as a disease predictor and therapeutic target have yielded some exciting and promising results. More research will help people better understand PLK2 from principle to practice.
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Affiliation(s)
- Chuanyong Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Chuangye Ni
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
| | - Hao Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- *Correspondence: Hao Lu,
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10
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Pellegrino R, Castoldi M, Ticconi F, Skawran B, Budczies J, Rose F, Schwab C, Breuhahn K, Neumann UP, Gaisa NT, Loosen SH, Luedde T, Costa IG, Longerich T. LINC00152 Drives a Competing Endogenous RNA Network in Human Hepatocellular Carcinoma. Cells 2022; 11:cells11091528. [PMID: 35563834 PMCID: PMC9103153 DOI: 10.3390/cells11091528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/29/2022] [Accepted: 05/01/2022] [Indexed: 11/16/2022] Open
Abstract
Genomic and epigenomic studies revealed dysregulation of long non-coding RNAs in many cancer entities, including liver cancer. We identified an epigenetic mechanism leading to upregulation of the long intergenic non-coding RNA 152 (LINC00152) expression in human hepatocellular carcinoma (HCC). Here, we aimed to characterize a potential competing endogenous RNA (ceRNA) network, in which LINC00152 exerts oncogenic functions by sponging miRNAs, thereby affecting their target gene expression. Database and gene expression data of human HCC were integrated to develop a potential LINC00152-driven ceRNA in silico. RNA immunoprecipitation and luciferase assay were used to identify miRNA binding to LINC00152 in human HCC cells. Functionally active players in the ceRNA network were analyzed using gene editing, siRNA or miRNA mimic transfection, and expression vectors in vitro. RNA expression in human HCC in vivo was validated by RNA in situ hybridization. Let-7c-5p, miR-23a-3p, miR-125a-5p, miR-125b-5p, miR-143a-3p, miR-193-3p, and miR-195-5p were detected as new components of the potential LINC00152 ceRNA network in human HCC. LINC00152 was confirmed to sponge miR143a-3p in human HCC cell lines, thereby limiting its binding to their respective target genes, like KLC2. KLC2 was identified as a central mediator promoting pro-tumorigenic effects of LINC00152 overexpression in HCC cells. Furthermore, co-expression of LINC00152 and KLC2 was observed in human HCC cohorts and high KLC2 expression was associated with shorter patient survival. Functional assays demonstrated that KLC2 promoted cell proliferation, clonogenicity and migration in vitro. The LINC00152-miR-143a-3p-KLC2 axis may represent a therapeutic target in human HCC.
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Affiliation(s)
- Rossella Pellegrino
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
- Correspondence: ; Tel.: +49-(0)6221-56-34094
| | - Mirco Castoldi
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; (M.C.); (S.H.L.); (T.L.)
| | - Fabio Ticconi
- Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (F.T.); (I.G.C.)
| | - Britta Skawran
- Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany;
| | - Jan Budczies
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
| | - Fabian Rose
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
| | - Constantin Schwab
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
| | - Kai Breuhahn
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
| | - Ulf P. Neumann
- Department of General, Visceral and Transplant Surgery, University Hospital RWTH Aachen, 52074 Aachen, Germany;
- Department of Surgery, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands
| | - Nadine T. Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, Germany;
| | - Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; (M.C.); (S.H.L.); (T.L.)
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; (M.C.); (S.H.L.); (T.L.)
| | - Ivan G. Costa
- Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (F.T.); (I.G.C.)
| | - Thomas Longerich
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (J.B.); (F.R.); (C.S.); (K.B.); (T.L.)
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11
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Yang M, He H, Peng T, Lu Y, Yu J. Identification of 9 Gene Signatures by WGCNA to Predict Prognosis for Colon Adenocarcinoma. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:8598046. [PMID: 35392038 PMCID: PMC8983226 DOI: 10.1155/2022/8598046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 11/17/2022]
Abstract
Background A risk assessment model for prognostic prediction of colon adenocarcinoma (COAD) was established based on weighted gene co-expression network analysis (WGCNA). Methods From the Cancer Genome Atlas (TCGA) database, RNA-seq data and clinical data of COAD patients were retrieved. After screening of differentially expressed genes (DEGs), WGCNA was performed to identify gene modules and screen those associated with COAD progression. Then, via protein-protein interaction (PPI) network construction of module genes, hub genes were obtained, which were then subjected to the least absolute shrinkage and selection operator (LASSO) and Cox regression to build a hub gene-based prognostic scoring model. The receiver operating characteristic curve (ROC curve) was plotted for the optimal cutoff (OCO) of the risk score, based on which, patients were assigned to high or low-risk groups. Areas under the ROC curve (AUCs) were calculated, and model performance was visualized using Kaplan-Meier (KM) survival curves and verified in the external dataset GSE29621. Finally, the model's independent prognostic value was evaluated by univariate and multivariate Cox regression analyses, and a nomogram was built. Results Totally 2840 DEGs were screened from COAD dataset of TCGA, including 1401 upregulated ones and 1439 downregulated ones, which were divided into 10 modules by WGCNA. The eigenvalue of the black module was found to have a high correlation with COAD progression. PPI interaction networks were constructed for genes in the black module, and 34 hub genes were obtained by using the MCODE plug-in. A LASSO-Cox regression approach was utilized to analyze the hub genes, and a prognostic risk score model based on the signatures of 9 genes (CHEK1, DEPDC1B, FANCI, MCM10, NCAPG, PARPBP, PLK4, RAD51AP1, and RFC4) was constructed. KM analysis identified shorter overall lower survival in the high-risk group. The model was verified to have favorable predictive ability through training set and validation set. The nomogram, composed of tumor node metastasis (TNM) staging and risk score, was of good predictability. Conclusions The COAD prognostic risk model constructed upon the signatures of 9 genes (CHEK1, DEPDC1B, FANCI, MCM10, NCAPG, PARPBP, PLK4, RAD51AP1, and RFC4) can effectively predict the survival status of COAD patients.
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Affiliation(s)
- Mian Yang
- Department of Colon Anorectal Surgery, Lihuili Hospital, Ningbo Medical Center, Ningbo, Zhejiang, China
| | - Haibin He
- Department of Gastrointestinal Surgery, Lihuili Hospital, Ningbo Medical Center, Ningbo, Zhejiang, China
| | - Tao Peng
- Department of Colon Anorectal Surgery, Lihuili Hospital, Ningbo Medical Center, Ningbo, Zhejiang, China
| | - Yi Lu
- Department of Chemoradiotherapy, Lihuili Hospital, Ningbo Medical Center, Ningbo, Zhejiang, China
| | - Jiazi Yu
- Department of Colon Anorectal Surgery, Lihuili Hospital, Ningbo Medical Center, Ningbo, Zhejiang, China
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12
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Keep Calm and Carry on with Extra Centrosomes. Cancers (Basel) 2022; 14:cancers14020442. [PMID: 35053604 PMCID: PMC8774008 DOI: 10.3390/cancers14020442] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/01/2022] [Accepted: 01/03/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Precise chromosome segregation during mitosis is a vital event orchestrated by formation of bipolar spindle poles. Supernumerary centrosomes, caused by centrosome amplification, deteriorates mitotic processes, resulting in segregation defects leading to chromosomal instability (CIN). Centrosome amplification is frequently observed in various types of cancer and considered as a significant contributor to destabilization of chromosomes. This review provides a comprehensive overview of causes and consequences of centrosome amplification thoroughly describing molecular mechanisms. Abstract Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of tumor formation and progression. This concept, first posited by Boveri over 100 years ago, has been an area of interest to cancer researchers. We have now begun to understand the processes by which these numerical and structural anomalies may lead to cancer, and vice-versa: how key events that occur during carcinogenesis could lead to amplification of centrosomes. Despite the proliferative advantages that having extra centrosomes may confer, their presence can also lead to loss of essential genetic material as a result of segregational errors and cancer cells must deal with these deadly consequences. Here, we review recent advances in the current literature describing the mechanisms by which cancer cells amplify their centrosomes and the methods they employ to tolerate the presence of these anomalies, focusing particularly on centrosomal clustering.
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Wang J, Sui L, Huang J, Miao L, Nie Y, Wang K, Yang Z, Huang Q, Gong X, Nan Y, Ai K. MoS 2-based nanocomposites for cancer diagnosis and therapy. Bioact Mater 2021; 6:4209-4242. [PMID: 33997503 PMCID: PMC8102209 DOI: 10.1016/j.bioactmat.2021.04.021] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 12/24/2022] Open
Abstract
Molybdenum is a trace dietary element necessary for the survival of humans. Some molybdenum-bearing enzymes are involved in key metabolic activities in the human body (such as xanthine oxidase, aldehyde oxidase and sulfite oxidase). Many molybdenum-based compounds have been widely used in biomedical research. Especially, MoS2-nanomaterials have attracted more attention in cancer diagnosis and treatment recently because of their unique physical and chemical properties. MoS2 can adsorb various biomolecules and drug molecules via covalent or non-covalent interactions because it is easy to modify and possess a high specific surface area, improving its tumor targeting and colloidal stability, as well as accuracy and sensitivity for detecting specific biomarkers. At the same time, in the near-infrared (NIR) window, MoS2 has excellent optical absorption and prominent photothermal conversion efficiency, which can achieve NIR-based phototherapy and NIR-responsive controlled drug-release. Significantly, the modified MoS2-nanocomposite can specifically respond to the tumor microenvironment, leading to drug accumulation in the tumor site increased, reducing its side effects on non-cancerous tissues, and improved therapeutic effect. In this review, we introduced the latest developments of MoS2-nanocomposites in cancer diagnosis and therapy, mainly focusing on biosensors, bioimaging, chemotherapy, phototherapy, microwave hyperthermia, and combination therapy. Furthermore, we also discuss the current challenges and prospects of MoS2-nanocomposites in cancer treatment.
