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Zhu X, Feng Z, Peng X, Di T, Li Y, Bai J, Ma T, Li L, Zhang L. Threonine and tyrosine kinase promotes multiple myeloma progression by regulating regucalcin expression. Exp Cell Res 2025; 446:114454. [PMID: 39961467 DOI: 10.1016/j.yexcr.2025.114454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/17/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
Multiple myeloma (MM) is a malignant proliferative disorder of plasma cells and remains an incurable disease. Threonine and tyrosine kinase (TTK) is a dual-specific protein kinase that targets serine/threonine and tyrosine residues for phosphorylation. Its elevated expression has been linked to unfavorable outcomes in several types of cancer. Although the role of TTK in MM are still incompletely understood. In this research, we assessed TTK mRNA and protein expression levels in 51 MM patients and 30 healthy donors using qRT-PCR and western blotting. The impact of TTK expression on MM cell apoptosis, proliferation, and the cell cycle were assessed through CCK-8 assay, flow cytometry, and western blotting. Our findings revealed a significant overexpression of TTK in multiple myeloma patients and cell lines. TTK knockdown promoted apoptosis and G0/G1 phase arrest while inhibiting proliferation in MM cells, whereas TTK overexpression reduced apoptosis and G0/G1 phase arrest, enhancing proliferation in MM cells. Next, we identified regucalcin (RGN) as a downstream target of TTK through proteomic analysis. In NDMM, the expression of RGN was decreased. Cell function experiments showed that RGN knockdown significantly promoted MM cell proliferation, inhibited apoptosis and reduced cell cycle arrest, and reversed the increased apoptosis, weakened proliferation, and enhanced cell cycle arrest caused by TTK knockdown. Finally, a xenograft mouse model showed that TTK significantly promotes MM development. In summary, we demonstrated that the TTK-RGN axis regulates cell apoptosis, G0/G1 phase arrest, and proliferation in MM, highlighting TTK as a potential target for therapeutic intervention in this cancer.
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Affiliation(s)
- Xiaofeng Zhu
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Zuxi Feng
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Xiaohuan Peng
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Tianning Di
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - YanHong Li
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Key Laboratory of the Hematology of Gansu Province, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Gansu Clinical Medical Research Center of Hematology (National Sub-Center), The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Jun Bai
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Key Laboratory of the Hematology of Gansu Province, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Gansu Clinical Medical Research Center of Hematology (National Sub-Center), The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Tao Ma
- Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Lijuan Li
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Key Laboratory of the Hematology of Gansu Province, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Gansu Clinical Medical Research Center of Hematology (National Sub-Center), The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Liansheng Zhang
- Department of Hematology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Key Laboratory of the Hematology of Gansu Province, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China; Gansu Clinical Medical Research Center of Hematology (National Sub-Center), The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
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AiErken N, Wang X, Wang J, Ma W, Cui L, Zhang M, Ma W, Liu D. NUF2 Promotes Breast Cancer Metastasis via Activating Wnt/β-Catenin Pathways. FRONT BIOSCI-LANDMRK 2024; 29:371. [PMID: 39614440 DOI: 10.31083/j.fbl2911371] [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: 05/30/2024] [Revised: 08/22/2024] [Accepted: 09/06/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND Breast cancer is the most common malignancy and the leading cause of cancer death among women. NDC80 kinetochore complex component (NUF2) is demonstrated to implicate the progression of human cancer. But the role of NUF2 in breast cancer progression is unclear. Here, we aimed to study the role and regulatory mechanisms of NUF2 in breast cancer metastasis. METHODS Immunohistochemistry was used to determine UNF2 expression in clinical samples. Transwell assas were used to determine the role of NUF2 in breast cancer migration and invasion. Animal model in vivo was used to determine the rold of NUF2 in breast cancer metastasis. RESULTS NUF2 was upregulated significantly in breast cancer tissues and cells. Worse prognosis was noted in patients with high NUF2 levels compared with that in patients with low NUF2 levels. NUF2 overexpression markedly enhanced, while NUF2 knockdown inhibited, breast cancer cell invasion and migration. Mechanistically, NUF2 was observed to upregulate Wnt/β-catenin signaling pathway activity. The promoting effect of NUF2 on cell migration and invasion were blocked by inhibition of the Wnt/β-catenin pathway. CONCLUSIONS We revealed that NUF2 promotes breast cancer progression via activating Wnt/β-catenin signaling, suggesting that NUF2 might be a new potential target for breast cancer treatment.
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Affiliation(s)
- Nijiati AiErken
- Department of Breast and Thyroid Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107 ShenZhen, Guangdong, China
| | - Xidi Wang
- Department of Breast and Thyroid Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107 ShenZhen, Guangdong, China
| | - Jiamei Wang
- Department of Microbiology, School of Public Health, Southern Medical University, 510515 Guangzhou, Guangdong, China
| | - Weisen Ma
- Department of Microbiology, School of Public Health, Southern Medical University, 510515 Guangzhou, Guangdong, China
| | - Lingfei Cui
- Department of Breast and Thyroid Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107 ShenZhen, Guangdong, China
| | - Mingxia Zhang
- Department of Breast and Thyroid Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107 ShenZhen, Guangdong, China
| | - Weifeng Ma
- Department of Microbiology, School of Public Health, Southern Medical University, 510515 Guangzhou, Guangdong, China
| | - Dongwei Liu
- Department of General Practice, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107 ShenZhen, Guangdong, China
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Shirakami C, Ikeda K, Hinokuma H, Nishi W, Shinchi Y, Matsubara E, Osumi H, Fujino K, Suzuki M. NUF2 Expression in Cancer Tissues and Lymph Nodes Suggests Post-Surgery Recurrence of Non-Small Cell Lung Cancer. Diagnostics (Basel) 2024; 14:471. [PMID: 38472943 DOI: 10.3390/diagnostics14050471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection.
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Affiliation(s)
- Chika Shirakami
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Koei Ikeda
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hironori Hinokuma
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Wataru Nishi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yusuke Shinchi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Eri Matsubara
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hironobu Osumi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Kosuke Fujino
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Liu W, Bruggeman JW, Lei Q, van Pelt AMM, Koster J, Hamer G. Germline specific genes increase DNA double-strand break repair and radioresistance in lung adenocarcinoma cells. Cell Death Dis 2024; 15:38. [PMID: 38216586 PMCID: PMC10786935 DOI: 10.1038/s41419-024-06433-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 12/18/2023] [Accepted: 01/04/2024] [Indexed: 01/14/2024]
Abstract
In principle, germline cells possess the capability to transmit a nearly unaltered set of genetic material to infinite future generations, whereas somatic cells are limited by strict growth constraints necessary to assure an organism's physical structure and eventual mortality. As the potential to replicate indefinitely is a key feature of cancer, we hypothesized that the activation of a "germline program" in somatic cells can contribute to oncogenesis. Our group recently described over one thousand germline specific genes that can be ectopically expressed in cancer, yet how germline specific processes contribute to the malignant properties of cancer is poorly understood. We here show that the expression of germ cell/cancer (GC) genes correlates with malignancy in lung adenocarcinoma (LUAD). We found that LUAD cells expressing more GC genes can repair DNA double strand breaks more rapidly, show higher rates of proliferation and are more resistant to ionizing radiation, compared to LUAD cells that express fewer GC genes. In particular, we identified the HORMA domain protein regulator TRIP13 to be predominantly responsible for this malignant phenotype, and that TRIP13 inhibition or expression levels affect the response to ionizing radiation and subsequent DNA repair. Our results demonstrate that GC genes are viable targets in oncology, as they induce increased radiation resistance and increased propagation in cancer cells. Because their expression is normally restricted to germline cells, we anticipate that GC gene directed therapeutic options will effectively target cancer, with limited side effects besides (temporary) infertility.
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Affiliation(s)
- Wenqing Liu
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Jan Willem Bruggeman
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Qijing Lei
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Ans M M van Pelt
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Jan Koster
- Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Geert Hamer
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
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Deng Y, Li J, Zhang Y, Hu H, Wan F, Min H, Zhou H, Gu L, Liao X, Zhou J, Zhou J. NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator. Int J Mol Sci 2023; 24:ijms24044226. [PMID: 36835637 PMCID: PMC9965662 DOI: 10.3390/ijms24044226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/31/2022] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA.
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Yang C, Yang Y, Wang W, Zhou W, Zhang X, Xiao Y, Zhang H. CEP55 3'-UTR promotes epithelial-mesenchymal transition and enhances tumorigenicity of bladder cancer cells by acting as a ceRNA regulating miR-497-5p. Cell Oncol (Dordr) 2022; 45:1217-1236. [PMID: 36374443 DOI: 10.1007/s13402-022-00712-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Centrosomal protein 55 (CEP55) is implicated in the tumorigenesis of bladder cancer (BC) but the detailed molecular mechanisms are unknown. We aim to develop a potential competing endogenous RNA (ceRNA) network related with CEP55 in BC. METHODS We first extracted the expression profiles of RNAs from The Cancer Genome Atlas (TCGA) database and used bioinformatic analysis to establish ceRNAs in BC. Real-time quantity PCR (RT-qPCR) and immunohistochemical analysis were performed to measure CEP55 expression in different bladder cell lines and different grades of cancer. Bioinformatics analysis and luciferase assays were conducted to predict potential binding sites among miR-497-5p, CEP55, parathyroid hormone like hormone (PTHLH) and high mobility group A2 (HMGA2). Tumor xenograft model was used to show the effect of CEP55 3'-UTR on cisplatin therapy. Bioinformatics analysis, luciferase assays, and 5' rapid amplification of cDNA ends (5'RACE) were to explore the function of CEP55 3'-untranslated region (3'-UTR) on targeting miR-497-5p. Western blot and immunofluorescence assays were to detect the epithelial-mesenchymal transition (EMT) induction of CEP55 3'-UTR. RESULTS CEP55 expression as well as the expression levels of the oncogenic proteins PTHLH and HMGA2 were upregulated in BC cells while miR-497-5p was downregulated. Low miR-497-5p expression and high CEP55 and HMGA2 expression levels were associated with more advanced tumor clinical stage and pathological grade. Overexpression of the CEP55 3'-UTR promoted the proliferation, migration, and invasion of the EJ cell line in vitro and accelerated EJ-derived tumor growth in nude mice, while inhibition of the CEP55 3'-UTR suppressed all of these oncogenic processes. In addition, CEP55 3'-UTR upregulation reduced the cisplatin sensitivity of BC cell lines and xenograft tumors. Bioinformatics analysis, luciferase assays, and 5'RACE suggested that the CEP55 3'-UTR functions as a ceRNA targeting miR-497-5p, leading to miR-497-5p downregulation and disinhibition of PTHLH and HMGA2 expression. Further, CEP55 downregulated miR-497-5p transcription by promoting NF-[Formula: see text]B signaling. In turn, CEP55 3'-UTR ultimately promotes EMT and tumorigenesis by activating P38MAPK and ERK 1/2 pathways. CONCLUSIONS These results suggest that a ceRNA regulatory network involving CEP55 upregulates PTHLH and HMGA2 expression by suppressing endogenous miR-497-5p. We unveiled a novel mechanism of BC metastasis, and could become novel therapeutics targets in BC.