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Affiliation(s)
- Jianling Wang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Lihua Sui
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Jia Huang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Lu Miao
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yubing Nie
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Kuansong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- Department of Pathology, School of Basic Medical Science, Central South University, Changsha, Hunan, 410013, China
| | - Zhichun Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Qiong Huang
- Department of Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xue Gong
- Department of Radiology, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Yayun Nan
- Geriatric Medical Center, Ningxia People's Hospital, Yinchuan, China
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
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Niedziela DA, Naranjo-Lucena A, Molina-Hernández V, Browne JA, Martínez-Moreno Á, Pérez J, MacHugh DE, Mulcahy G. Timing of Transcriptomic Peripheral Blood Mononuclear Cell Responses of Sheep to Fasciola hepatica Infection Differs From Those of Cattle, Reflecting Different Disease Phenotypes. Front Immunol 2021; 12:729217. [PMID: 34616397 PMCID: PMC8488161 DOI: 10.3389/fimmu.2021.729217] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/18/2021] [Indexed: 01/17/2023] Open
Abstract
Infection with the zoonotic trematode Fasciola hepatica, common in many regions with a temperate climate, leads to delayed growth and loss of productivity in cattle, while infection in sheep can have more severe effects, potentially leading to death. Previous transcriptomic analyses revealed upregulation of TGFB1, cell death and Toll-like receptor signalling, T-cell activation, and inhibition of nitric oxide production in macrophages in response to infection. However, the differences between ovine and bovine responses have not yet been explored. The objective of this study was to further investigate the transcriptomic response of ovine peripheral blood mononuclear cells (PBMC) to F. hepatica infection, and to elucidate the differences between ovine and bovine PBMC responses. Sixteen male Merino sheep were randomly assigned to infected or control groups (n = 8 per group) and orally infected with 120 F. hepatica metacercariae. Transcriptomic data was generated from PBMC at 0, 2 and 16 weeks post-infection (wpi), and analysed for differentially expressed (DE) genes between infected and control animals at each time point (analysis 1), and for each group relative to time 0 (analysis 2). Analysis 2 was then compared to a similar study performed previously on bovine PBMC. A total of 453 DE genes were found at 2 wpi, and 2 DE genes at 16 wpi (FDR < 0.1, analysis 1). Significantly overrepresented biological pathways at 2 wpi included role of PKR in interferon induction and anti-viral response, death receptor signalling and RIG-I-like receptor signalling, which suggested that an activation of innate response to intracellular nucleic acids and inhibition of cellular apoptosis were taking place. Comparison of analysis 2 with the previous bovine transcriptomic study revealed that anti-inflammatory response pathways which were significantly overrepresented in the acute phase in cattle, including IL-10 signalling, Th2 pathway, and Th1 and Th2 activation were upregulated only in the chronic phase in sheep. We propose that the earlier activation of anti-inflammatory responses in cattle, as compared with sheep, may be related to the general absence of acute clinical signs in cattle. These findings offer scope for "smart vaccination" strategies for this important livestock parasite.
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Affiliation(s)
| | | | - Verónica Molina-Hernández
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - John A. Browne
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
| | - Álvaro Martínez-Moreno
- Departamento de Sanidad Animal (Parasitología), Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - José Pérez
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - David E. MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Grace Mulcahy
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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Yang Z, Sun H, Ma W, Wu K, Peng G, Ou T, Wu S. Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activation of the p38/p53/p21 signalling pathway in bladder cancer. FEBS Open Bio 2021; 11:2631-2646. [PMID: 34342940 PMCID: PMC8409300 DOI: 10.1002/2211-5463.13262] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/22/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022] Open
Abstract
Polo-like kinase 4 (PLK4) has been reported to contribute to tumor growth, invasion, and metastasis. However, the role of PLK4 in human bladder cancer (BC) remains unclear. Here, we demonstrate the regulatory function of PLK4 in human BC progression. PLK4 is overexpressed in BC cell lines and tissues, and its overexpression correlated with poor prognosis. Our transcriptome analysis combined with subsequent functional assays indicated that PLK4 inhibition can suppress BC cell growth and induce cell cycle arrest at G1 phase via activation of the p38/p53/p21 pathway in vitro and in vivo. Overall, our data suggest that PLK4 is a critical regulator of BC cell proliferation, and thus it may have potential as a novel molecular target for BC treatment.
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Affiliation(s)
- Ziyi Yang
- Shenzhen University Health Science Center, Shenzhen, Guangdong province, China.,Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Haiyan Sun
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Wenlong Ma
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Kai Wu
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Guoyu Peng
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Tong Ou
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Song Wu
- Shenzhen University Health Science Center, Shenzhen, Guangdong province, China.,Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
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Deng M, Li S, Mei J, Lin W, Zou J, Wei W, Guo R. High SGO2 Expression Predicts Poor Overall Survival: A Potential Therapeutic Target for Hepatocellular Carcinoma. Genes (Basel) 2021; 12:genes12060876. [PMID: 34200261 PMCID: PMC8226836 DOI: 10.3390/genes12060876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/29/2021] [Accepted: 06/03/2021] [Indexed: 02/08/2023] Open
Abstract
Shugoshin2 (SGO2) may participate in the occurrence and development of tumors by regulating abnormal cell cycle division, but its prognostic value in hepatocellular carcinoma (HCC) remains unclear. In this study, we accessed The Cancer Genome Atlas (TCGA) database to get the clinical data and gene expression profile of HCC. The expression of SGO2 in HCC tissues and nontumor tissues and the relationship between SGO2 expression, survival, and clinicopathological parameters were analyzed. The SGO2 expression level was significantly higher in HCC tissues than in nontumor tissues (p < 0.001). An analysis from the Oncomine and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases also demonstrated that SGO2 was upregulated in HCC (all p < 0.001). A logistic regression analysis revealed that the high expression of SGO2 was significantly correlated with gender, tumor grade, pathological stage, T classification, and Eastern Cancer Oncology Group (ECOG) score (all p < 0.05). The overall survival (OS) of HCC patients with higher SGO2 expression was significantly poor (p < 0.001). A multivariate analysis showed that age and high expression of SGO2 were independent predictors of poor overall survival (all p < 0.05). Twelve signaling pathways were significantly enriched in samples with the high-SGO2 expression phenotype. Ten proteins and 34 genes were significantly correlated with SGO2. In conclusion, the expression of SGO2 is closely related to the survival of HCC. It may be used as a potential therapeutic target and prognostic marker of HCC.
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Affiliation(s)
- Min Deng
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shaohua Li
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jie Mei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenping Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jingwen Zou
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wei Wei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Rongping Guo
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Correspondence: ; Tel.: +86-188-1980-9988
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Kressin M, Fietz D, Becker S, Strebhardt K. Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer. Cells 2021; 10:1176. [PMID: 34065956 PMCID: PMC8151477 DOI: 10.3390/cells10051176] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/06/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs' applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.
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Affiliation(s)
- Monika Kressin
- Institute for Veterinary Anatomy, Histology and Embryology, Justus Liebig University Giessen, 35392 Giessen, Germany;
| | - Daniela Fietz
- Institute for Veterinary Anatomy, Histology and Embryology, Justus Liebig University Giessen, 35392 Giessen, Germany;
| | - Sven Becker
- Department of Gynecology, Goethe-University, 60590 Frankfurt, Germany; (S.B.); (K.S.)
| | - Klaus Strebhardt
- Department of Gynecology, Goethe-University, 60590 Frankfurt, Germany; (S.B.); (K.S.)
- German Cancer Consortium (DKTK), German Cancer Research Center, Partner Site Frankfurt am Main, 60590 Frankfurt, Germany
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Zhang X, Wei C, Liang H, Han L. Polo-Like Kinase 4's Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy. Front Oncol 2021; 11:587554. [PMID: 33777739 PMCID: PMC7994899 DOI: 10.3389/fonc.2021.587554] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Polo-like kinases (Plks) are critical regulatory molecules during the cell cycle process. This family has five members: Plk1, 2, 3, 4, and 5. Plk4 has been identified as a master regulator of centriole replication, and its aberrant expression is closely associated with cancer development. In this review, we depict the DNA, mRNA, and protein structure of Plk4, and the regulation of Plk4 at a molecular level. Then we list the downstream targets of Plk4 and the hallmarks of cancer associated with these targets. The role of Plk4 in different cancers is also summarized. Finally, we review the inhibitors that target Plk4 in the hope of discovering effective anticancer drugs. From authors' perspective, Plk4 might represent a valuable tumor biomarker and critical target for cancer diagnosis and therapy.