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Affiliation(s)
- Chenglin Yang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Yue Yang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China.,The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Wei Wang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China. .,The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Wuer Zhou
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Xiaoming Zhang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Yuansong Xiao
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Huifen Zhang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
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de Assis JV, Coutinho LA, Oyeyemi IT, Oyeyemi OT, Grenfell RFEQ. Diagnostic and therapeutic biomarkers in colorectal cancer: a review. Am J Cancer Res 2022; 12:661-680. [PMID: 35261794 PMCID: PMC8900002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/22/2022] [Indexed: 06/14/2023] Open
Abstract
Colorectal cancer (CRC) is a public health concern and the second most common type of cancer among men and women causing a significant mortality. Biomarkers closely linked to the disease morbidity could holds potential as diagnostic and/or prognostic biomarker for the disease. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through genomics and proteomics according to clinical function and application. Specifically, a number of biomarkers were identified and discussed. Emphasis was placed on their clinical applications relative to the diagnosis and prognosis of CRC. The discovery of more sensitive and specific markers for CRC is an urgent need, and the study of molecular targets is extremely important in this process, as they will allow for a better understanding of colorectal carcinogenesis, identification and validation of potential genetic signatures.
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Affiliation(s)
- Jéssica Vieira de Assis
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
| | - Lucélia Antunes Coutinho
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
| | | | - Oyetunde Timothy Oyeyemi
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
- Department of Biological Sciences, University of Medical SciencesOndo, Ondo State, Nigeria
| | - Rafaella Fortini e Queiroz Grenfell
- Diagnosis and Therapy of Infectious Diseases and Cancer, René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz)Belo Horizonte, Minas Gerais, Brazil
- Department of Infectious Diseases, College of Veterinary Medicine, University of GeorgiaAthens, Georgia, United States of America
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Singh PK, Bhatt MLB, Singh P, Rath SK, Dalela D, Goel MM. Frequent expression of a novel cancer testis antigen, protein kinase human monopolar spindle 1 (hMps1/TTK) in human urinary bladder transitional cell carcinoma. Drug Discov Ther 2021; 15:204-209. [PMID: 34456216 DOI: 10.5582/ddt.2021.01010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Urothelial bladder cancer (UBC) is a frequently occurring malignancy of the urinary tract. The present study was undertaken to evaluate the mRNA and immunohistochemical (IHC) expression of protein kinase human monopolar spindle 1 (hMps1/TTK) gene in transitional cell carcinoma (TCC) of the bladder and correlate its expression with the clinicopathological characteristics of patients. In the present study, quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to evaluate TTK mRNA expression in TCC. IHC analysis of TTK was also evaluated. Independent Student's t, ANOVA and chi-square (χ2) tests were used to analyze the data statistically. The frequency of TTK mRNA over expression was detected in 50% of UBC (38/76) by qRT-PCR. Relative mean fold expression of TTK mRNA was found significantly (p < 0.05) higher in muscle-invasive bladder cancer (MIBC) as compared to non-muscle-invasive bladder cancer (NMIBC) patients (8.96 ± 4.51 vs. 5.64 ± 3.53, p = 0.03). Moreover, IHC reveals heterogenous immunostaining pattern of TTK in TCC tissues. The frequency of TTK protein over expression was detected in 56.9% (37 of 65) UBC patients. No significant IHC expression of TTK was detected among adjacent noncancerous tissues (ANCTs) and benign prostatic hyperplasia (BPH) used as control. Collectively our study observations conclude that TTK is a novel cancer/testis antigen (CTA) as a diagnostic marker for early diagnosis of UBC.
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Affiliation(s)
- Pankaj Kumar Singh
- Department of Biochemistry, All India Institute of Medical Sciences Bibinagar, Telangana, India.,Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Madan Lal Brahma Bhatt
- Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Prabhat Singh
- Department of Biological Sciences, Indian Institute of Science Education and Research Berhampur, Odisha, India
| | - Srikanta Kumar Rath
- Genotoxicity Laboratory, Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Diwakar Dalela
- Department of Urology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Madhu Mati Goel
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
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Niu T, Wu Z, Xiao W. Uev1A promotes breast cancer cell migration by up-regulating CT45A expression via the AKT pathway. BMC Cancer 2021; 21:1012. [PMID: 34503444 PMCID: PMC8431945 DOI: 10.1186/s12885-021-08750-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/28/2021] [Indexed: 11/18/2022] Open
Abstract
Background UEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting metastasis remains to be investigated. Methods In this study, we experimentally manipulated UEV1A and CT45A gene expression and monitored their effects on cancer-related gene expression, cell migration and the signal transduction cascade. Results It was found that UEV1A overexpression induces CT45A family gene expression in breast cancer cells. Indeed, ectopic expression of UEV1A was sufficient to induce CT45A and its downstream genes involved in tumorigenesis, epithelial-mesenchymal transition (EMT), stemness and metastasis, and to promote cell migration and EMT signaling. Consistently, depletion of CT45A abolished the above effects, indicating that CT45A is a critical downstream effector of Uev1A. The Uev1A-induced cell migration and EMT signaling was dependent on AKT but independent of NF-κB, indicating that CT45A acts downstream of the AKT pathway. Conclusions Based on previous reports and observations in this study, we propose that the Ubc13-Uev1A complex activates AKT through K63-linked polyubiquitination, which leads to enhanced CT45A expression, stimulated cell migration and EMT signaling in breast cells. Since similar effects were also observed in a colorectal cancer cell line, the Ubc13/Uev1A-AKT-CT45A axis may also promote tumorigenesis and metastasis in other tissues. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08750-3.
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Affiliation(s)
- Tong Niu
- Beijing Key Laboratory of DNA Damage Responses and College of Life Sciences, Capital Normal University, Beijing, 100048, China.,Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada
| | - Zhaojia Wu
- Beijing Key Laboratory of DNA Damage Responses and College of Life Sciences, Capital Normal University, Beijing, 100048, China.,Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada
| | - Wei Xiao
- Beijing Key Laboratory of DNA Damage Responses and College of Life Sciences, Capital Normal University, Beijing, 100048, China. .,Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
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10
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Li Y, Sun R, Li R, Chen Y, Du H. Prognostic Nomogram Based on Circular RNA-Associated Competing Endogenous RNA Network for Patients with Lung Adenocarcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9978206. [PMID: 34497684 PMCID: PMC8421160 DOI: 10.1155/2021/9978206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/14/2021] [Indexed: 11/29/2022]
Abstract
Evidence is increasingly indicating that circular RNAs (circRNAs) are closely involved in tumorigenesis and cancer progression. However, the function and application of circRNAs in lung adenocarcinoma (LUAD) are still unknown. In this study, we constructed a circRNA-associated competitive endogenous RNA (ceRNA) network to investigate the regulatory mechanism of LUAD procession and further constructed a prognostic signature to predict overall survival for LUAD patients. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were selected to construct the ceRNA network. Based on the TargetScan prediction tool and Pearson correlation coefficient, we constructed a circRNA-associated ceRNA network including 11 DEcircRNAs, 8 DEmiRNAs, and 49 DEmRNAs. GO and KEGG enrichment indicated that the ceRNA network might be involved in the regulation of GTPase activity and endothelial cell differentiation. After removing the discrete points, a PPI network containing 12 DEmRNAs was constructed. Univariate Cox regression analysis showed that three DEmRNAs were significantly associated with overall survival. Therefore, we constructed a three-gene prognostic signature for LUAD patients using the LASSO method in the TCGA-LUAD training cohort. By applying the signature, patients could be categorized into the high-risk or low-risk subgroups with significant survival differences (HR: 1.62, 95% CI: 1.12-2.35, log-rank p = 0.009). The prognostic performance was confirmed in an independent GEO cohort (GSE42127, HR: 2.59, 95% CI: 1.32-5.10, log-rank p = 0.004). Multivariate Cox regression analysis proved that the three-gene signature was an independent prognostic factor. Combining the three-gene signature with clinical characters, a nomogram was constructed. The primary and external verification C-indexes were 0.717 and 0.716, respectively. The calibration curves for the probability of 3- and 5-year OS showed significant agreement between nomogram predictions and actual observations. Our findings provided a deeper understanding of the circRNA-associated ceRNA regulatory mechanism in LUAD pathogenesis and further constructed a useful prognostic signature to guide personalized treatment of LUAD patients.
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Affiliation(s)
- Yang Li
- Department of Central Laboratory, Affiliated Xuzhou Central Hospital, Clinical School of Xuzhou Medical University, Xuzhou 221009, China
| | - Rongrong Sun
- Department of Medical Oncology, Affiliated Xuzhou Central Hospital, Clinical School of Xuzhou Medical University, Xuzhou 221009, China
| | - Rui Li
- Department of Central Laboratory, Affiliated Xuzhou Central Hospital, Clinical School of Xuzhou Medical University, Xuzhou 221009, China
| | - Yonggang Chen
- Department of Clinical Pharmacy, Xuzhou Central Hospital, Clinical School of Xuzhou Medical University, Xuzhou 221009, China
| | - He Du
- Department of Medical Oncology, Affiliated Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China
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11
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Pezeshki S, Hashemi P, Salimi A, Ebrahimi S, Javanzad M, Monfaredan A. Evaluation of NUF2 and GMNN Expression in Prostate Cancer: Potential Biomarkers for Prostate Cancer Screening. Rep Biochem Mol Biol 2021; 10:224-232. [PMID: 34604412 PMCID: PMC8480293 DOI: 10.52547/rbmb.10.2.224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 06/13/2023]
Abstract
BACKGROUND Prostate cancer (PC) is one of the most abundant cancers among men, and In Iran, has been responsible for 6% of all deaths from cancer in men. NUF2 and GMNN genes are considered as loci of susceptibility to tumorigenesis in humans. Alterations in expression of these genes have been reported in various malignancies. The aim of our study was to test whether different NUF2 and GMNN expression levels are associated with PC incidence and hence, might be considered as new molecular tools for PC screening. METHODS Biopsy samples from 40 PC patients and 41 healthy Iranian men were used to determine the relative gene expression. After RNA extraction and cDNA synthesis, samples were analyzed using TaqMan Quantitative Real time PCR. Patients' background information, included smoking habits and family histories of PC, were recorded. Stages and grades of their PC were classified by the TNM tumor, node, metastasis (TMN) staging system based on standard guidelines. RESULTS NUF2 expression did not significantly differ between the groups, while GMNN expression was significantly greater in the PC specimens than in the controls. CONCLUSION Regarding the significant role of GMNN in various tumor phenotypes, and its importance in PC progression, the alteration in GMNN expression in PC samples vs. controls indicate that the genetic profiling of this cancer might be considered to personalize therapy for each patient in the future.