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Affiliation(s)
| | | | | | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
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Abreu P, Ivanics T, Jiang K, Chen K, E Hansen B, Sapisochin G, Ghanekar A. Novel biomarker for hepatocellular carcinoma: high tumoral PLK-4 expression is associated with better prognosis in patients without microvascular invasion. HPB (Oxford) 2021; 23:359-366. [PMID: 32800449 DOI: 10.1016/j.hpb.2020.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/15/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) recurrence after liver resection (LR) adversely affects prognosis but is difficult to predict. Aberrant expression of Polo-Like Kinase 4 (PLK-4) is implicated in several adult malignancies. We sought to evaluate the prognostic value of PLK-4 expression in HCC after curative-intent LR. METHODS Patients undergoing LR for HCC between July-2015 and November-2017 at our centre were retrospectively identified. PLK-4 expression was measured in tumour and adjacent non-tumour liver tissue using quantitative RT-PCR. Disease-free survival (DFS) was evaluated by Kaplan-Meier and Cox proportional hazard models. RESULTS A total of 145 patients were identified. Patients were divided according to PLK-4 expression (high: n = 58, low: n = 87) by generating a receiver operating characteristic curve for recurrence with an area under the curve of 0.72 (95% CI: 0.6-0.8). Recurrence and death rates were similar between groups. In patients without mVI, low PLK-4 expression was associated with worse actuarial DFS (low 1-, 3-, 5-year 83%, 60%, 47% vs. high 91%, 81%, 81%; p = 0.02). In patients without mVI, high PLK-4 expression was an independent predictor of survival (HR 0.3, 95% CI: 0.1-1.0; p = 0.04). CONCLUSION PLK-4 represents a biomarker for good prognosis in patients with HCC who do not have mVI. This could aid clinical decision making for adjuvant clinical trials.
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Affiliation(s)
- Phillipe Abreu
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Keruo Jiang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Kui Chen
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada; Division of General Surgery, University Health Network, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
| | - Anand Ghanekar
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Division of General Surgery, University Health Network, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
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20
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Pellegrino R, Thavamani A, Calvisi DF, Budczies J, Neumann A, Geffers R, Kroemer J, Greule D, Schirmacher P, Nordheim A, Longerich T. Serum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC. Cancers (Basel) 2021; 13:E199. [PMID: 33429878 PMCID: PMC7829828 DOI: 10.3390/cancers13020199] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 01/10/2023] Open
Abstract
Different molecular mechanisms support the overexpression of the mouse double minute homolog 4 (MDM4), a functional p53 inhibitor, in human hepatocellular carcinoma (HCC). However, the transcription factors (TFs) leading to its transcriptional upregulation remain unknown. Following promoter and gene expression analyses, putative TFs were investigated using gene-specific siRNAs, cDNAs, luciferase reporter assays, chromatin immunoprecipitation, and XI-011 drug treatment in vitro. Additionally, MDM4 expression was investigated in SRF-VP16iHep transgenic mice. We observed a copy-number-independent upregulation of MDM4 in human HCCs. Serum response factor (SRF), ELK1 and ELK4 were identified as TFs activating MDM4 transcription. While SRF was constitutively detected in TF complexes at the MDM4 promoter, presence of ELK1 and ELK4 was cell-type dependent. Furthermore, MDM4 was upregulated in SRF-VP16-driven murine liver tumors. The pharmacological inhibitor XI-011 exhibited anti-MDM4 activity by downregulating the TFs driving MDM4 transcription, which decreased HCC cell viability and increased apoptosis. In conclusion, SRF drives transcriptional MDM4 upregulation in HCC, acting in concert with either ELK1 or ELK4. The transcriptional regulation of MDM4 may be a promising target for precision oncology of human HCC, as XI-011 treatment exerts anti-MDM4 activity independent from the MDM4 copy number and the p53 status.
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Affiliation(s)
- Rossella Pellegrino
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Abhishek Thavamani
- Department for Molecular Biology, Interfaculty Institute of Cell Biology, University of Tuebingen, 72074 Tuebingen, Germany; (A.T.); (A.N.)
| | - Diego F. Calvisi
- Institute of Pathology, University Hospital Regensburg, 93053 Regensburg, Germany;
| | - Jan Budczies
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Ariane Neumann
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
| | - Jasmin Kroemer
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Damaris Greule
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
| | - Alfred Nordheim
- Department for Molecular Biology, Interfaculty Institute of Cell Biology, University of Tuebingen, 72074 Tuebingen, Germany; (A.T.); (A.N.)
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.B.); (A.N.); (J.K.); (D.G.); (P.S.); (T.L.)
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21
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Zhang C, Wang X, Fang D, Xu P, Mo X, Hu C, Abdelatty A, Wang M, Xu H, Sun Q, Zhou G, She J, Xia J, Hui KM, Xia H. STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway. Theranostics 2021; 11:2108-2122. [PMID: 33500714 PMCID: PMC7797677 DOI: 10.7150/thno.48112] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Rationale: Protein kinases are critical therapeutic targets for curing hepatocellular carcinoma (HCC). As a serine/threonine kinase, the potential roles of serine/threonine kinase 39 (STK39) in HCC remain to be explored. Methods: The expression of STK39 was examined by RT-qPCR, western blotting and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK8 and TUNEL kit. Cell migration and invasion assays were performed using a transwell system with or without Matrigel. RNA-seq, mass spectrometry and luciferase reporter assays were used to identify STK39 binding proteins. Results: Here, we firstly report that STK39 was highly overexpressed in clinical HCC tissues compared with adjacent tissues, high expression of STK39 was induced by transcription factor SP1 and correlated with poor patient survival. Gain and loss of function assays revealed that overexpression of STK39 promoted HCC cell proliferation, migration and invasion. In contrast, the depletion of STK39 attenuated the growth and metastasis of HCC cells. Moreover, knockdown of STK39 induced the HCC cell cycle arrested in the G2/M phase and promoted apoptosis. In mechanistic studies, RNA-seq revealed that STK39 positively regulated the ERK signaling pathway. Mass spectrometry identified that STK39 bound to PLK1 and STK39 promoted HCC progression and activated ERK signaling pathway dependent on PLK1. Conclusions: Thus, our study uncovers a novel role of STK39/PLK1/ERK signaling axis in the progress of HCC and suggests STK39 as an indicator for prognosis and a potential drug target of HCC.
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Affiliation(s)
- Chengfei Zhang
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, Jiangsu, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, Anhui, China
| | - Dan Fang
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Ping Xu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Xiao Mo
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Chao Hu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Alaa Abdelatty
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Mei Wang
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Haojun Xu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Qi Sun
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Guoren Zhou
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, Jiangsu, China
| | - Junjun She
- Department of High Talent & General Surgery & Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, Shaanxi, China
| | - Jinglin Xia
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Kam Man Hui
- Laboratory of Cancer Genomics, National Cancer Centre Singapore & Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
| | - Hongping Xia
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, Jiangsu, China
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, Jiangsu, China
- Department of High Talent & General Surgery & Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, Shaanxi, China
- Laboratory of Cancer Genomics, National Cancer Centre Singapore & Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
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22
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Pavlović N, Calitz C, Thanapirom K, Mazza G, Rombouts K, Gerwins P, Heindryckx F. Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma. eLife 2020; 9:e55865. [PMID: 33103995 PMCID: PMC7661042 DOI: 10.7554/elife.55865] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Carlemi Calitz
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Kess Thanapirom
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Guiseppe Mazza
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Krista Rombouts
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Pär Gerwins
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
- Department of Radiology, Uppsala University HospitalUppsalaSweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
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23
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Li L, Shen L, Ma J, Zhou Q, Li M, Wu H, Wei M, Zhang D, Wang T, Qin S, Xing T. Evaluating Distribution and Prognostic Value of New Tumor-Infiltrating Lymphocytes in HCC Based on a scRNA-Seq Study With CIBERSORTx. Front Med (Lausanne) 2020; 7:451. [PMID: 33043022 PMCID: PMC7527443 DOI: 10.3389/fmed.2020.00451] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/07/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a commonly diagnosed cancer with high mortality rates. The immune response plays an important role in the progression of HCC. Immunotherapies are becoming an increasingly promising tool for treating cancers. Advancements in scRNA-seq (single-cell RNA sequencing) have allowed us to identify new subsets in the immune microenvironment of HCC. Yet, distribution of these new cell types and their potential prognostic value in bulk samples from large cohorts remained unclear. This study aimed to investigate the tumor-infiltration and prognostic value of new cell subsets identified by a previous scRNA-seq study in a TCGA HCC cohort using CIBERSORTx, a machine learning method to estimate cell proportion and infer cell-type-specific gene expression profiles. We observed different distributions of tumor-infiltrating lymphocytes between tumor and normal cells. Among these, the CD4-GZMA cell subset showed association with prognosis (log-rank test, p < 0.05). We further analyzed CD4-GZMA cell specific gene expression with CIBERSORTx, and found 19 prognostic genes (univariable cox regression, p < 0.05). Finally, we applied Least absolute shrinkage and selection operator (LASSO) Cox regression to construct an immune risk score model and performed a prognostic assessment of our model in TCGA and ICGC cohorts. Taken together, the immune landscape in HCC bulk samples may be more complex than assumed, with heterogeneity and different tumor-infiltration relative to scRNA-seq results. Additionally, CD4-GZMA cells and their characteristics may yield therapeutic benefits in the immune treatment of HCC.