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Affiliation(s)
- Shaghayegh Pezeshki
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Payam Hashemi
- School of Medicine, Tehran University of Medical Science, Tehran, Iran.
| | - Alireza Salimi
- Department of Molecular and Cellular Sciences, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sheida Ebrahimi
- Department of Genetic, Faculty of biology, Yazd University, Yazd, Iran.
| | | | - Amir Monfaredan
- Department of Hematology, Faculty of Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
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12
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Subramonian D, Chen TA, Paolini N, Zhang XDD. Poly-SUMO-2/3 chain modification of Nuf2 facilitates CENP-E kinetochore localization and chromosome congression during mitosis. Cell Cycle 2021; 20:855-873. [PMID: 33910471 DOI: 10.1080/15384101.2021.1907509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
SUMO modification is required for the kinetochore localization of the kinesin-like motor protein CENP-E, which subsequently mediates the alignment of chromosomes to the spindle equator during mitosis. However, the underlying mechanisms by which sumoylation regulates CENP-E kinetochore localization are still unclear. In this study, we first elucidate that the kinetochore protein Nuf2 is not only required for CENP-E kinetochore localization but also preferentially modified by poly-SUMO-2/3 chains. In addition, poly-SUMO-2/3 modification of Nuf2 is significantly upregulated during mitosis, which is temporally correlated to the kinetochore localization of CENP-E during mitosis. We further show that the mitotic defects in CENP-E kinetochore localization and chromosome congression caused by global inhibition of sumoylation can be rescued by expressing a fusion protein between Nuf2 and the SUMO-conjugating enzyme Ubc9 for stimulating Nuf2 SUMO-2/3 modification. Moreover, the expression of another fusion protein between Nuf2 and three SUMO-2 moieties (SUMO-2 trimer), which mimics the trimeric SUMO-2/3 chain modification of Nuf2, can also rescue the mitotic defects due to global inhibition of sumoylation. Conversely, expressing the other forms of Nuf2-SUMO fusion proteins, which imitate Nuf2 modifications by SUMO-2/3 monomer, SUMO-2/3 dimer, and SUMO-1 trimer, respectively, cannot rescue the same mitotic defects. Lastly, compared to Nuf2, the fusion protein simulating the trimeric SUMO-2 chain-modified Nuf2 exhibits a significantly higher binding affinity to CENP-E wild type containing a functional SUMO-interacting motif (SIM) but not the CENP-E SIM mutant. Hence, our results support a model that poly-SUMO-2/3 chain modification of Nuf2 facilitates CENP-E kinetochore localization and chromosome congression during mitosis.Abbreviations: CENP-E, centromere-associated protein E; SUMO, small ubiquitin-related modifier; SIM, SUMO-interacting motif.
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Affiliation(s)
- Divya Subramonian
- Department of Biological Sciences, Wayne State University, Detroit, MI, USA
| | - Te-An Chen
- Department of Biology, SUNY Buffalo State, Buffalo, NY, USA
| | | | - Xiang-Dong David Zhang
- Department of Biological Sciences, Wayne State University, Detroit, MI, USA.,Department of Biology, SUNY Buffalo State, Buffalo, NY, USA
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13
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Khalvandi A, Abolhasani M, Madjd Z, Shekarabi M, Kourosh-Arami M, Mohsenzadegan M. Nuclear overexpression levels of MAGE-A3 predict poor prognosis in patients with prostate cancer. APMIS 2021; 129:291-303. [PMID: 33743542 DOI: 10.1111/apm.13132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/04/2021] [Indexed: 12/29/2022]
Abstract
Melanoma antigen gene A3 (MAGE-A3) is one of the most immunogenic cancer testis antigens and is common in various types of cancers. In this study, for the first time, we performed immunohistochemical analysis to evaluate the expression of MAGE-A3 in 153 prostate tissue samples including prostate cancer (PCa), benign prostatic hyperplasia (BPH), and high-grade prostatic intraepithelial neoplasia (HPIN). Increased both nuclear and cytoplasmic expression of MAGE-A3 was significantly found in PCa tissues compared with both HPIN and BPH tissues (nuclear expression at p = 0.011, and cytoplasmic expression at p = 0.034; for both comparisons p < 0.0001, respectively). A significant correlation was observed between higher nuclear and cytoplasmic expressions of MAGE-A3 with Gleason score (p < 0.0001 and 0.006, respectively). Increased expression of MAGE-A3 was associated with shorter biochemical recurrence-free survival (BCR-FS) and disease-free survival (DFS) of patients (p = 0.042 and = 0.0001, respectively). In multivariate analysis, nuclear expression of MAGE-A3 and Gleason score (≤7 vs >7) was independent predictors of the DFS (both; p = 0.019). Nuclear expression of MAGE-A3 was also significantly related to BCR-FS (p = 0.015). MAGE-A3 can be considered as a predictor for poor prognosis and an option for vaccine immunotherapy in patients with PCa.
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Affiliation(s)
- Azadeh Khalvandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Abolhasani
- Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran.,Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Shekarabi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Monireh Mohsenzadegan
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
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14
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Context-Dependent Tumorigenic Effect of Testis-Specific Mitochondrial Protein Tiny Tim 2 in Drosophila Somatic Epithelia. Cells 2020; 9:cells9081842. [PMID: 32781577 PMCID: PMC7465004 DOI: 10.3390/cells9081842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 11/17/2022] Open
Abstract
We have undertaken a study towards understanding the effect of ectopic expression of testis proteins in the soma in Drosophila. Here, we show that in the larval neuroepithelium, ectopic expression of the germline-specific component of the inner mitochondrial translocation complex tiny tim 2 (ttm2) brings about cell autonomous hyperplasia and extension of G2 phase. In the wing discs, cells expressing ectopic ttm2 upregulate Jun N-terminal kinase (JNK) signaling, present extended G2, become invasive, and elicit non-cell autonomous G2 extension and overgrowth of the wild-type neighboring tissue. Ectopic tomboy20, a germline-specific member of the outer mitochondrial translocation complex is also tumorigenic in wing discs. Our results demonstrate the tumorigenic potential of unscheduled expression of these two testis proteins in the soma. They also show that a unique tumorigenic event may trigger different tumor growth pathways depending on the tissular context.
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15
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Fu L, Wang H, Wei D, Wang B, Zhang C, Zhu T, Ma Z, Li Z, Wu Y, Yu G. The value of CEP55 gene as a diagnostic biomarker and independent prognostic factor in LUAD and LUSC. PLoS One 2020; 15:e0233283. [PMID: 32437446 PMCID: PMC7241791 DOI: 10.1371/journal.pone.0233283] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 05/01/2020] [Indexed: 12/24/2022] Open
Abstract
Objective To investigate the value of CEP55 as a diagnostic marker and independent prognostic factor in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and to analyze its co-expression genes and related signaling pathways. Methods TCGA database and GEO database were used to analyze the expression of CEP55 in LUAD and LUSC compared with normal tissues. The co-expression genes of CEP55 in LUAD and LUSC were excavated by cBioPortal and enriched by KEGG and GO. Establishing Receiver operating characteristic (ROC) curve to evaluate the value of CEP55 as a diagnostic and prognostic factor. The association between CEP55 expression and the clinicopathological features was evaluated using χ2 tests. ROC curves for diagnosis and prognosis detection were constructed. Prognostic values were analyzed by univariate and multivariate Cox regression models. Results Compared with normal lung tissues, CEP55 expression was significantly upregulated in both LUAD and LUSC. ROC curve analysis showed that CEP55 could be used as an effective diagnostic target for LUAD (AUC = 0.969) and LUSC (AUC = 0.994). When CEP55 gene was selected as an independent prognostic factor, high expression of CEP55 was more disadvantageous to OS and RFS of LUAD patients (P<0.05), but no significant difference was found in LUSC patients (P>0.05). The number of co-expression genes of CEP55 in LUAD is more than that in LUSC, and is related to cell cycle, DNA replication and P53 signaling pathway. Conclusion CEP55 can be used as a diagnostic marker for LUAD and LUSC, but only as an independent prognostic factor for LUAD rather than LUSC.
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Affiliation(s)
- Linhai Fu
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Haiyong Wang
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Desheng Wei
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Bin Wang
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Chu Zhang
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Ting Zhu
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Zhifeng Ma
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Zhupeng Li
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Yuanlin Wu
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
| | - Guangmao Yu
- The Department of Thoracic and Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Republic of China
- * E-mail:
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16
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Fu S, Liu T, Lv C, Fu C, Zeng R, Kakehi Y, Kulkarni P, Getzenberg RH, Zeng Y. Stromal-epithelial interactions in prostate cancer: Overexpression of PAGE4 in stromal cells inhibits the invasive ability of epithelial cells. J Cell Biochem 2020; 121:4406-4418. [PMID: 32003504 DOI: 10.1002/jcb.29664] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 01/09/2020] [Indexed: 12/17/2022]
Abstract
It is now widely recognized that carcinoma-associated fibroblasts which are believed to be myofibroblasts, promote the transformation of prostate epithelial cells to cancer cells, enhance their proliferation and invasiveness, and induce the acquisition of resistance to cancer therapy and immune evasiveness. Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein that is remarkably prostate-specific. PAGE4 is also a stress-response protein that functions as a transcriptional regulator and is upregulated in early-stage prostate cancer (PCa) and its precursor lesions. However, PAGE4 is downregulated in high-grade PCa and metastatic disease. Here, we show that PAGE4 is highly expressed in the stromal cells surrounding the cancer-adjacent "normal" glands and low-grade PCa lesions but not in lesions proximal to high-grade PCa. Overexpression of PAGE4 in a stromal cell line inhibits the migration and invasion of PCa epithelial cells in multiple coculture systems. PAGE4 overexpression also inhibits the downregulation of E-cadherin in PCa epithelial cells when cocultured with stromal cells. Furthermore, signaling via tumor necrosis factor-α and transforming growth factor-β pathways is decreased in the stromal cells overexpressing PAGE4 suggesting that PAGE4 appears to play a protective role against disease progression by perturbing interactions between epithelial cells and stromal cells in PCa. Taken together, these findings support previous observations that upregulation of PAGE4 in PCa correlates with a better prognosis and highlight PAGE4 as a novel therapeutic target for early-stage "low-risk" disease.
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Affiliation(s)
- Shui Fu
- Department of Urology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tao Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chengcheng Lv
- Department of Urology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Cheng Fu
- Department of Urology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ruoheng Zeng
- Department of Neuroscience, College of Art and Science, New York University, New York, New York
| | - Yoshiyuki Kakehi
- Department of Urology, Kagawa University Faculty of Medicine, Kagawa, Kita-gun, Japan
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
| | - Robert H Getzenberg
- Research Division, College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida
| | - Yu Zeng
- Department of Urology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China
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17
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Si M, Zhang J, Cao J, Xie Z, Shu S, Zhu Y, Lang J. Integrated Analysis To Identify Molecular Biomarkers Of High-Grade Serous Ovarian Cancer. Onco Targets Ther 2019; 12:10057-10075. [PMID: 31819501 PMCID: PMC6877452 DOI: 10.2147/ott.s228678] [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: 08/26/2019] [Accepted: 10/30/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose Ovarian cancer is the leading cause of gynecologic cancer-related death worldwide. Early diagnosis of ovarian cancer can significantly improve patient prognosis. Hence, there is an urgent need to identify key diagnostic and prognostic biomarkers specific for ovarian cancer. Because high-grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer and accounts for the majority of deaths, we identified potential biomarkers for the early diagnosis and prognosis of HGSOC. Methods Six datasets (GSE14001, GSE18520, GSE26712, GSE27651, GSE40595, and GSE54388) were downloaded from the Gene Expression Omnibus database for analysis. Differentially expressed genes (DEGs) between HGSOC and normal ovarian surface epithelium samples were screened via integrated analysis. Hub genes were identified by analyzing protein-protein interaction (PPI) network data. The online Kaplan-Meier plotter was utilized to evaluate the prognostic roles of these hub genes. The expression of these hub genes was confirmed with Oncomine datasets and validated by quantitative real-time PCR and Western blotting. Results A total of 103 DEGs in patients with HGSOC-28 upregulated genes and 75 downregulated genes-were successfully screened. Enrichment analyses revealed that the upregulated genes were enriched in cell division and cell proliferation and that the downregulated genes mainly participated in the Wnt signaling pathway and various metabolic processes. Ten hub genes were associated with HGSOC pathogenesis. Seven overexpressed hub genes were partitioned into module 1 of the PPI network, which was enriched in the cell cycle and DNA replication pathways. Survival analysis revealed that MELK, CEP55 and KDR expression levels were significantly correlated with the overall survival of HGSOC patients (P < 0.05). The RNA and protein expression levels of these hub genes were validated experimentally. Conclusion Based on an integrated analysis, we propose the further investigation of MELK, CEP55 and KDR as promising diagnostic and prognostic biomarkers of HGSOC.
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Affiliation(s)
- Manfei Si
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Junji Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jianzhong Cao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Zhibo Xie
- Department of Vascular Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Shan Shu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Yapei Zhu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jinghe Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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18
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Yamamoto S, Takayama KI, Obinata D, Fujiwara K, Ashikari D, Takahashi S, Inoue S. Identification of new octamer transcription factor 1-target genes upregulated in castration-resistant prostate cancer. Cancer Sci 2019; 110:3476-3485. [PMID: 31454442 PMCID: PMC6825001 DOI: 10.1111/cas.14183] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 08/18/2019] [Accepted: 08/25/2019] [Indexed: 12/12/2022] Open
Abstract
Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)‐interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration‐resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR‐positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1‐target genes, disks large‐associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non‐SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer‐specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.
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Affiliation(s)
- Shinichiro Yamamoto
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,Department of Urology, Nihon University School of Medicine, Tokyo, Japan
| | - Ken-Ichi Takayama
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Daisuke Obinata
- Department of Urology, Nihon University School of Medicine, Tokyo, Japan
| | - Kyoko Fujiwara
- Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.,Department of Anatomy, Nihon University School of Dentistry, Tokyo, Japan
| | - Daisaku Ashikari
- Department of Urology, Nihon University School of Medicine, Tokyo, Japan
| | - Satoru Takahashi
- Department of Urology, Nihon University School of Medicine, Tokyo, Japan
| | - Satoshi Inoue
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Tokyo, Japan
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19
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Xu W, Wang Y, Wang Y, Lv S, Xu X, Dong X. Screening of differentially expressed genes and identification of NUF2 as a prognostic marker in breast cancer. Int J Mol Med 2019; 44:390-404. [PMID: 31198978 PMCID: PMC6605639 DOI: 10.3892/ijmm.2019.4239] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 05/29/2019] [Indexed: 12/24/2022] Open
Abstract
The aims of the present study were to screen differentially expressed genes (DEGs) in breast cancer (BC) and investigate NDC80 kinetochore complex component (NUF2) as a prognostic marker of BC in detail. A total of four BC microarray datasets, downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, were used to screen DEGs. A total of 190 DEGs with the same expression trends were identified in the 4 datasets, including 65 upregulated and 125 downregulated DEGs. Functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. The upregulated DEGs were enriched for 10 Gene Ontology (GO) terms and 7 pathways, and the downregulated DEGs were enriched for 10 GO terms and 10 pathways. A protein‑protein interaction network containing 149 nodes and 930 edges was constructed using the Search Tool for the Retrieval of Interacting Genes, and 2 functional modules were identified using the MCODE plugin of Cytoscape. Based on an in‑depth analysis of module 1 and literature mining, NUF2 was selected for further research. Oncomine database analysis and reverse transcription‑quantitative PCR showed that NUF2 is significantly upregulated in BC tissues. In analyses of correlations between NUF2 and clinical pathological characteristics, NUF2 was significantly associated with the malignant features of BC. Using 5 additional datasets from GEO, it was demonstrated that NUF2 has a significant prognostic role in both ER‑positive and ER‑negative BC. A Gene Set Enrichment Analysis indicated that NUF2 may regulate breast carcinogenesis and progression via cell cycle‑related pathways. The results of the present study demonstrated that NUF2 is overexpressed in BC and is significantly associated with its multiple pathological features and prognosis.
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Affiliation(s)
- Wenjie Xu
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Yizhen Wang
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Yanan Wang
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Shanmei Lv
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Xiuping Xu
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
| | - Xuejun Dong
- Department of Clinical Laboratory Center, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
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20
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Kulkarni V, Kulkarni P. Intrinsically disordered proteins and phenotypic switching: Implications in cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 166:63-84. [PMID: 31521237 DOI: 10.1016/bs.pmbts.2019.03.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It is now well established that intrinsically disordered proteins (IDPs) that constitute a large part of the proteome across the three kingdoms, play critical roles in several biological processes including phenotypic switching. However, dysregulated expression of IDPs that engage in promiscuous interactions can lead to pathological states. In this chapter, using cancer as a paradigm, we discuss how IDP conformational dynamics and the resultant conformational noise can modulate phenotypic switching. Thus, contrary to the prevailing wisdom that phenotypic switching is highly deterministic (has a genetic underpinning) in cancer, emerging evidence suggests that non-genetic mechanisms, at least in part due to the conformational noise, may also be a confounding factor in phenotypic switching.
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Affiliation(s)
- Vivek Kulkarni
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, United States
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States.
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21
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Chen X, Li W, Xiao L, Liu L. Nuclear division cycle 80 complex is associated with malignancy and predicts poor survival of hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:1233-1247. [PMID: 31933938 PMCID: PMC6947052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/26/2018] [Indexed: 06/10/2023]
Abstract
The NDC80 (nuclear division cycle 80) complex takes part in chromosome segregation by forming an outer kinetochore and providing a platform for the interaction between chromosomes and microtubules, thus impacting the progression of mitosis and the cell cycle. The clinical significance of its components, NDC80, nuf2, spc24, and spc25, were widely explored in various malignancies respectively, yet seldom were they studied from the perspective of a complex. This paper explores the clinical importance of the NDC80 kinetochore complex components in terms of their expression level, prognostic value, and therapeutic potential in HCC (hepatocellular carcinoma) patients. With the data from several paired HCC samples from Nanfang Hospital, HCC patients from the TCGA database and other cases from GSE89377, we analyzed the expression levels of the NDC80 complex components, NDC80/nuf2/spc24/spc25, along with the survival data as well as other clinical features using statistical methods and GSEA. The study found that a high expression of NDC80 complex predicts poor survival, and these components have the potential to be used as therapeutic targets.
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Affiliation(s)
- Xiaowei Chen
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong, P. R. China
| | - Wenwen Li
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong, P. R. China
| | - Lushan Xiao
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong, P. R. China
| | - Li Liu
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong, P. R. China
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22
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Lv C, Fu S, Dong Q, Yu Z, Zhang G, Kong C, Fu C, Zeng Y. PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:24. [PMID: 30658679 PMCID: PMC6339303 DOI: 10.1186/s13046-019-1032-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 01/09/2019] [Indexed: 02/08/2023]
Abstract
Background Prostate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear. Methods Western blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues. Results In this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2. Conclusion Our findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications. Electronic supplementary material The online version of this article (10.1186/s13046-019-1032-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chengcheng Lv
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, Liaoning, China
| | - Shui Fu
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, Liaoning, China
| | - Qingzhuo Dong
- Department of Urology, The First Hospital of China Medical University, 155 Nanjing North Road, Shenyang, 110001, Liaoning, China
| | - Zi Yu
- Department of Urology, The First Hospital of China Medical University, 155 Nanjing North Road, Shenyang, 110001, Liaoning, China
| | - Gejun Zhang
- Department of Urology, The First Hospital of China Medical University, 155 Nanjing North Road, Shenyang, 110001, Liaoning, China
| | - Chuize Kong
- Department of Urology, The First Hospital of China Medical University, 155 Nanjing North Road, Shenyang, 110001, Liaoning, China
| | - Cheng Fu
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, Liaoning, China
| | - Yu Zeng
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, Liaoning, China.
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23
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Xiao H, Xu D, Chen P, Zeng G, Wang X, Zhang X. Identification of Five Genes as a Potential Biomarker for Predicting Progress and Prognosis in Adrenocortical Carcinoma. J Cancer 2018; 9:4484-4495. [PMID: 30519354 PMCID: PMC6277665 DOI: 10.7150/jca.26698] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 09/20/2018] [Indexed: 12/19/2022] Open
Abstract
Background: Adrenocortical carcinoma (ACC) is a limited endocrine fatality with a minor diagnosis and rare remedial options. The progressive and predictive meaning of message RNA (mRNA) expression oddity in ACC has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable. Methods: An extensive study of GEO datasets was conducted to define potential mRNA biomarkers for ACC. The study compared the mRNA expression profiles of ACC tissues and neighboring noncancerous adrenal tissues in the pair. The study covered a sum of 165 tumors and 36 benign control samples. Hub genes were identified through a protein-protein interaction (PPI) network and Robust Rank Aggregation method. Then the Cancer Genome Atlas (TCGA) and Oncomine database were used to perform the validation of hub genes. 4 ACC tissues and 4 normal tissues were collected and then Polymerase Chain Reaction (PCR), Western-blot and immunofluorescence were conducted to validate the expression of five hub genes. Results: We identified five statistically significant genes (TOP2A, NDC80, CEP55, CDKN3, CDK1) corrected with clinical features. The expression of five hub genes in TCGA and Oncomine database were significantly overexpressed in ACC compared with normal ones. Among all the TCGA ACC cases, the strong expression of TOP2A (logrank p=1.4e-04, HR=4.7), NDC80 (logrank p=8.8e-05, HR=4.9), CEP55 (logrank p=5.2e-07, HR=8.6), CDKN3 (log rank p=2.3e-06, HR=7.6) and CDK1 (logrank p=7e-08, HR=11) were correlated with low comprehensive survival, disease free survival (logrank p < 0.001), pathology stage and pathology T stage (FDR < 0.001). PCR results showed that the transcriptional levels of these five genes were significantly higher in ACC tissues than in normal tissues. The western blotting results also showed that the translational level of TOP2A was significantly higher in tumor tissues than in normal tissues. The results of immunofluorescence showed that TOP2A was abundantly observed in the adrenal cortical cell membrane and nucleus and its expression in ACC tissues was significantly higher than that in normal tissues. Conclusions: The distinguished five genes may be utilized to form a board of progressive and predictive biomarkers for ACC for clinical purpose.
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Affiliation(s)
- He Xiao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Deqiang Xu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Ping Chen
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Guang Zeng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China.,Biomedical Engineering, Stony Brook University, New York 11790
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Xinhua Zhang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
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24
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Herbert KJ, Ashton TM, Prevo R, Pirovano G, Higgins GS. T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics. Cell Death Dis 2018; 9:1089. [PMID: 30356039 PMCID: PMC6200809 DOI: 10.1038/s41419-018-1131-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/03/2018] [Accepted: 10/08/2018] [Indexed: 12/17/2022]
Abstract
'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
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Affiliation(s)
- Katharine J Herbert
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
| | - Thomas M Ashton
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Remko Prevo
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Giacomo Pirovano
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Geoff S Higgins
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
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25
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Kalimutho M, Sinha D, Jeffery J, Nones K, Srihari S, Fernando WC, Duijf PH, Vennin C, Raninga P, Nanayakkara D, Mittal D, Saunus JM, Lakhani SR, López JA, Spring KJ, Timpson P, Gabrielli B, Waddell N, Khanna KK. CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer. EMBO Mol Med 2018; 10:e8566. [PMID: 30108112 PMCID: PMC6127888 DOI: 10.15252/emmm.201708566] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 07/15/2018] [Accepted: 07/18/2018] [Indexed: 12/28/2022] Open
Abstract
The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2-PLK1 represents a potential therapeutic strategy for MYC-CEP55-dependent basal-like, triple-negative breast cancers.