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Affiliation(s)
- Lixing Li
- Department of General Surgery, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Shen
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jingsong Ma
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Mo Li
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Wu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Muyun Wei
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Di Zhang
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Wang
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Shengying Qin
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Tonghai Xing
- Department of General Surgery, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
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24
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Chow AKM, Yau SWL, Ng L. Novel molecular targets in hepatocellular carcinoma. World J Clin Oncol 2020; 11:589-605. [PMID: 32879846 PMCID: PMC7443834 DOI: 10.5306/wjco.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/04/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Affiliation(s)
- Ariel Ka-Man Chow
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Simon Wing-Lung Yau
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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25
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Hu Z, Dong L, Li S, Li Z, Qiao Y, Li Y, Ding J, Chen Z, Wu Y, Wang Z, Huang S, Gao Q, Zhao Y, He X. Splicing Regulator p54 nrb /Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma. Hepatology 2020; 72:548-568. [PMID: 31815296 DOI: 10.1002/hep.31062] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 11/18/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Alternative splicing (AS) is a key step that increases the diversity and complexity of the cancer transcriptome. Recent evidence has highlighted that AS has an increasingly crucial role in cancer. Nonetheless, the mechanisms underlying AS and its dysregulation in hepatocellular carcinoma (HCC) remain elusive. Here, we report that the expression of RNA-binding protein p54nrb /non-POU domain-containing octamer-binding protein (NONO) is frequently increased in patients with HCC and is associated with poor outcomes. APPROACH AND RESULTS Knockdown of NONO significantly abolished liver cancer cell proliferation, migration, and tumor formation. RNA-sequencing revealed that NONO regulates MYC box-dependent interacting protein 1 (or bridging integrator 1 [BIN1]; also known as amphiphysin 2 3P9) exon 12a splicing. In the normal liver, BIN1 generates a short isoform (BIN1-S) that acts as a tumor suppressor by inhibiting the binding of c-Myc to target gene promoters. In HCC, NONO is highly up-regulated and produces a long isoform (BIN1-L, which contains exon 12a) instead of BIN1-S. High levels of BIN1-L promote carcinogenesis by binding with the protein polo-like kinase 1 to enhance its stability through the prevention of ubiquitin/proteasome-dependent cullin 3 degradation. Further analysis revealed that NONO promotes BIN1 exon 12a inclusion through interaction with DExH-box helicase 9 (DHX9) and splicing factor proline and glutamine-rich (SFPQ). Notably, frequent coexpression of DHX9-NONO-SFPQ is observed in patients with HCC. CONCLUSIONS Taken together, our findings identify the DHX9-NONO-SFPQ complex as a key regulator manipulating the oncogenic splicing switch of BIN1 and as a candidate therapeutic target in liver cancer.
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Affiliation(s)
- Zhixiang Hu
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liangqing Dong
- Key Laboratory of Carcinogenesis and Cancer Invasion, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Ministry of Education, Fudan University, Shanghai, China
| | - Shengli Li
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhe Li
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yejun Qiao
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuchen Li
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jie Ding
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiao Chen
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yangjun Wu
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhen Wang
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shenglin Huang
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiang Gao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Ministry of Education, Fudan University, Shanghai, China
| | - Yingjun Zhao
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xianghuo He
- Fudan University Shanghai Cancer Centers, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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26
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Li W, Zhang X, Xi X, Li Y, Quan H, Liu S, Wu L, Wu P, Lan W, Shao Y, Li H, Chen K, Hu Z. PLK2 modulation of enriched TAp73 affects osteogenic differentiation and prognosis in human osteosarcoma. Cancer Med 2020; 9:4371-4385. [PMID: 32349184 PMCID: PMC7300400 DOI: 10.1002/cam4.3066] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/26/2020] [Accepted: 03/29/2020] [Indexed: 02/05/2023] Open
Abstract
There are three subtypes of undifferentiated human conventional osteosarcoma (HCOS): osteoblastic osteosarcoma (OOS), chondroblastic osteosarcoma (COS), and fibroblastic osteosarcoma (FOS). HCOS also exhibits heterogeneous pathological maldifferentiation in individual patients. Currently, the mechanism regulating HCOS differentiation remains unclear, and therapies are ineffective. Osteopontin (OPN) and osteocalcin (OCN) are markers of osteoblast maturation, and their expression is inhibited in HCOS. A previous study found that PLK2 inhibited TAp73 phosphorylation and consequent anti-OS function of TAp73 in OS cells with enriched TAp73. TAp73 was also reported to regulate bone cell calcification. Here, OOS was found to have higher TAp73 levels and PLK2 expression than those in COS, which is correlated with HCOS maldifferentiation according to Spearman analysis and affects patient prognosis according to Kaplan-Meier survival analysis. In the conventional OS cell-line Saos2 and in patient-derived xenograft OS (PDX-OS) cells, increased PLK2 expression owing to abundant TAp73 levels affected OPN and OCN content as measured by RT-PCR and Western blotting, and alizarin red staining showed that PLK2 affected calcium deposition in OS cells. In addition, PLK2 inhibition in PDX-OS cells prohibited clone formation, as indicated by a clonogenic assay, and sensitized OS cells to cisplatin (CDDP) (which consequently limited proliferation), as shown by the CCK-8 assay. In an established PDX animal model with abundant TAp73 levels, PLK2 inhibition or CDDP treatment prevented tumor growth and prolonged median survival. The combined therapeutic effect of PLK2 inhibition with CDDP treatment was better than that of either monotherapy. These results indicate that increased PLK2 levels due to enriched TAp73 affect osteogenic differentiation and maturation and OS prognosis. In conclusion, PLK2 is a potential target for differentiation therapy of OS with enriched TAp73.
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Affiliation(s)
- Wenhu Li
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
| | - Xianliao Zhang
- Orthopedics CenterZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Xinhua Xi
- Department of OrthopaedicsThe Affiliated Yuebei People's Hospital of Shantou University Medical CollegeShaoguanChina
| | - Yufa Li
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
- Department of PathologyGuangdong provincial people's Hospital & Guangdong, Academy of Medical SciencesGuangzhouChina
| | - Hong Quan
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
| | - Shifeng Liu
- Orthopedics CenterDongguan Eighth People's HospitalDongguanChina
| | - Liqi Wu
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
| | - Penghuan Wu
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
- Orthopedics CenterZhujiang Hospital of Southern Medical UniversityGuangzhouChina
| | - Wenxing Lan
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
| | - Yongjun Shao
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
| | - Haomiao Li
- Orthopedics CenterThe Third Affiliated Hospital of Southern Medical UniversityOrthopedics institute of Guangdong ProvinceGuangzhouChina
| | - Kebing Chen
- Orthopedics CenterThe Third Affiliated Hospital of Southern Medical UniversityOrthopedics institute of Guangdong ProvinceGuangzhouChina
| | - Zhengbo Hu
- Department of OrthopedicsShaoguan First People's Hospital Affiliated to Southern Medical UniversityShaoguanChina
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27
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Xie XL, Zhu HX, Li YM, Chen DT, Fan TY. Differential expression of AURKA/PLK4 in quiescence and senescence of osteosarcoma U2OS cells. Cell Cycle 2020; 19:884-894. [PMID: 32200684 DOI: 10.1080/15384101.2020.1731054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
This study aimed to identify co-expressed differentially expressed genes (DEGs) in quiescence and senescence of osteosarcoma (OS) U2OS cells and investigate their biological functions. GSE94805 from Gene Expression Omnibus database was extracted, involving 12 samples of OS U2OS cells (4 quiescence, 4 senescence, and 4 control samples). After analysis of DEGs by limma package, VENN analysis was performed to identify co-expressed DEGs in quiescence and senescent. The Cytoscape software was used to construct an interactive network of co-expressed DEGs. Finally, box-plot was drawn for the co-expressed DEGs in sub-network. Besides, the relation literatures were selected in GenCLiP database for the co-expressed DEGs. Seven hundred and forty-three DEGs (255 up-regulated genes, 488 down-regulated genes) were obtained in quiescence and 2135 DEGs (1189 up-regulated genes, 946 down-regulated genes) in senescence. Through VENN analysis, 448 DEGs (131 up-regulated genes, 317 down-regulated genes) were co-expressed in quiescent and senescence. In the co-expressed DEGs network, 896 nodes (448 nodes in quiescent, 448 nodes in senescent) were obtained. Finally, 16 co-expressed DEGs were obtained in the sub-network analysis, in which Aurora kinase A (AURKA) and polo-like kinase (PLK4) had been reported in OS. AURKA and PLK4 might be the key genes in quiescence and senescence of OS U2OS cells.
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Affiliation(s)
- Xiao-Liang Xie
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hai-Xia Zhu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu-Mei Li
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - De-Ta Chen
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tian-You Fan
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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28
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Kronschnabl P, Grünweller A, Hartmann RK, Aigner A, Weirauch U. Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in vitro and in vivo primarily through the modulation of cell cycle progression. Int J Oncol 2019; 56:448-459. [PMID: 31894300 PMCID: PMC6959465 DOI: 10.3892/ijo.2019.4936] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/21/2019] [Indexed: 01/05/2023] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related mortality worldwide with limited therapeutic options. Thus, novel treatment strategies are urgently required. While the oncogenic kinase, proviral integration site for Moloney murine leukemia virus 2 (PIM2), has been shown to be overexpressed in liver cancer, little is known about the role of PIM2 in this tumor entity. In this study, we explored the functional relevance and therapeutic potential of PIM2 in liver cancer. Using PIM2-specific siRNAs, we examined the effects of PIM2 knockdown on proliferation (WST-1 assays and spheroid assays), 3D-colony formation and colony spread, apoptosis (flow cytometry and caspase 3/caspase 7 activity), as well as cell cycle progression (flow cytometry, RT-qPCR and western blot analysis) in the two liver cancer cell lines, HepG2 and Huh-7. In subcutaneous liver cancer xenografts, we assessed the effects of PIM2 knockdown on tumor growth via the systemic delivery of polyethylenimine (PEI)-complexed siRNA. The knockdown of PIM2 resulted in potent anti-proliferative effects in cells grown on plastic dishes, as well as in spheroids. This was due to G0/G1 cell cycle blockade and the subsequent downregulation of genes related to the S phase as well as the G2/M phase of the cell cycle, whereas the apoptotic rates remained unaltered. Furthermore, colony formation and colony spread were markedly inhibited by PIM2 knockdown. Notably, we found that HepG2 cells were more sensitive to PIM2 knockdown than the Huh-7 cells. In vivo, the therapeutic nanoparticle-mediated delivery of PIM2 siRNA led to profound anti-tumor effects in a liver cancer xenograft mouse model. On the whole, the findings of this study underscore the oncogenic role of PIM2 and emphasize the potential of targeted therapies based on the specific inhibition of PIM2 in liver cancer.