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Affiliation(s)
- Murugan Kalimutho
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- School of Natural Sciences, Griffith University, Nathan, Qld, Australia
| | - Debottam Sinha
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- School of Natural Sciences, Griffith University, Nathan, Qld, Australia
| | - Jessie Jeffery
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Katia Nones
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia
| | - Sriganesh Srihari
- Computational Systems Biology Laboratory, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia
| | | | - Pascal Hg Duijf
- University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
| | - Claire Vennin
- Cancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
| | - Prahlad Raninga
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | | | - Deepak Mittal
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Jodi M Saunus
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
| | - Sunil R Lakhani
- Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
- School of Medicine, The University of Queensland, Herston, Qld, Australia
- Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Qld, Australia
| | - J Alejandro López
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
- School of Natural Sciences, Griffith University, Nathan, Qld, Australia
| | - Kevin J Spring
- Liverpool Clinical School, University of Western Sydney, Liverpool, NSW, Australia
- Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, NSW, Australia
| | - Paul Timpson
- Cancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
| | - Brian Gabrielli
- University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia
| | - Nicola Waddell
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
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26
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Jiang C, Zhang Y, Li Y, Lu J, Huang Q, Xu R, Feng Y, Yan S. High CEP55 expression is associated with poor prognosis in non-small-cell lung cancer. Onco Targets Ther 2018; 11:4979-4990. [PMID: 30154666 PMCID: PMC6103653 DOI: 10.2147/ott.s165750] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objectives Lung cancer is the most common and lethal malignancy worldwide. CEP55 was found to be overexpressed in multiple types of cancer. However, the expression pattern of CEP55 and its clinical significance in non-small-cell lung carcinoma (NSCLC) have not been investigated by immunohistochemistry. Materials and methods In this study, we analyzed 203 primary NSCLC specimens from Sun Yat-Sen University Cancer Center to investigate the clinical role of CEP55 in lung cancer. Tissue microarray was successfully generated for immunohistochemical evaluation. The correlation between CEP55 expression and clinical characteristics and survival was analyzed statistically. The predictive effect of CEP55 and APOBEC3B (AP3B) coexpression in lung cancer patients’ prognosis was evaluated. Results We found that the CEP55 expression was commonly elevated in NSCLC tissues and overexpression of CEP55 was correlated with unfavorable prognosis in the patients with NSCLC. Furthermore, the combination of CEP55 and AP3B expression was significantly predictive of clinical outcome in all NSCLC patients. Conclusion CEP55 may act as a useful and novel prognostic biomarker for NSCLC. Further studies into the mechanism of CEP55 are warranted.
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Affiliation(s)
- Chao Jiang
- Department of Oncology, The People's Hospital of Baoan District, Shenzhen, Guangdong, People's Republic of China
| | - Yu Zhang
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
| | - Yong Li
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
| | - Jiabin Lu
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
| | - Qitao Huang
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
| | - Rui Xu
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, People's Republic of China
| | - Yanfeng Feng
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
| | - Shumei Yan
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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27
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Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target. J Clin Med 2018; 7:jcm7060156. [PMID: 29914187 PMCID: PMC6025510 DOI: 10.3390/jcm7060156] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 06/13/2018] [Accepted: 06/15/2018] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PCa) is a leading cause of mortality and morbidity globally. While genomic alterations have been identified in PCa, in contrast to some other cancers, use of such information to personalize treatment is still in its infancy. Here, we discuss how PAGE4, a protein which appears to act both as an oncogenic factor as well as a metastasis suppressor, is a novel therapeutic target for PCa. Inhibiting PAGE4 may be a viable strategy for low-risk PCa where it is highly upregulated. Conversely, PAGE4 expression is downregulated in metastatic PCa and, therefore, reinstituting its sustained expression may be a promising option to subvert or attenuate androgen-resistant PCa. Thus, fine-tuning the levels of PAGE4 may represent a novel approach for personalized medicine in PCa.
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28
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Faramarzi S, Ghafouri-Fard S. Expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy. Immunotherapy 2018; 9:1019-1034. [PMID: 28971747 DOI: 10.2217/imt-2017-0083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer is a prevalent disorder among men with a heterogeneous etiological background. Several molecular events and signaling perturbations have been found in this disorder. Among genes whose expressions have been altered during the prostate cancer development are cancer-testis antigens (CTAs). This group of antigens has limited expression in the normal adult tissues but aberrant expression in cancers. This property provides them the possibility to be used as cancer biomarkers and immunotherapeutic targets. Several CTAs have been shown to be immunogenic in prostate cancer patients and some of the have entered clinical trials. Based on the preliminary data obtained from these trials, it is expected that CTA-based therapeutic options are beneficial for at least a subset of prostate cancer patients.
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Affiliation(s)
- Sepideh Faramarzi
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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29
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Shimazaki J, Chung LWK, Zhau HE, Ichikawa T. Dr. Coffey's visionary contributions to urological research in China and Japan. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY 2018; 6:15-22. [PMID: 29666826 PMCID: PMC5902716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 03/19/2018] [Indexed: 06/08/2023]
Affiliation(s)
- Jun Shimazaki
- Department of Urology, Graduate School of Medicine, Chiba UniversityChiba, Japan
| | - Leland WK Chung
- Department of Medicine and Surgery, Cedars-Sinai Medical CenterLos Angeles, CA. 90048, USA
| | - Haiyen E Zhau
- Department of Medicine and Surgery, Cedars-Sinai Medical CenterLos Angeles, CA. 90048, USA
| | - Tomohiko Ichikawa
- Department of Urology, Graduate School of Medicine, Chiba UniversityChiba, Japan
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30
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Park S, Sung Y, Jeong J, Choi M, Lee J, Kwon W, Jang S, Park SJ, Kim HS, Lee MH, Kim DJ, Liu K, Kim SH, Dong Z, Ryoo ZY, Kim MO. hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways. Oncotarget 2018; 8:37115-37127. [PMID: 28415749 PMCID: PMC5514895 DOI: 10.18632/oncotarget.16184] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/06/2017] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most abundant cancer worldwide and a severe problem for women. Notably, breast cancer has a high mortality rate, mainly because of tumor progression and metastasis. Triple-negative breast cancer (TNBC) is highly progressive and lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Therefore, there are no established therapeutic targets against TNBC. In this study, we investigated whether the expression of human melanoma-associated antigen A2 (MAGEA2) is associated with TNBC. We found that hMAGEA2 is significantly overexpressed in human TNBC tissues; we also observed oncogenic properties using TNBC cell lines (MDA-MB-231 and MDA-MB-468). The overexpression of hMAGEA2 in MDA-MB-231 cell line showed dramatically increased cellular proliferation, colony formation, invasion, and xenograft tumor formation and growth. Conversely, knockdown of hMAEGA2 in MDA-MB-468 cell line suppressed cellular proliferation, colony formation, and xenograft tumor formation. Additionally, we showed that hMAGEA2 regulated the activation of Akt and Erk1/2 signaling pathways. These data indicate that hMAGEA2 is important for progression of TNBC and may serve as a novel molecular therapeutic target.
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Affiliation(s)
- Song Park
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Yonghun Sung
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Jain Jeong
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Minjee Choi
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Jinhee Lee
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Wookbong Kwon
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Soyoung Jang
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Si Jun Park
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Hyeng-Soo Kim
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Mee-Hyun Lee
- China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Dong Joon Kim
- China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Kangdong Liu
- China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Sung-Hyun Kim
- Institute of Life Science and Biotechnology, Kyungpook National University, Buk-ku, Daegu 41566, Republic of Korea.,China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Zigang Dong
- China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Zae Young Ryoo
- School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu, 41566, Republic of Korea
| | - Myoung Ok Kim
- The School of Animal BT Science, Kyungpook National University, Sangju-si, Gyeongsangbuk-do 37224, Republic of Korea
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31
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Yang X, Zhu S, Li L, Zhang L, Xian S, Wang Y, Cheng Y. Identification of differentially expressed genes and signaling pathways in ovarian cancer by integrated bioinformatics analysis. Onco Targets Ther 2018; 11:1457-1474. [PMID: 29588600 PMCID: PMC5858852 DOI: 10.2147/ott.s152238] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background The mortality rate associated with ovarian cancer ranks the highest among gynecological malignancies. However, the cause and underlying molecular events of ovarian cancer are not clear. Here, we applied integrated bioinformatics to identify key pathogenic genes involved in ovarian cancer and reveal potential molecular mechanisms. Results The expression profiles of GDS3592, GSE54388, and GSE66957 were downloaded from the Gene Expression Omnibus (GEO) database, which contained 115 samples, including 85 cases of ovarian cancer samples and 30 cases of normal ovarian samples. The three microarray datasets were integrated to obtain differentially expressed genes (DEGs) and were deeply analyzed by bioinformatics methods. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed by DAVID and KOBAS online analyses, respectively. The protein–protein interaction (PPI) networks of the DEGs were constructed from the STRING database. A total of 190 DEGs were identified in the three GEO datasets, of which 99 genes were upregulated and 91 genes were downregulated. GO analysis showed that the biological functions of DEGs focused primarily on regulating cell proliferation, adhesion, and differentiation and intracellular signal cascades. The main cellular components include cell membranes, exosomes, the cytoskeleton, and the extracellular matrix. The molecular functions include growth factor activity, protein kinase regulation, DNA binding, and oxygen transport activity. KEGG pathway analysis showed that these DEGs were mainly involved in the Wnt signaling pathway, amino acid metabolism, and the tumor signaling pathway. The 17 most closely related genes among DEGs were identified from the PPI network. Conclusion This study indicates that screening for DEGs and pathways in ovarian cancer using integrated bioinformatics analyses could help us understand the molecular mechanism underlying the development of ovarian cancer, be of clinical significance for the early diagnosis and prevention of ovarian cancer, and provide effective targets for the treatment of ovarian cancer.
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Affiliation(s)
- Xiao Yang
- Department of Obstetrics and Gynecology
| | - Shaoming Zhu
- Department of Urology, Renmin Hospital of Wuhan University
| | - Li Li
- sDepartment of Pharmacology, Wuhan University Health Science Center, Wuhan, Hubei, People's Republic of China
| | - Li Zhang
- Department of Obstetrics and Gynecology
| | - Shu Xian
- Department of Obstetrics and Gynecology
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32
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Xu Q, Xu Y, Pan B, Wu L, Ren X, Zhou Y, Mao F, Lin Y, Guan J, Shen S, Zhang X, Wang C, Zhong Y, Zhou L, Liang Z, Zhao H, Sun Q. TTK is a favorable prognostic biomarker for triple-negative breast cancer survival. Oncotarget 2018; 7:81815-81829. [PMID: 27833085 PMCID: PMC5348432 DOI: 10.18632/oncotarget.13245] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Previous studies demonstrate that threonine and tyrosine kinase (TTK) is overexpressed in triple-negative breast cancer (TNBC), but there are conflicting results regarding its effect on TNBC survival. The purpose of this study was to assess the prognostic significance of TTK expression in primary TNBC. RESULTS Of 169 consecutive cases eligible for this study, 164 included follow-up information. Cytoplasm and membrane TTK staining was observed in 99.4% of cases, while 5.9% displayed whole cell immunostaining. At a discriminating threshold of 55, elevated TTK expression was associated with prolonged disease free survival (DFS) (p < 0.001) and overall survival (OS) (p = 0.024) in primary TNBC and prolonged DFS in individual basal-like (p = 0.001) and non-basal-like (p = 0.001) TNBC subtypes. In addition, Cox regression analysis demonstrated that elevated TTK expression was an independent prognostic factor for DFS in TNBC (p < 0.001). METHODS TTK expression of 169 samples was tested by immunohistochemistry (IHC). A receiver operating characteristic (ROC) curve was used to identify a cutpoint for TTK expression, which was analyzed for its association with patients' clinicopathological factors and survival using Chi-square, log-rank, and Cox regression analyses. CONCLUSIONS TTK is a favorable prognostic biomarker associated with TNBC survival.
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Affiliation(s)
- Qianqian Xu
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yali Xu
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Pan
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Ren
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yidong Zhou
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Feng Mao
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Lin
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinghong Guan
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Songjie Shen
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaohui Zhang
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Zhong
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liangrui Zhou
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Li F, Jin D, Tang C, Gao D. CEP55 promotes cell proliferation and inhibits apoptosis via the PI3K/Akt/p21 signaling pathway in human glioma U251 cells. Oncol Lett 2018; 15:4789-4796. [PMID: 29552118 PMCID: PMC5840555 DOI: 10.3892/ol.2018.7934] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 11/29/2017] [Indexed: 12/13/2022] Open
Abstract
Human glioma is one of the major malignancies worldwide with an increased mortality rate. Centrosomal protein of 55 kDa (CEP55) is an essential component of the CEP family and has been identified as a prognostic marker for multiple types of cancer. However, the function of CEP55 during glioma tumorigenesis remains unclear. In the present study, the data derived from the Oncomine database indicated that the expression of CEP55 is increased in glioma tissues compared with normal tissues. Furthermore, the expression of CEP55 was also increased at the level of mRNA and protein in glioma cell lines compared with normal human astrocytes. The knockdown of CEP55 expression inhibited the proliferation of glioma U251 cells, whereas overexpression of CEP55 induced the proliferation of U251 cells. Flow cytometric analysis indicated that the knockdown of CEP55 resulted in an increased number of cells arrested at G2/M phase, and apoptosis was promoted. Further investigations revealed that the overexpression of CEP55 increased the phosphorylation of Akt and inhibited the activity of p21. By contrast, the knockdown of CEP55 resulted in the opposite effects. Taken together, the results of the present study suggested that CEP55 regulated the proliferation of glioma cells, further attributing to the carcinogenesis and progression of glioma via the PI3K/Akt/p21 signaling pathway. Therefore, CEP55 may be a novel therapeutic target for the treatment of glioma.
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Affiliation(s)
- Feng Li
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
| | - Dan Jin
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.,Department of Otolaryngology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Chuanxi Tang
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
| | - Dianshuai Gao
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
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Adeola HA, Smith M, Kaestner L, Blackburn JM, Zerbini LF. Novel potential serological prostate cancer biomarkers using CT100+ cancer antigen microarray platform in a multi-cultural South African cohort. Oncotarget 2017; 7:13945-64. [PMID: 26885621 PMCID: PMC4924690 DOI: 10.18632/oncotarget.7359] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 01/29/2016] [Indexed: 12/17/2022] Open
Abstract
There is a growing need for high throughput diagnostic tools for early diagnosis and treatment monitoring of prostate cancer (PCa) in Africa. The role of cancer-testis antigens (CTAs) in PCa in men of African descent is poorly researched. Hence, we aimed to elucidate the role of 123 Tumour Associated Antigens (TAAs) using antigen microarray platform in blood samples (N = 67) from a South African PCa, Benign prostatic hyperplasia (BPH) and disease control (DC) cohort. Linear (fold-over-cutoff) and differential expression quantitation of autoantibody signal intensities were performed. Molecular signatures of candidate PCa antigen biomarkers were identified and analyzed for ethnic group variation. Potential cancer diagnostic and immunotherapeutic inferences were drawn. We identified a total of 41 potential diagnostic/therapeutic antigen biomarkers for PCa. By linear quantitation, four antigens, GAGE1, ROPN1, SPANXA1 and PRKCZ were found to have higher autoantibody titres in PCa serum as compared with BPH where MAGEB1 and PRKCZ were highly expressed. Also, p53 S15A and p53 S46A were found highly expressed in the disease control group. Statistical analysis by differential expression revealed twenty-four antigens as upregulated in PCa samples, while 11 were downregulated in comparison to BPH and DC (FDR = 0.01). FGFR2, COL6A1and CALM1 were verifiable biomarkers of PCa analysis using urinary shotgun proteomics. Functional pathway annotation of identified biomarkers revealed similar enrichment both at genomic and proteomic level and ethnic variations were observed. Cancer antigen arrays are emerging useful in potential diagnostic and immunotherapeutic antigen biomarker discovery.
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Affiliation(s)
- Henry A Adeola
- International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa.,Faculty of Health Sciences, Division of Medical Biochemistry, Institute of Infectious Diseases & Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Muneerah Smith
- Faculty of Health Sciences, Division of Medical Biochemistry, Institute of Infectious Diseases & Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Lisa Kaestner
- Urology Department, Grootes Schuur Hospital, Cape Town, South Africa
| | - Jonathan M Blackburn
- Faculty of Health Sciences, Division of Medical Biochemistry, Institute of Infectious Diseases & Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Luiz F Zerbini
- International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa.,Faculty of Health Sciences, Division of Medical Biochemistry, Institute of Infectious Diseases & Molecular Medicine, University of Cape Town, Cape Town, South Africa
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Zhang D, Liu E, Kang J, Yang X, Liu H. MiR-3613-3p affects cell proliferation and cell cycle in hepatocellular carcinoma. Oncotarget 2017; 8:93014-93028. [PMID: 29190974 PMCID: PMC5696240 DOI: 10.18632/oncotarget.21745] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/23/2017] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors with poor sensitivity to chemotherapy drugs and poor prognosis among patients. In the present study, we downloaded the original data from the Gene Expression Omnibus and compared gene expression profiles of liver cancer cells in patients with HCC with those of colon epithelial cells of healthy controls to identify differentially expressed genes (DEGs). After filtering target microRNAs (miRNA) from core DEGs, we cultured HepG2 cells in vitro, knocked down the miRNA and core mRNAs, and analyzed the effects. We found 228 differentially expressed genes between liver cancer tissue and healthy control tissue. We also integrated the protein-proteininteraction network and module analysis to screen 13 core genes, consisting of 12 up-regulated genes and 1 down-regulated gene. Five core genes were regulated hsa-miR-3613-3p, therefor we hypothesized that hsa-miR-3613-3p was a critical miRNA. After the transfection procedure, we found that changes in hsa-miR-3613-3p were the most obvious. Therefore, we speculated that hsa-miR-3613-3p was a main target miRNA. In addition, we transfected with si (BIRC5, CDK1, NUF2, ZWINT and SPC24), to target genes that can be targeted by miR-3613-3p. Our data shows that BIRC5, NUF2, and SPC24 may be promising liver cancer biomarkers that may not only predict disease occurrence but also potential personalized treatment options.
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Affiliation(s)
- Donghui Zhang
- Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China
| | - Enqin Liu
- Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China
| | - Jian Kang
- Department of Colorectal Surgery, Tai’an City Central Hospital, Tai’an 271000, China
| | - Xin Yang
- Culverhouse College of Commerce and Business Administration, The University of Alabama, Tuscaloosa, AL 35401, USA
| | - Hong Liu
- Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China
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36
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Sheng J, Zhao J, Xu Q, Wang L, Zhang W, Zhang Y. Bioinformatics analysis of SRSF1-controlled gene networks in colorectal cancer. Oncol Lett 2017; 14:5393-5399. [PMID: 29113173 PMCID: PMC5656040 DOI: 10.3892/ol.2017.6900] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 06/15/2017] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer is the third most common type of cancer and the fourth leading cause of cancer-associated mortality worldwide. Serine/arginine-rich splicing factor 1 (SRSF1) is a well-characterized oncogenic factor that promotes tumorigenesis by controlling a number of alternative splicing events. However, there is limited network analysis, from a global aspect, to study the effect of SRSF1 on colorectal cancer. In the present study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of available gene regulation data from The Cancer Genome Atlas database revealed the enriched functions and signaling pathways of SRSF1. Subsequently, Oncomine analysis was performed, which demonstrated that SRSF1 was upregulated in a number of types of colon cancer. From overlapping the analysis of 2,678 SRSF1-related genes and 3,625 colorectal cancer genes in GeneCards, 468 genes were identified as SRSF1-related colorectal cancer genes. The GO results revealed that these overlapped genes were primarily enriched in metabolic processes, response to DNA damage, regulation of the cell cycle and a number of additional biological processes. KEGG pathway analysis revealed that SRSF1-related colorectal cancer genes were associated with the cell cycle, deregulated signaling pathways associated with cancer progression and colorectal cancer signaling pathways. In addition, the Search Tool for the Retrieval of Interacting Genes/Proteins database and Cytoscape analysis demonstrated that 468 SRSF1-related colorectal cancer genes exhibit potential interaction networks in which these genes were enriched in DNA metabolic processes, cell cycle regulation and regulation of apoptosis. The results of the present study suggested that SRSF1 exhibited an increased degree of interaction with key molecules, including NUF2 NDC80 kinetochore complex component, kinesin family member 2C, structural maintenance of chromosomes 3, ATM serine/threonine kinase, BRCA1 DNA repair associated, protein kinase DNA-activated catalytic polypeptide, heat shock protein 90 alpha family class A member 1, ras homolog family member A, and phosphatase and tensin homolog. Collectively, the bioinformatics analysis of the present study indicated that SRSF1 may have key functions in the progression and development of colorectal cancer.
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Affiliation(s)
- Junxiu Sheng
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jinyao Zhao
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Qiuhong Xu
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Linlin Wang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Wenjing Zhang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yang Zhang
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
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37
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Xie Y, Lin JZ, Wang AQ, Xu WY, Long JY, Luo YF, Shi J, Liang ZY, Sang XT, Zhao HT. Threonine and tyrosine kinase may serve as a prognostic biomarker for gallbladder cancer. World J Gastroenterol 2017; 23:5787-5797. [PMID: 28883705 PMCID: PMC5569294 DOI: 10.3748/wjg.v23.i31.5787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/03/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of threonine and tyrosine kinase (TTK) in gallbladder cancer (GBC) specimens and analyze the associations between TTK expression and clinicopathological parameters and clinical prognosis.
METHODS A total of 68 patients with GBC who underwent surgical resection were enrolled in this study. The expression of TTK in GBC tissues was detected by immunohistochemistry. The assessment of TTK expression was conducted using the H-scoring system. H-score was calculated by the multiplication of the overall staining intensity with the percentage of positive cells. The expression of TTK in the cytoplasm and nucleus was scored separately to achieve respective H-score values. The correlations between TTK expression and clinicopathological parameters and clinical prognosis were analyzed using Chi-square test, Kaplan-Meier method and Cox regression.
RESULTS In both the nucleus and cytoplasm, the expression of TTK in tumor tissues was significantly lower than that in normal tissues (P < 0.001 and P = 0.026, respectively). Using the median H-score as the cutoff value, it was discovered that, GBC patients with higher levels of TTK expression in the nucleus, but not the cytoplasm, had favorable overall survival (P < 0.001), and it was still statistically meaningful in Cox regression analysis. Further investigation indicated that there were close negative correlations between TTK expression and tumor differentiation (P = 0.041), CA 19-9 levels (P = 0.016), T stage (P < 0.001), nodal involvement (P < 0.001), distant metastasis (P = 0.024) and TNM stage (P < 0.001).
CONCLUSION The expression of TTK in GBC is lower than that in normal tissues. Higher levels of TTK expression in GBC are concomitant with longer overall survival. TTK is a favorable prognostic biomarker for patients with GBC.