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Affiliation(s)
- Pia Kronschnabl
- Rudolf‑Boehm‑Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D‑04107 Leipzig, Germany
| | - Arnold Grünweller
- Institute of Pharmaceutical Chemistry, Philipps‑University Marburg, D‑35037 Marburg, Germany
| | - Roland K Hartmann
- Institute of Pharmaceutical Chemistry, Philipps‑University Marburg, D‑35037 Marburg, Germany
| | - Achim Aigner
- Rudolf‑Boehm‑Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D‑04107 Leipzig, Germany
| | - Ulrike Weirauch
- Rudolf‑Boehm‑Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D‑04107 Leipzig, Germany
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29
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Zhou B, Ho SS, Greer SU, Spies N, Bell JM, Zhang X, Zhu X, Arthur JG, Byeon S, Pattni R, Saha I, Huang Y, Song G, Perrin D, Wong WH, Ji HP, Abyzov A, Urban AE. Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2. Nucleic Acids Res 2019; 47:3846-3861. [PMID: 30864654 PMCID: PMC6486628 DOI: 10.1093/nar/gkz169] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/19/2019] [Accepted: 03/01/2019] [Indexed: 12/19/2022] Open
Abstract
HepG2 is one of the most widely used human cancer cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher order genomic structural features are largely unknown. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data from HepG2 requires an understanding of the cell line’s genome sequence and genome structure. Using a variety of sequencing and analysis methods, we identified a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments at high resolution, SNVs and Indels (corrected for aneuploidy), regions with loss of heterozygosity, phased haplotypes extending to entire chromosome arms, retrotransposon insertions and structural variants (SVs) including complex and somatic genomic rearrangements. A large number of SVs were phased, sequence assembled and experimentally validated. We re-analyzed published HepG2 datasets for allele-specific expression and DNA methylation and assembled an allele-specific CRISPR/Cas9 targeting map. We demonstrate how deeper insights into genomic regulatory complexity are gained by adopting a genome-integrated framework.
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Affiliation(s)
- Bo Zhou
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Steve S Ho
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Stephanie U Greer
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Noah Spies
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.,Genome-scale Measurements Group, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA
| | - John M Bell
- Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
| | - Xianglong Zhang
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Xiaowei Zhu
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Joseph G Arthur
- Department of Statistics, Stanford University, Stanford, CA 94305, USA
| | - Seunggyu Byeon
- School of Computer Science and Engineering, College of Engineering, Pusan National University, Busan 46241, South Korea
| | - Reenal Pattni
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ishan Saha
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yiling Huang
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Giltae Song
- School of Computer Science and Engineering, College of Engineering, Pusan National University, Busan 46241, South Korea
| | - Dimitri Perrin
- Science and Engineering Faculty, Queensland University of Technology, Brisbane, QLD 4001, Australia
| | - Wing H Wong
- Department of Statistics, Stanford University, Stanford, CA 94305, USA.,Department of Biomedical Data Science, Bio-X Program, Stanford University, Stanford, CA 94305, USA
| | - Hanlee P Ji
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
| | - Alexej Abyzov
- Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Alexander E Urban
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.,Tashia and John Morgridge Faculty Scholar, Stanford Child Health Research Institute, Stanford, CA 94305, USA
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30
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Zhao Y, Wang X. PLK4: a promising target for cancer therapy. J Cancer Res Clin Oncol 2019; 145:2413-2422. [PMID: 31492983 DOI: 10.1007/s00432-019-02994-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 08/05/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. METHODS The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. CONCLUSIONS PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.
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Affiliation(s)
- Yi Zhao
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, No. 324, Jingwu Road, Jinan, 250021, Shandong, People's Republic of China.
- School of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China.
- Key Laboratory for Kidney Regeneration of Shandong Province, Jinan, 250021, Shandong, China.
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31
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Zhu HR, Yu XN, Zhang GC, Shi X, Bilegsaikhan E, Guo HY, Liu LL, Cai Y, Song GQ, Liu TT, Dong L, Janssen HLA, Weng SQ, Wu J, Shen XZ, Zhu JM. Comprehensive analysis of long non‑coding RNA‑messenger RNA‑microRNA co‑expression network identifies cell cycle‑related lncRNA in hepatocellular carcinoma. Int J Mol Med 2019; 44:1844-1854. [PMID: 31485608 PMCID: PMC6777664 DOI: 10.3892/ijmm.2019.4323] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 07/24/2019] [Indexed: 12/30/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been shown to contribute to progression and prognosis of hepatocellular carcinoma (HCC). However, expression profiling and interaction of lncRNAs with messenger RNAs (mRNAs) and microRNAs (miRNAs) remain largely unknown in HCC. The expression profiling of lncRNAs, mRNA and miRNAs was obtained using microarray. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to characterize potential functions of differentially expressed mRNAs. Cytoscape was applied to construct an lncRNA-miRNA-mRNA co-expression network and candidate lncRNAs were validated via quantitative PCR in 30 pairs of HCC and adjacent tumor-free tissues. In this study, 1,056 upregulated and 1,288 downregulated lncRNAs were identified, while 2,687 mRNAs and 6 miRNAs were aberrantly expressed in HCC compared with adjacent tumor-free tissues. Potential functions of differentially expressed mRNAs were demonstrated to significantly participate in modulating critical genes in the cell cycle, such as cyclin E1 and cyclin B2. After screening, 95 lncRNAs, 5 miRNAs and 36 mRNAs were recruited for construction of lncRNA-mRNA-miRNA co-expression network in the cell cycle pathway. Subsequently, the top 5 lncRNAs that potentially modulate critical genes in the cell cycle were selected as the candidates for further verification. Kaplan-Meier curves using the Cancer Genome Atlas database showed that 13 targeted mRNAs were associated with overall survival of HCC patients. Finally, three lncRNAs, including ENST00000522221, lnc-HACE1-6:1 and lnc-ICOSLG-11:1, are significantly upregulated in HCC tissues compared with adjacent tumor-free tissues. These findings suggest that lncRNAs play essential roles in the pathogenesis of HCC via regulating coding genes and miRNAs, and may be important targets for diagnosis and treatment of this disease.
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Affiliation(s)
- Hai-Rong Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Xiang-Nan Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Guang-Cong Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Xuan Shi
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Enkhnaran Bilegsaikhan
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Hong-Ying Guo
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Li-Li Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Yu Cai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Guang-Qi Song
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Harry L A Janssen
- Division of Gastroenterology, University of Toronto and University Health Network, Toronto, ON M5G 2C4, Canada
| | - Shu-Qiang Weng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Jian Wu
- Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
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32
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Fleischmann M, Martin D, Peña-Llopis S, Oppermann J, von der Grün J, Diefenhardt M, Chatzikonstantinou G, Fokas E, Rödel C, Strebhardt K, Becker S, Rödel F, Tselis N. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy. Front Oncol 2019; 9:742. [PMID: 31475104 PMCID: PMC6702309 DOI: 10.3389/fonc.2019.00742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 07/23/2019] [Indexed: 12/22/2022] Open
Abstract
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses. Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
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Affiliation(s)
- Max Fleischmann
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Daniel Martin
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Samuel Peña-Llopis
- Division of Solid Tumor Translational Oncology, West German Cancer Center, Essen University Hospital, Essen, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK) Partner Site, Essen/Düsseldorf, Germany
| | - Julius Oppermann
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Jens von der Grün
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Markus Diefenhardt
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | | | - Emmanouil Fokas
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Klaus Strebhardt
- German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany.,Department of Gynecology, Goethe-University, Frankfurt, Germany
| | - Sven Becker
- Department of Gynecology, Goethe-University, Frankfurt, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Nikolaos Tselis
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
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33
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Recent advances in liver transplantation for cancer: The future of transplant oncology. JHEP Rep 2019; 1:377-391. [PMID: 32039389 PMCID: PMC7005652 DOI: 10.1016/j.jhepr.2019.07.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with recent therapeutic advances, as well as efforts to increase the donor pool, liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid haemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the newest indications for liver transplantation, with a special focus on future perspectives within the recently established concept of transplant oncology.
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34
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Liu W, Zha Z, Wang H. Upregulation of microRNA‐27a inhibits synovial angiogenesis and chondrocyte apoptosis in knee osteoarthritis rats through the inhibition of PLK2. J Cell Physiol 2019; 234:22972-22984. [PMID: 31134620 DOI: 10.1002/jcp.28858] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/11/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Wenjing Liu
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province Orthopedic Hospital of Henan Province Zhengzhou Henan China
| | - Zhuqing Zha
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province Orthopedic Hospital of Henan Province Zhengzhou Henan China
| | - Haitao Wang
- Department of Orthopedics Weihai Central Hospital Weihai Shandong China
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35
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Lin C, Bai S, Du T, Lai Y, Chen X, Peng S, Ma X, Wu W, Guo Z, Huang H. Polo-like kinase 3 is associated with poor prognosis and regulates proliferation and metastasis in prostate cancer. Cancer Manag Res 2019; 11:1517-1524. [PMID: 30863161 PMCID: PMC6388943 DOI: 10.2147/cmar.s176762] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Biological mechanism of prostate cancer (PCa) recurrence and progress is complex but many of the key elements are not fully understood. Polo-like kinases (Plks) represent a family of highly conserved serine–threonine kinases that play essential roles in cell cycle progression. Plk3 plays contradictory roles in different cancers. However, the roles of Plk3 in PCa remain largely unexplored. Methods Kaplan–Meier analysis and Cox regression analysis were performed to evaluate the relationship between Plk3 and prognosis of patients with PCa. Gene set enrichment analysis (GSEA) was conducted to evaluate proliferation and metastasis gene sets using The Cancer Genome Atlas Dataset. MTS assay, clone formation assay, cell migration, and wound healing assay were carried out to investigate biological functions of Plk3. Results We found that high Plk3 expression was closely correlated with poor prognosis. GSEA revealed that Plk3 was involved in proliferation and metastasis. Loss-of-function assays demonstrated that Plk3 promoted proliferation and metastasis in PCa cells in vitro. Conclusion We discovered that Plk3 plays a critical role in PCa, indicating that it may be a potential prognostic marker and help predict the progression, especially recurrence of PCa.
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Affiliation(s)
- Chunhao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ; .,Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Shoumin Bai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ; .,Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Tao Du
- Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yiming Lai
- Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Xianju Chen
- Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518017, China
| | - Shengmeng Peng
- Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Xiaoming Ma
- Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Wanhua Wu
- Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Zhenghui Guo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ; .,Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
| | - Hai Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ; .,Department of Urology, Sun Yatsen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China, ;
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36
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Xu C, Zhang W, Zhang X, Zhou D, Qu L, Liu J, Xiao M, Ni R, Jiang F, Ni W, Lu C. Coupling function of cyclin-dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma. Cancer Sci 2019; 110:540-549. [PMID: 30444001 PMCID: PMC6361569 DOI: 10.1111/cas.13882] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/06/2018] [Accepted: 11/14/2018] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with a poorly defined molecular mechanism. Cyclin-dependent kinase 2 (CDK2) and Septin2 (SEPT2) are 2 known oncogenic molecules but the mechanism of functional interactions remains unclear. Here, we interestingly found that CDK2 and SEPT2 show very similar dynamic expression during the cell cycle. Both CDK2 and SEPT2 show the highest protein levels in the G2/M phase, resulting in CDK2 interacting with SEPT2 and stabilizing SEPT2 in HCC. In a panel of 8 pairs of fresh HCC tissues and corresponding adjacent tissues, both western blot and immunohistochemistry (IHC) assays demonstrate that CDK2 expression is highly correlated with SEPT2. HCC with high expression of both CDK2 and SEPT2 are more likely to relapse. This observation is further demonstrated by a large panel of 100 HCC patients. In this large panel, high expression of both CDK2 and SEPT2 significantly correlates with tumor differentiation and microvascular invasion, which is an independent prognostic factor in HCC patients. In summary, our results reveal a cooperative function between CDK2 and SEPT2. HCC with high expression of CDK2 and SEPT2 might be more aggressive and respond poorly to current therapy.
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Affiliation(s)
- Chenzhou Xu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Wei Zhang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Xuening Zhang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Danhua Zhou
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Lishuai Qu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Jinxia Liu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Mingbing Xiao
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongChina
| | - Runzhou Ni
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Feng Jiang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Wenkai Ni
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Cuihua Lu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
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Liao Z, Zhang H, Fan P, Huang Q, Dong K, Qi Y, Song J, Chen L, Liang H, Chen X, Zhang Z, Zhang B. High PLK4 expression promotes tumor progression and induces epithelial‑mesenchymal transition by regulating the Wnt/β‑catenin signaling pathway in colorectal cancer. Int J Oncol 2019; 54:479-490. [PMID: 30570110 PMCID: PMC6317648 DOI: 10.3892/ijo.2018.4659] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 10/24/2018] [Indexed: 02/07/2023] Open
Abstract
Polo‑like kinase 4 (PLK4) has been identified as an oncogene, which is overexpressed in various types of human cancer; however, its role in colorectal cancer (CRC) development remains unknown. The present study demonstrated that PLK4 protein expression was upregulated in CRC tissues compared with in normal tissues through western blotting. In addition, immunohistochemical analysis of 39 CRC specimens further demonstrated that PLK4 protein expression was upregulated in 64.1% (25/39) of samples. Increased PLK4 expression was closely associated with enhanced tumor size (P=0.031), lymph node metastasis (P=0.016) and TNM stage (P=0.001). Subsequently, cell viability, wound scratch, migration and invasion assays were conducted in vitro, and nude mice CRC xenograft models were generated. The results demonstrated that knockdown of PLK4 in CRC cells resulted in significant decreases in cell viability and proliferation, and decreased the protein expression levels of N‑cadherin and snail, which are biomarkers of epithelial‑mesenchymal transition. Furthermore, PLK4 knockdown inactivated the Wnt/β‑catenin pathway in CRC cells in vitro and in vivo, and suppressed the growth of xenograft tumors in nude mice. In conclusion, these results suggested that PLK4 may promote the carcinogenesis and metastasis of CRC, thus indicating that PLK4 may be considered a molecular target for CRC treatment.
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Affiliation(s)
- Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
- Key Laboratory of Organ Transplantation, Ministry of Education and Ministry Health, Wuhan, Hubei 430030
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Pan Fan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Qibo Huang
- Department of Clinical Medicine, Medical College of Wuhan University of Science and Technology, Wuhan, Hubei 430081, P.R. China
| | - Keshuai Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Yongqiang Qi
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
- Key Laboratory of Organ Transplantation, Ministry of Education and Ministry Health, Wuhan, Hubei 430030
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
- Key Laboratory of Organ Transplantation, Ministry of Education and Ministry Health, Wuhan, Hubei 430030
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery
- Key Laboratory of Organ Transplantation, Ministry of Education and Ministry Health, Wuhan, Hubei 430030
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Bao J, Yu Y, Chen J, He Y, Chen X, Ren Z, Xue C, Liu L, Hu Q, Li J, Cui G, Sun R. MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway. Cell Death Dis 2018; 9:1045. [PMID: 30315225 PMCID: PMC6185973 DOI: 10.1038/s41419-018-1020-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/21/2018] [Accepted: 08/30/2018] [Indexed: 12/30/2022]
Abstract
Emerging evidence has shown that microRNA-126 (miR-126) is aberrantly downregulated and plays a vital role in carcinogenesis in various cancers, including HCC. However, the underlying biological mechanisms of miR-126 in HCC are still largely unknown. In present study, we found that miR-126 was downregulated both in HCC tissues and cell lines. Low expression level of miR-126 was associated with poor overall survival (OS), late TNM stage and the presence of recurrence. Overexpression of miR-126 significantly decreased cell proliferation, metastasis and promoted apoptosis in vitro. Additional, high miR-126 expression reduced the tumor growth in vivo. Further we discovered that PLK (polo-like kinases)-4, a critical regulator in cell cycle, was a target of miR-126. PLK-4 overexpression could rescue the inhibitory effects of miR-126 on cell proliferation and invasion. Moreover, PLK-4 mRNA and protein levels were significantly upregulated in HCC tissues and positively associated with malignancies and poor OS. Knockdown PLK-4 significantly inhibited cell proliferation, invasion and promoted cell apoptosis in vitro whereas decreased tumor growth in vivo. More importantly, bioinformatics analysis combined with validation experiments in vitro and in vivo showed that activation of the ATR/CHEK1 pathway was involved in the oncogenic functions of PLK4 in HCC. We also validated that PLK4 could directly interact with ATR through CoIP assay. Taken together, we demonstrate that miRNA-126/PLK-4 axis is critical for tumorigenesis and progression of HCC, and the newly identified PLK-4/ATR/CHEK1 pathway may be a potential therapeutic target for HCC treatment.