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Affiliation(s)
- Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jian-Zhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - An-Qiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wei-Yu Xu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jun-Yu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu-Feng Luo
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jie Shi
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhi-Yong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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38
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Zhang J, Jiang Y, Zhao Y, Wang W, Xie Y, Wang H, Yang Y. Downregulation of tyrosine threonine kinase inhibits tumor growth via G2/M arrest in human endometrioid endometrial adenocarcinoma. Tumour Biol 2017; 39:1010428317712444. [PMID: 28718377 DOI: 10.1177/1010428317712444] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Endometrial cancer is the most common gynecologic malignancy, about 80% of which is endometrial endometrioid carcinoma. Dysregulation of spindle assembly checkpoint plays a vital role in endometrial endometrioid carcinoma tumorigenesis and progression. The purpose of this study was to explore how tyrosine threonine kinase, a spindle assembly checkpoint-related protein, promotes the endometrial endometrioid carcinoma progression. We found that both messenger RNA and protein levels of tyrosine threonine kinase in endometrial endometrioid carcinoma tissues are higher than those in normal endometrial tissues, and its expression is associated with tumor stages. Genetic depletion of tyrosine threonine kinase by RNA interference in two endometrial endometrioid carcinoma cell lines significantly inhibits cell proliferation and induces apoptosis. Mechanistically, depletion of tyrosine threonine kinase induces G2/M cell cycle arrest and triggers caspase-dependent cell apoptosis. Collectively, tyrosine threonine kinase is significantly upregulated in endometrial endometrioid carcinoma, and downregulation of tyrosine threonine kinase can suppress endometrial endometrioid carcinoma cell proliferation and promote apoptosis via G2/M cell cycle arrest. Our study demonstrates that tyrosine threonine kinase can be a potential therapeutic target for endometrial endometrioid carcinoma treatment.
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Affiliation(s)
- Jiamiao Zhang
- 1 Reproductive Medicine Center of the Affiliated Hospital, Guilin Medical University, Guilin, China
| | - Yan Jiang
- 2 Department of Obstetrics and Gynecology of The Zhong Kang Hospital in Zhengzhou, Zhengzhou, China
| | - Yu Zhao
- 3 Li Ka Shing Institute of Health Sciences and Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
| | - Wanxue Wang
- 1 Reproductive Medicine Center of the Affiliated Hospital, Guilin Medical University, Guilin, China
| | - Yiran Xie
- 1 Reproductive Medicine Center of the Affiliated Hospital, Guilin Medical University, Guilin, China
| | - Huating Wang
- 3 Li Ka Shing Institute of Health Sciences and Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
| | - Yihua Yang
- 1 Reproductive Medicine Center of the Affiliated Hospital, Guilin Medical University, Guilin, China
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Cancer/Testis Antigens: "Smart" Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers. Int J Mol Sci 2017; 18:ijms18040740. [PMID: 28362316 PMCID: PMC5412325 DOI: 10.3390/ijms18040740] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 03/22/2017] [Accepted: 03/27/2017] [Indexed: 12/22/2022] Open
Abstract
A clinical dilemma in the management of prostate cancer (PCa) is to distinguish men with aggressive disease who need definitive treatment from men who may not require immediate intervention. Accurate prediction of disease behavior is critical because radical treatment is associated with high morbidity. Here, we highlight the cancer/testis antigens (CTAs) as potential PCa biomarkers. The CTAs are a group of proteins that are typically restricted to the testis in the normal adult but are aberrantly expressed in several types of cancers. Interestingly, >90% of CTAs are predicted to belong to the realm of intrinsically disordered proteins (IDPs), which do not have unique structures and exist as highly dynamic conformational ensembles, but are known to play important roles in several biological processes. Using prostate-associated gene 4 (PAGE4) as an example of a disordered CTA, we highlight how IDP conformational dynamics may regulate phenotypic heterogeneity in PCa cells, and how it may be exploited both as a potential biomarker as well as a promising therapeutic target in PCa. We also discuss how in addition to intrinsic disorder and post-translational modifications, structural and functional variability induced in the CTAs by alternate splicing represents an important feature that might have different roles in different cancers. Although it is clear that significant additional work needs to be done in the outlined direction, this novel concept emphasizing (multi)functionality as an important trait in selecting a biomarker underscoring the theranostic potential of CTAs that is latent in their structure (or, more appropriately, the lack thereof), and casts them as next generation or “smart” biomarker candidates.
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40
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Song MH, Kim YR, Bae JH, Lee CH, Lee SY. Effect of cancer/testis antigen NY-SAR-35 on the proliferation, migration and invasion of cancer cells. Oncol Lett 2017; 13:784-790. [PMID: 28356959 PMCID: PMC5351105 DOI: 10.3892/ol.2016.5498] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 11/10/2016] [Indexed: 11/26/2022] Open
Abstract
NY-SAR-35 is a cancer/testis (CT) antigen that was identified by serological analysis of recombinant complementary DNA expression libraries. The gene encoding NY-SAR-35 is located on the × chromosome and is aberrantly expressed in a number of cancer types and germ cells, such as those in the testes, but not in normal tissue. It has been reported that treatment with a demethylating agent induced the expression of NY-SAR-35 in several types of cancer cells. However, the function of NY-SAR-35 in cancer remains undetermined. In present study, the role of NY-SAR-35 in human lung adenocarcinoma (SK-LC-14) and hepatocellular carcinoma (SNU-449) cells was investigated following stable transfection of the NY-SAR-35 gene. NY-SAR-35 was observed to be expressed in the cytoplasm of the cells. In addition, the bromodeoxyuridine incorporation assay and immunofluorescence staining for proliferating cell nuclear antigen and Ki-67 demonstrated that proliferation was increased in cells transfected with NY-SAR-35. In addition, the trypan blue exclusion assay indicated that NY-SAR-35 increased cancer cell viability. Furthermore, NY-SAR-35 increased the migration and invasion of the cells. These results indicate that NY-SAR-35 increases cancer cell viability, proliferation, migration and invasion.
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Affiliation(s)
- Myung-Ha Song
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea
| | - Ye-Rin Kim
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea
| | - Jae-Ho Bae
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea
| | - Chang-Hun Lee
- Department of Pathology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea
| | - Sang-Yull Lee
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea
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41
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Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity. Proc Natl Acad Sci U S A 2017; 114:E2644-E2653. [PMID: 28289210 DOI: 10.1073/pnas.1700082114] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgen-dependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgen-dependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.
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Sulek JE, Robinson SP, Petrossian AA, Zhou S, Goliadze E, Manjili MH, Toor A, Guruli G. Role of Epigenetic Modification and Immunomodulation in a Murine Prostate Cancer Model. Prostate 2017; 77:361-373. [PMID: 27862100 DOI: 10.1002/pros.23275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 10/21/2016] [Indexed: 11/07/2022]
Abstract
INTRODUCTION Decreased expression of highly immunogenic cancer-testis antigens (CTA) might help tumor to achieve low immunogenicity, escape immune surveillance and grow unimpeded. Our aim was to evaluate CTA expression in tumor and normal tissues and to investigate possible means of improving the immune response in a murine prostate cancer (CaP) model by using the combination of epigenetic modifier 5-azacitidine (5-AzaC) and immunomodulator lenalidomide. No study to date has examined the effect of this combination on the prostate cancer or its impact on antigen-presenting cells (APC). MATERIALS AND METHODS Gene microarrays were performed to compare expression of several CTA in murine prostate cancer (RM-1 cells) and normal prostate. RM-1 cells were treated with 5-AzaC and real-time PCR was performed to investigate the expression of several CTA. Western blotting was used to determine whether expression of CTA-specific mRNA induced by 5-AzaC resulted in increase in the corresponding protein. Effect of the epigenetic agents and immunomodulators was assessed on dendritic cells (DC) using flow cytometry, ELISA and T-cell proliferation assay. RESULTS Gene arrays demonstrated decreased expression of 35 CTA in CaP tissue compared to normal prostate. 5-AzaC treatment of RM-1 prostate cancer cells upregulated the expression of all 13 CTA tested in a dose-dependent fashion. DC were treated with 5-AzaC and lenalidomide and the expression of surface markers MHC Class I, MHC Class II, CD80, CD86, CD 205, and CD40 was increased. Combination of 5-AzaC and lenalidomide enhances the ability of DC to stimulate T-cell proliferation in mixed leukocyte reaction. Secretion of IL-12 and IL-15 by DC increased significantly with addition of 5-AzaC or 5-AzaC and lenalidomide. CONCLUSIONS Decreased expression of CTA by prostate cancer may be a means of escaping immune monitoring. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide increased tumor immunogenicity and enhanced DC function and may be used in the treatment of advanced prostate cancer. Prostate 77: 361-373, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jay E Sulek
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Samuel P Robinson
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Albert A Petrossian
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Shaoqing Zhou
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Ekaterine Goliadze
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
- Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Masoud H Manjili
- Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Amir Toor
- Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia
| | - Georgi Guruli
- Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
- Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia
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Xie Y, Wang A, Lin J, Wu L, Zhang H, Yang X, Wan X, Miao R, Sang X, Zhao H. Mps1/TTK: a novel target and biomarker for cancer. J Drug Target 2016; 25:112-118. [PMID: 27819146 DOI: 10.1080/1061186x.2016.1258568] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Monopolar spindle1 (Mps1, also known as TTK) is the core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells. Mps1 is hardly detectable in normal organs except the testis and placenta. However, high levels of Mps1 are found in many types of human malignancies, including glioblastoma, thyroid carcinoma, breast cancer, and other cancers. Several Mps1 inhibitors can inhibit the proliferation of cancer cells and exhibit demonstrable survival benefits. Mps1 can be utilized as a new immunogenic epitope, which is able to induce potent cytotoxic T lymphocyte activity against cancer cells while sparing normal cells. Some clinical trials have validated its safety, immunogenicity and clinical response. Thus, Mps1 may be a novel target for cancer therapy. Mps1 is differentially expressed between normal and malignant tissues, indicating its potential as a molecular biomarker for diagnosis. Meanwhile, the discovery that it clearly correlates with recurrence and survival time suggests it may serve as an independent prognostic biomarker as well.
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Affiliation(s)
- Yuan Xie
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Anqiang Wang
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Jianzhen Lin
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Liangcai Wu
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Haohai Zhang
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Xiaobo Yang
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Xueshuai Wan
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Ruoyu Miao
- b Liver Center and The Transplant Institute, Department of Medicine , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
| | - Xinting Sang
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Haitao Zhao
- a Department of Liver Surgery , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
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Lazzarini N, Widera P, Williamson S, Heer R, Krasnogor N, Bacardit J. Functional networks inference from rule-based machine learning models. BioData Min 2016; 9:28. [PMID: 27597880 PMCID: PMC5011349 DOI: 10.1186/s13040-016-0106-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 08/11/2016] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Functional networks play an important role in the analysis of biological processes and systems. The inference of these networks from high-throughput (-omics) data is an area of intense research. So far, the similarity-based inference paradigm (e.g. gene co-expression) has been the most popular approach. It assumes a functional relationship between genes which are expressed at similar levels across different samples. An alternative to this paradigm is the inference of relationships from the structure of machine learning models. These models are able to capture complex relationships between variables, that often are different/complementary to the similarity-based methods. RESULTS We propose a protocol to infer functional networks from machine learning models, called FuNeL. It assumes, that genes used together within a rule-based machine learning model to classify the samples, might also be functionally related at a biological level. The protocol is first tested on synthetic datasets and then evaluated on a test suite of 8 real-world datasets related to human cancer. The networks inferred from the real-world data are compared against gene co-expression networks of equal size, generated with 3 different methods. The comparison is performed from two different points of view. We analyse the enriched biological terms in the set of network nodes and the relationships between known disease-associated genes in a context of the network topology. The comparison confirms both the biological relevance and the complementary character of the knowledge captured by the FuNeL networks in relation to similarity-based methods and demonstrates its potential to identify known disease associations as core elements of the network. Finally, using a prostate cancer dataset as a case study, we confirm that the biological knowledge captured by our method is relevant to the disease and consistent with the specialised literature and with an independent dataset not used in the inference process. AVAILABILITY The implementation of our network inference protocol is available at: http://ico2s.org/software/funel.html.