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Affiliation(s)
- Jie Bao
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yan Yu
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jianan Chen
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuting He
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiaolong Chen
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhigang Ren
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chen Xue
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Liwen Liu
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qiuyue Hu
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Juan Li
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Guangying Cui
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Ranran Sun
- Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- National Engineering Laboratory for Internet Medical System and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Okamoto A, Asai T, Hirai Y, Shimizu K, Koide H, Minamino T, Oku N. Systemic Administration of siRNA with Anti-HB-EGF Antibody-Modified Lipid Nanoparticles for the Treatment of Triple-Negative Breast Cancer. Mol Pharm 2018; 15:1495-1504. [PMID: 29502423 DOI: 10.1021/acs.molpharmaceut.7b01055] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Triple-negative breast cancer is one of the intractable cancers that are not sensitive to treatment with existing molecular-targeted drugs. Recently, there has been much interest in RNA interference-mediated treatment of triple-negative breast cancer. In the present study, we have developed lipid nanoparticles encapsulating siRNA (LNP-siRNA) decorated with an Fab' antibody against heparin-binding EGF-like growth factor (αHB-EGF LNP-siRNA). αHB-EGF LNP-siRNA targeting polo-like kinase 1 (PLK1) was prepared and evaluated for its anticancer effect using MDA-MB-231 human triple-negative breast cancer cells overexpressing HB-EGF on their cell surface. Biodistribution data of radioisotope-labeled LNP and fluorescence-labeled siRNA indicated that αHB-EGF LNP effectively delivered siRNA to tumor tissue in MDA-MB-231 carcinoma-bearing mice. Expression of PLK1 protein in the tumors was clearly suppressed after intravenous injection of αHB-EGF LNP-siPLK1. In addition, tumor growth was significantly inhibited by treatment with this formulation of siRNA and an antibody-modified carrier. These findings indicate that αHB-EGF LNP is a promising carrier for the treatment of HB-EGF-expressing cancers, including triple-negative breast cancer.
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Affiliation(s)
- Ayaka Okamoto
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
- Japan Society for the Promotion of Science , 5-3-1 Kojimachi, Chiyoda-ku , Tokyo 102-0083 , Japan
| | - Tomohiro Asai
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
| | - Yusuke Hirai
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
| | - Kosuke Shimizu
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
- Department of Molecular Imaging, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center , Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi-ku , Hamamatsu City , Shizuoka 431-3192 Japan
| | - Hiroyuki Koide
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
| | - Tetsuo Minamino
- Department of Cardiovascular Medicine, Graduate School of Medicine , Kagawa University , 1750-1 Ikenobe, Miki-cho , Kita-gun , Kagawa 761-0793 Japan
| | - Naoto Oku
- Department of Medical Biochemistry, School of Pharmaceutical Sciences , University of Shizuoka , 52-1 Yada, Suruga-ku , Shizuoka 422-8526 , Japan
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Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy. Oncotarget 2018; 7:53339-53349. [PMID: 27462786 PMCID: PMC5288191 DOI: 10.18632/oncotarget.10801] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/13/2016] [Indexed: 12/11/2022] Open
Abstract
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
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The clinical and prognostic value of polo-like kinase 1 in lung squamous cell carcinoma patients: immunohistochemical analysis. Biosci Rep 2017; 37:BSR20170852. [PMID: 28724602 PMCID: PMC5554781 DOI: 10.1042/bsr20170852] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/09/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023] Open
Abstract
Polo-like kinase 1 (PLK1) has been suggested to serve as an oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma, and normal lung tissues through analyzing microarray dataset (GEO accession numbers: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. In our results, the levels of PLK1 in lung squamous cell carcinoma tissues were higher than that in lung adenocarcinoma tissues. Compared with paired adjacent normal lung tissues, the PLK1 expression was increased in lung squamous cell carcinoma tissues. Furthermore, high expression of PLK1 protein was correlated with differentiated degree, clinical stage, tumor size, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses showed PLK1 protein high expression was an unfavorable prognostic biomarker for lung squamous cell carcinoma patients. In conclusion, high expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients.
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Chai Y, Zhao M. iTRAQ-Based Quantitative Proteomic Analysis of the Inhibitory Effects of Polysaccharides from Viscum coloratum (Kom.) Nakai on HepG2 Cells. Sci Rep 2017; 7:4596. [PMID: 28676664 PMCID: PMC5496916 DOI: 10.1038/s41598-017-04417-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 05/03/2017] [Indexed: 01/02/2023] Open
Abstract
Viscum coloratum (Kom.) Nakai is one of active medicinal plants, and its active components, especially polysaccharides, have been shown to exhibit bioactivity. In this study, we examined the effects of three polysaccharide fractions from Viscum coloratum (Kom.) Nakai on HepG2 cell growth in a dose-dependent manner by using a CCK-8 assay kit. Flow cytometry analysis showed that VCP2 treatment delayed the cell cycle in the G1 phase and induced apoptosis in HepG2 cells, a result possibly due to the increased expression of p21Wafl/Cip1 and Cyclin D and the decreased expression of Cyclin E and CDK4. The increased expression of Bad, Smac and Caspase-3 and the decreased expression of Bcl-XL and XIAP may be some of the reasons for the induction of apoptosis in VCP2-treated HepG2 cells. Through iTRAQ and 2D-LC-MSMS, 113 and 198 differentially expressed proteins were identified in normal and VCP2-treated HepG2 and Caco2 cells. The mRNA and protein levels of Histone H3.1, Cytoskeletal 9 and Vitronectin agreed with iTRAQ proteomic results. GO, pathways and the PPI of differentially expressed proteins were further analyzed. These findings broaden the understanding of the anti-tumor mechanisms of mistletoe polysaccharides and provide new clues for screening proteins that are responsive to polysaccharides.
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Affiliation(s)
| | - Min Zhao
- Northeast Forestry University, Harbin, PR China.
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Pezuk JA, Brassesco MS, de Oliveira RS, Machado HR, Neder L, Scrideli CA, Tone LG. PLK1-associated microRNAs are correlated with pediatric medulloblastoma prognosis. Childs Nerv Syst 2017; 33:609-615. [PMID: 28283778 DOI: 10.1007/s00381-017-3366-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/09/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE Medulloblastoma (MB) is the most common malignant tumor of the central nervous system (CNS) in children. Despite its relative good survival rates, treatment can cause long time sequels and may impair patients' lifespan and quality, making the search for new treatment options still necessary. Polo like kinases (PLKs) constitute a five-member serine/threonine kinases family (PLK 1-5) that regulates different stages during cell cycle. Abnormal PLKs expression has been observed in several cancer types, including MB. As gene regulators, miRNAs have also been described with variable expression in cancer. METHODS We evaluated gene expression profiles of all PLK family members and related miRNAs (miR-100, miR-126, miR-219, and miR-593*) in MB cell lines and tumor samples. RESULTS RT-qPCR analysis revealed increased levels of PLK1-4 in all cell lines and in most MB samples, while PLK5 was found underexpressed. In parallel, miR-100 was also found upregulated while miR-129, miR-216, and miR-593* were decreased in MB cell lines. Variable miRNAs expression patterns were observed in MB samples. However, a correlation between miR-100 and PLK4 expression was observed, and associations between miR-100, miR-126, and miR-219 expression and overall and event free survival were also evinced in our cohort. Moreover, despite the lack of association with clinico-pathological features, when comparing primary tumors to those relapsed, we found a consistent decrease on PLK2, miR-219, and miR-598* and an increase on miR-100 and miR-126. CONCLUSION Specific dysregulation on PLKs and associated miRNAs may be important in MB and can be used to predict prognosis. Although miRNAs sequences are fundamental to predict its target, the cell type may also be consider once that mRNA repertoire can define different roles for specific miRNA in a given cell.
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Affiliation(s)
- Julia Alejandra Pezuk
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
- Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil.
| | - María Sol Brassesco
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | | | | | - Luciano Neder
- Department of Pathology, University of São Paulo, São Paulo, Brazil
| | - Carlos Alberto Scrideli
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Luiz Gonzaga Tone
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
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Miyamoto T, Minase G, Shin T, Ueda H, Okada H, Sengoku K. Human male infertility and its genetic causes. Reprod Med Biol 2017; 16:81-88. [PMID: 29259455 PMCID: PMC5661822 DOI: 10.1002/rmb2.12017] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/16/2016] [Indexed: 01/11/2023] Open
Abstract
Background Infertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation. Methods We mainly describe the SYCP3 and PLK4 genes that we have studied in our laboratory, and add comments on other genes associated with human male infertility. Results Up to now, The 17 genes causing male infertility by their mutation have been reported in human. Conclusions Infertility caused by nonobstructive azoospermia (NOA) is very important in the field of assisted reproductive technology. Even with the aid of chromosomal analysis, ultrasonography of the testis, and detailed endocrinology, only MD‐TESE can confirm the presence of immature spermatozoa in the testes. We strongly hope that these studies help clinics avoid ineffective MD‐TESE procedures.
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Affiliation(s)
- Toshinobu Miyamoto
- Department of Obstetrics and Gynecology Asahikawa Medical University Asahikawa Japan
| | - Gaku Minase
- Department of Obstetrics and Gynecology Asahikawa Medical University Asahikawa Japan
| | - Takeshi Shin
- Department of Urology Dokkyo Medical University Koshigaya Hospital Koshigaya City Japan
| | - Hiroto Ueda
- Department of Obstetrics and Gynecology Asahikawa Medical University Asahikawa Japan
| | - Hiroshi Okada
- Department of Urology Dokkyo Medical University Koshigaya Hospital Koshigaya City Japan
| | - Kazuo Sengoku
- Department of Obstetrics and Gynecology Asahikawa Medical University Asahikawa Japan
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Wang ZD, Shen LP, Chang C, Zhang XQ, Chen ZM, Li L, Chen H, Zhou PK. Long noncoding RNA lnc-RI is a new regulator of mitosis via targeting miRNA-210-3p to release PLK1 mRNA activity. Sci Rep 2016; 6:25385. [PMID: 27160062 PMCID: PMC4861912 DOI: 10.1038/srep25385] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 04/15/2016] [Indexed: 01/01/2023] Open
Abstract
Increasing evidence indicates that lncRNAs play critical roles in various biological processes, but many have not been functionally characterized. Here, we report a novel radiation-inducible lncRNA, namely lnc-RI which is essential for cell survival and appropriate mitotic progression. Our data indicated that knockdown of lnc-RI resulted in spindle abnormalities and mitotic arrest simultaneously with sharply decreased mRNA and protein expression of PLK1, a key regulator of mitosis. Our data demonstrated that PLK1 is a key downstream mediator of lnc-RI in regulating mitosis, whereby lnc-RI competitively bound to the negative PLK1 regulating miRNA, miRNA-210-p3. Taken together, we have identified lnc-RI as a new regulator of mitosis which acts by releasing PLK1 mRNA activity via competition for binding to miRNA-210-3p.