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Affiliation(s)
- Nicola Lazzarini
- Interdisciplinary Computing and Complex BioSystems (ICOS) research group, School of Computing Science, Newcastle University, Newcastle upon Tyne, UK
| | - Paweł, Widera
- Interdisciplinary Computing and Complex BioSystems (ICOS) research group, School of Computing Science, Newcastle University, Newcastle upon Tyne, UK
| | - Stuart Williamson
- Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Rakesh Heer
- Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Natalio Krasnogor
- Interdisciplinary Computing and Complex BioSystems (ICOS) research group, School of Computing Science, Newcastle University, Newcastle upon Tyne, UK
| | - Jaume Bacardit
- Interdisciplinary Computing and Complex BioSystems (ICOS) research group, School of Computing Science, Newcastle University, Newcastle upon Tyne, UK
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Expression of Cancer Testis Antigens in Colorectal Cancer: New Prognostic and Therapeutic Implications. DISEASE MARKERS 2016; 2016:1987505. [PMID: 27635108 PMCID: PMC5007337 DOI: 10.1155/2016/1987505] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 07/28/2016] [Indexed: 12/11/2022]
Abstract
Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study. We selected a panel of 18 CTAs that were previously detected in CRC as well as some new gene candidates, and their expression was detected at the mRNA level by employing RQ-PCR. Additionally, we evaluated CTA expression in three colon cancer cell lines (CL-188, HTB-39, and HTB-37) after exposure to the DNA methylation-modifying drug 5-azacytidine. Results. We report that 6 out of 18 (33%) CTAs tested (MAGEA3, OIP5, TTK, PLU1, DKKL1, and FBXO39) were significantly (p < 0.05) overexpressed in tumor tissue compared with healthy colon samples isolated from the same patients. Conclusions. Moreover, we found that MAGEA3, PLU-1, and DKKL expression positively correlated with disease progression, evaluated according to the Dukes staging system. Finally, 5-azacytidine exposure significantly upregulated expression of CTAs on CRC cells, which indicates that this demethylation agent could be employed therapeutically to enhance the immune response against tumor cells.
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Brown-Clay JD, Shenoy DN, Timofeeva O, Kallakury BV, Nandi AK, Banerjee PP. PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion. Oncotarget 2016; 6:15594-609. [PMID: 25909225 PMCID: PMC4558173 DOI: 10.18632/oncotarget.3709] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 03/11/2015] [Indexed: 12/31/2022] Open
Abstract
A Current challenge in prostate cancer treatment is how to differentiate aggressive disease from indolent prostate cancer. There is an urgent need to identify markers that would accurately distinguish indolent prostate cancer from aggressive disease. The aim of this study was to evaluate the role of PDZ Domain-binding kinase (PBK) in prostate cancer and to determine if PBK expression enhances aggressiveness in prostate cancer. Using archival tissue samples, gain-of-function and loss-of-function studies, we show that PBK expression is up-regulated in prostate cancer, and its expression level is commensurate with invasiveness. Modulation of PBK expression and function causally regulates the invasive ability of prostate cancer cells. Production of matrix metalloproteinases-2 and -9, which are key players in metastatic invasion, is up-regulated, and the promoters of these genes are transcriptionally activated by PBK via increased β-catenin-TCF/LEF signaling. Prostate cancer tissue specimens show that PBK's expression correlates with aggressive disease and distant metastasis in bone, lymph node and abdomen. Our in vitro and in situ data are in agreement that PBK could be a prognostic biomarker for prostate cancer that would discriminate aggressive prostate cancer from indolent disease, and is a potential target for the therapeutic intervention of aggressive prostate cancer in men.
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Affiliation(s)
- Joshua D Brown-Clay
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
| | - Deepika N Shenoy
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
| | - Olga Timofeeva
- Departments of Oncology and Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
| | | | - Partha P Banerjee
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
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Zhang W, Niu C, He W, Hou T, Sun X, Xu L, Zhang Y. Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma. Tumour Biol 2015; 37:6239-54. [PMID: 26615423 PMCID: PMC4875171 DOI: 10.1007/s13277-015-4419-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 11/10/2015] [Indexed: 12/22/2022] Open
Abstract
Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and β-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.
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Affiliation(s)
- Weijing Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Chunhao Niu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Weiling He
- Department of Gastrointestinopancreatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan Second Road 58, Guangzhou, 510080, People's Republic of China
| | - Teng Hou
- Department of Urology, Wuhan Union Hospital of Huazhong University of Science and Technology, No.1277, Han Kou Jie Fang Road, Wuhan, 430022, People's Republic of China
| | - Xiaoying Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Liqun Xu
- Department of Gynecology, Women and Children Hospital of Guangdong Province, No.13, Guang Yuan Road, Guangzhou, 510060, People's Republic of China
| | - Yanna Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
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Terada N, Shiraishi T, Zeng Y, Aw-Yong KM, Mooney SM, Liu Z, Takahashi S, Luo J, Lupold SE, Kulkarni P, Getzenberg RH. Correlation of Sprouty1 and Jagged1 with aggressive prostate cancer cells with different sensitivities to androgen deprivation. J Cell Biochem 2015; 115:1505-15. [PMID: 24604720 DOI: 10.1002/jcb.24805] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 01/16/2014] [Indexed: 11/06/2022]
Abstract
Prostate cancer is a heterogeneous disease and thus, it is important to understand whether among the heterogeneous collection of cell types, androgen-deprivation insensitive cells exist prior to hormonal manipulation. We established several LNCaP subclones with distinct insensitivities to androgen deprivation from a parental LNCaP cell line. In the resulting clones, the sensitivity to androgen-deprivation negatively correlated with their PSA expression levels. In two of these clones, an androgen insensitive clone, LNCaP-cl1, and an androgen sensitive clone, LNCaP-cl5, the DNA copy number differed significantly, indicating that these clones contain genetically distinct cells. LNCaP-cl1 had higher PSA expression but lower invasiveness and tumor growth potential than LNCaP-cl5. The expression levels of two genes that are known to be regulated by miR-21, an androgen-regulated microRNA, Sprouty1 (SPRY1) and Jagged1 (JAG1) were significantly lower in LNCaP-cl1 than in LNCaP-cl5. Knocking down SPRY1 in LNCaP cells enhanced PSA expression and cell proliferation. JAG1 administration in LNCaP cells enhanced cell invasion and JAG1 knockdown in PC3 cells suppressed cell invasion and tumor formation. These results indicated that the expression differences in SPRY1 and JAG1 may contribute to the phenotypic differences between the LNCaP-cl1 and LNCaP-cl5 clones. In tissue samples, SPRY1 expression levels were significantly lower in prostate cancer patients with PSA recurrence after surgical treatment (P = 0.0076) and JAG1 expression levels were significantly higher in Gleason sum (GS) 8-9 disease than in GS 5-6 (P = 0.0121). In summary a random population of LNCaP cells comprises a heterogeneous group of cells with different androgen-deprivation sensitivities and potential for invasiveness.
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Affiliation(s)
- Naoki Terada
- Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Takahashi S, Shiraishi T, Miles N, Trock BJ, Kulkarni P, Getzenberg RH. Nanowire analysis of cancer-testis antigens as biomarkers of aggressive prostate cancer. Urology 2015; 85:704.e1-7. [PMID: 25733303 DOI: 10.1016/j.urology.2014.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/19/2014] [Accepted: 12/03/2014] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To demonstrate the ability of the nCounter Analysis System, a nanowire technology, to sensitively and accurately detect cancer-testis antigens (CTAs) in men with prostate cancer and correlate them with disease parameters. The clinical implementation of novel biomarkers is necessary to provide for individual disease treatment planning for men with prostate cancer. The CTAs, as cancer-associated biomarkers that may correlate with aggressive disease, have the potential to play an important role. METHODS Formalin-fixed, paraffin embedded samples were used from men undergoing radical prostatectomy for prostate cancer. The expression of CTAs along with control genes was measured from formalin-fixed, paraffin-embedded prostate cancer tissues using real-time polymerase chain reaction and the nCounter assay. RESULTS Using a nanowire-based assay, ribonucleic acid (RNA) expression levels of the CTAs CSAG2 and NOL4 were found to be significantly higher in men with Gleason score (GS) 8-10 disease than those with GS ≤4+3 disease. On the contrary, the RNA expression level of PAGE4 was lower in men with GS 8-10 disease than those with GS ≤6 group. This study demonstrates that CTAs can be detected with a nanostring assay that is translatable and that a set of CTAs correlates with the clinical characteristics of the disease. CONCLUSION CTAs represent unique, cancer-associated biomarkers with potential utility in the clinic. The nCounter nanowire technology provides an opportunity to evaluate this panel of CTAs associated with aggressive prostate cancer in a multi-institutional fashion.
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Affiliation(s)
- Sayuri Takahashi
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, University of Tokyo
| | - Takumi Shiraishi
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nancy Miles
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Bruce J Trock
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Prakash Kulkarni
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Robert H Getzenberg
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
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Hu P, Shangguan J, Zhang L. Downregulation of NUF2 inhibits tumor growth and induces apoptosis by regulating lncRNA AF339813. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:2638-2648. [PMID: 26045769 PMCID: PMC4440078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 02/28/2015] [Indexed: 06/04/2023]
Abstract
Recent studies have shown that NUF2 (Ndc80 kinetochore complex component) play important roles in multiple human cancers. In our previous report, NUF2 expression was stronger in tumor tissues than in normal pancreatic tissues. However, whether and how NUF2 play a role in pancreatic cancer progression remains largely unknown. The aim of our study is to investigate the expression and functional role of NUF2 in human PC. NUF2 expression was measured in 10 pairs of PC cancerous and noncancerous tissue samples by quantitative real-time PCR. The effects of NUF2 on PC cells were studied by RNA interference. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using MTT. CDK4/CDK6 activity was measured by Western blot assay. LncRNAs regulated by NUF2 were gained from bioinformatics analysis. The role of LncRNA AF339813, regulated by NUF2, was finally characterized in PC cells by siRNA. Our results showed that NUF2 mRNA and protein were significantly overexpressed in Human PC tissues and several PC cell lines. Through bioinformatics analysis and knockdown NUF2 in PC cells, we found LncRNA AF339813 was positively regulated by NUF2. We further demonstrated that knockdown of AF339813 by siRNA in PC cells significantly reduced cell proliferation and promoted apoptosis. Thus, we conclude that NUF2 is consistently overexpressed in human PC and NUF2 is closely linked with human PC progression through the meditator LncRNA AF339813. Our studies may contribute to understand the molecular mechanism of PC pathogenesis and clinical therapy.
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Affiliation(s)
- Peng Hu
- Department of Hepatobiliary Surgery, General Hospital of Lanzhou Military RegionLanzhou 730050, Gansu Province, China
| | - Jianying Shangguan
- Department of Hepatobiliary Surgery, General Hospital of Lanzhou Military RegionLanzhou 730050, Gansu Province, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical UniversityChongqing 400038, China
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