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Affiliation(s)
- Zhi-Dong Wang
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Li-Ping Shen
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Cheng Chang
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
- Institute for Environmental Medicine and Radiation Hygiene, College of Public Health, University of South China, Hengyang, Hunan Province, 421000, P.R. China
| | - Xue-Qing Zhang
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Zhong-Min Chen
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Lin Li
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Hong Chen
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
| | - Ping-Kun Zhou
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, P. R. China
- Institute for Environmental Medicine and Radiation Hygiene, College of Public Health, University of South China, Hengyang, Hunan Province, 421000, P.R. China
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Fernández-Aceñero MJ, Cortés D, Gómez del Pulgar T, Cebrián A, Estrada L, Martínez-Useros J, Celdrán A, García-Foncillas J, Pastor C. PLK-1 Expression is Associated with Histopathological Response to Neoadjuvant Therapy of Hepatic Metastasis of Colorectal Carcinoma. Pathol Oncol Res 2016; 22:377-383. [PMID: 26577686 DOI: 10.1007/s12253-015-0015-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 11/12/2015] [Indexed: 01/05/2023]
Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple human cancers, including leukemia and also many solid tumors. PLK1 knockdown has been shown to block proliferation of leukemic cell lines and the clonogenic potential of tumor cells grown from patients with cancer. PLK1 inhibition is a promising strategy for the treatment of some tumors. We aim to analyze expression of PLK1 in metastatic colorectal carcinoma. Retrospective analysis of colorectal carcinomas with hepatic metastasis during follow-up receiving neoadjuvant chemotherapy (NAC), based on oxaliplatin. Immunohistochemistry for PLK-1 in paraffin-embedded tissue from the primary and also from the metastasis. 50 patients. 32% showed good histopathological response. 43% of the primaries were positive for PLK1, as opposed to 23.5% of the metastasis. Expression of PLK1 was significantly reduced in metastasis compared with the primaries (p = 0.05), what could be due to therapy or to a phenotypic change of the metastatic nodule. Analysis of the prognostic influence of PLK1 expression showed significant association between PLK1 expression in metastasis and lower overall survival (p = 0.000). We have also found a significant association between PLK1 expression and histopathological response (p = 0.02). All the tumors with high expression of PLK1 showed minor response (11/11). This study shows the association between survival and poor histopathological response to therapy and high expression of PLK1 in metastasis. Our results could open a new therapeutic approach through the inhibition of PLK1.
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Affiliation(s)
- M J Fernández-Aceñero
- Department of Surgical Pathology, Hospital Clínico San Carlos, C/ Profesor Martín Lagos s/n, 28040, Madrid, Spain.
| | - D Cortés
- Department of Surgery, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - T Gómez del Pulgar
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - A Cebrián
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - L Estrada
- Department of Surgical Pathology, Hospital Clínico San Carlos, C/ Profesor Martín Lagos s/n, 28040, Madrid, Spain
| | - J Martínez-Useros
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - A Celdrán
- Department of Surgery, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - J García-Foncillas
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
| | - C Pastor
- Department of Surgery, Health Research Institute FJD-UAM, University Hospital Fundación Jiménez Diaz, Madrid, Spain
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47
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Huang YH, Tseng YH, Lin WR, Hung G, Chen TC, Wang TH, Lee WC, Yeh CT. HBV polymerase overexpression due to large core gene deletion enhances hepatoma cell growth by binding inhibition of microRNA-100. Oncotarget 2016; 7:9448-9461. [PMID: 26824500 PMCID: PMC4891051 DOI: 10.18632/oncotarget.7021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/17/2016] [Indexed: 01/04/2023] Open
Abstract
Different types of hepatitis B virus (HBV) core gene deletion mutants were identified in chronic hepatitis B patients. However, their clinical roles in different stages of natural chronic HBV infection remained unclear. To address this issue, HBV core genes were sequenced in three gender- and age-matched patient groups diagnosed as chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC), respectively. Functional analysis of the identified mutants was performed. A novel type of large-fragment core gene deletion (LFCD) was identified exclusively in HCC patients and significantly associated with unfavorable postoperative survival. The presence of LFCDs resulted in generation of precore-polymerase fusion protein or brought the polymerase reading frame under direct control of HBV precore/core promoter, leading to its over-expression. Enhanced cell proliferation and increased tumorigenicity in nude mice were found in hepatoma cells expressing LFCDs. Because of the epsilon-binding ability of HBV polymerase, we hypothesized that the over-expressed polymerase carrying aberrant amino-terminal sequence could bind to cellular microRNAs. Screening of a panel of microRNAs revealed physical association of a precore-polymerase fusion protein with microRNA-100. A binding inhibition effect on microRNA-100 by the precore-polymerase fusion protein with up-regulation of its target, polo-like kinase 1 (PLK1), was discovered. The binding inhibition and growth promoting effects could be reversed by overexpressing microRNA-100. Together, HCC patients carrying hepatitis B large-fragment core gene deletion mutants had an unfavorable postoperative prognosis. The growth promoting effect was partly due to polymerase overexpression, leading to binding inhibition of microRNA-100 and up-regulation of PLK1.
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MESH Headings
- Animals
- Apoptosis/genetics
- Base Sequence
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Cell Cycle Proteins/metabolism
- Cell Line, Tumor
- Cell Proliferation/genetics
- Cell Transformation, Neoplastic/genetics
- DNA, Viral/genetics
- Female
- Gene Deletion
- Gene Products, pol/biosynthesis
- Gene Products, pol/genetics
- Hep G2 Cells
- Hepatitis B virus/enzymology
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/virology
- Humans
- Liver Cirrhosis/virology
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- Middle Aged
- Neoplasm Transplantation
- Prognosis
- Protein Binding/genetics
- Protein Serine-Threonine Kinases/metabolism
- Proto-Oncogene Proteins/metabolism
- Sequence Analysis, DNA
- Transplantation, Heterologous
- Polo-Like Kinase 1
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Affiliation(s)
- Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Ying-Hsin Tseng
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - George Hung
- Department of Molecular Biology, Princeton University, NJ, USA
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tong-Hong Wang
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Chen Lee
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
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48
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Helmke C, Becker S, Strebhardt K. The role of Plk3 in oncogenesis. Oncogene 2016; 35:135-47. [PMID: 25915845 DOI: 10.1038/onc.2015.105] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/02/2015] [Accepted: 02/02/2015] [Indexed: 01/08/2023]
Abstract
The polo-like kinases (Plks) encompass a family of five serine/threonine protein kinases that play essential roles in many cellular processes involved in the control of the cell cycle, including entry into mitosis, DNA replication and the response to different types of stress. Plk1, which has been validated as a cancer target, came into the focus of many pharmaceutical companies for the development of small-molecule inhibitors as anticancer agents. Recently, FDA (Food and Drug Administration) has granted a breakthrough therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. However, the various ATP-competitive inhibitors of Plk1 that are currently in clinical development also inhibit the activities of Plk2 and Plk3, which are considered as tumor suppressors. Plk3 contributes to the control and progression of the cell cycle while acting as a mediator of apoptosis and various types of cellular stress. The aberrant expression of Plk3 was found in different types of tumors. Recent progress has improved our understanding of Plk3 in regulating stress signaling and tumorigenesis. When using ATP-competitive Plk1 inhibitors, the biological roles of Plk1-related family members like Plk3 in cancer cells need to be considered carefully to improve treatment strategies against cancer.
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Affiliation(s)
- C Helmke
- Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe University, Frankfurt, Germany
| | - S Becker
- Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe University, Frankfurt, Germany
| | - K Strebhardt
- Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe University, Frankfurt, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
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49
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Teng YC, Shen ZQ, Kao CH, Tsai TF. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. World J Gastroenterol 2016; 22:300-325. [PMID: 26755878 PMCID: PMC4698494 DOI: 10.3748/wjg.v22.i1.300] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 10/14/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.
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50
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Lee KS, Burke TR, Park JE, Bang JK, Lee E. Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy. Trends Pharmacol Sci 2015; 36:858-877. [PMID: 26478211 PMCID: PMC4684765 DOI: 10.1016/j.tips.2015.08.013] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/21/2015] [Accepted: 08/21/2015] [Indexed: 12/11/2022]
Abstract
Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are crucial for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of particular cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic kinase domain (KD), which phosphorylates substrates, and the C-terminal polo-box domain (PBD) which is essential for protein-protein interactions. In this review we summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders.
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Affiliation(s)
- Kyung S Lee
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Terrence R Burke
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
| | - Jung-Eun Park
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeong K Bang
- Division of Magnetic Resonance, Korea Basic Science Institute, 804-1, Yangcheong Ri, Ochang, Chungbuk, Cheongwon 363-883, Republic of Korea
| | - Eunhye Lee
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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