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Rakoczy K, Szymańska N, Stecko J, Kisiel M, Sleziak J, Gajewska-Naryniecka A, Kulbacka J. The Role of RAC2 and PTTG1 in Cancer Biology. Cells 2025; 14:330. [PMID: 40072059 PMCID: PMC11899714 DOI: 10.3390/cells14050330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Several molecular pathways are likely involved in the regulation of cancer stem cells (CSCs) via Ras-associated C3 botulinum toxin substrate 2, RAC2, and pituitary tumor-transforming gene 1 product, PTTG1, given their roles in cellular signaling, survival, proliferation, and metastasis. RAC2 is a member of the Rho GTPase family and plays a crucial role in actin cytoskeleton dynamics, reactive oxygen species production, and cell migration, contributing to epithelial-mesenchymal transition (EMT), immune evasion, and therapy resistance. PTTG1, also known as human securin, regulates key processes such as cell cycle progression, apoptosis suppression, and EMT, promoting metastasis and enhancing cancer cell survival. This article aims to describe the molecular pathways involved in the proliferation, invasiveness, and drug response of cancer cells through RAC2 and PTTG1, aiming to clarify their respective roles in neoplastic process dependencies. Both proteins are involved in critical signaling pathways, including PI3K/AKT, TGF-β, and NF-κB, which facilitate tumor progression by modulating CSC properties, angiogenesis, and immune response. This review highlights the molecular mechanisms by which RAC2 and PTTG1 influence tumorigenesis and describes their potential and efficacy as prognostic biomarkers and therapeutic targets in managing various neoplasms.
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Affiliation(s)
- Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Natalia Szymańska
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Jakub Stecko
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Michał Kisiel
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Jakub Sleziak
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Agnieszka Gajewska-Naryniecka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland;
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland;
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Santariškių g. 5, LT-08406 Vilnius, Lithuania
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Goh KY, Tham SC, Cheng TYD, Nadarajah R, Goh RCH, Wong SL, Ho TH, Chew GK, Tan AWK, Rajesh H, Chua HL, Yong TT, Yu SL, Kang JM, Lau KW, Tay AZE, Mantoo S, Busmanis I, Chew SH, Lim TYK, Wong WL, Ng QJ, Wang J, Tay SK, Cheok CF, Lim DWT, Lim EH. Cell Migration in Endometriosis Responds to Omentum-Derived Molecular Cues Similar to Ovarian Cancer. Int J Mol Sci 2025; 26:1822. [PMID: 40076450 PMCID: PMC11899264 DOI: 10.3390/ijms26051822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/14/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Endometriosis is common and poses significant morbidity of lasting impact to young, pre-menopausal women, while ovarian cancer is a lethal gynecologic condition. Both conditions need better treatment. The human omentum is an apron of adipose tissue in the abdominopelvic cavity, the same space in which endometriosis and ovarian cancer manifest. We aim to determine molecular cues emitted by the omentum that aid the trans-coelomic spread of endometriosis and ovarian cancer in the abdomen-pelvic/peritoneal space. Endometriosis and ovarian cancer patients were prospectively recruited. Primary cell cultures of surgically-resected omentum, endometriosis and ovarian cancer were generated, and conditioned media (CM) from the omentum was derived. They were used for in vitro assays to evaluate the effect of the omentum on cell migration, angiogenesis and proliferation in endometriosis and ovarian cancer. Omental CM promoted cell migration in primary cultures of endometriosis and ovarian cancer. Omental CM contained high levels of HGF, SDF-1a, MCP-1, VEGF-A, IL-6 and IL-8. The observed cell migration was blocked by c-MET inhibition, suggesting that HGF/c-MET signaling mediates cell migration in endometriosis and ovarian cancer. Furthermore, PTTG1 was consistently upregulated in the migrated cells in both endometriosis and ovarian cancer. The omentum provides a favorable environment for trans-coelomic spread of endometriosis and ovarian cancer. HGF, c-MET and PTTG1 are potential therapeutic targets for inhibiting the abdomen-pelvic/peritoneal spread of endometriosis and ovarian cancer.
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Affiliation(s)
- Kah Yee Goh
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore 168583, Singapore
| | - Su Chin Tham
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Terence You De Cheng
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Ravichandran Nadarajah
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Ronald Chin Hong Goh
- Department of Anatomical Pathology, Singapore General Hospital, Academia, College Road, Singapore 169856, Singapore
| | - Shing Lih Wong
- Department of Anatomical Pathology, Singapore General Hospital, Academia, College Road, Singapore 169856, Singapore
| | - Tew Hong Ho
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
- Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Ghee Kheng Chew
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Andy Wei Keat Tan
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Hemashree Rajesh
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Hong Liang Chua
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Tze Tein Yong
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Su Ling Yu
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Jia Min Kang
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore 168583, Singapore
| | - Kah Weng Lau
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Pathology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
| | - Amos Zhi En Tay
- Department of Anatomical Pathology, Singapore General Hospital, Academia, College Road, Singapore 169856, Singapore
| | - Sangeeta Mantoo
- Department of Anatomical Pathology, Singapore General Hospital, Academia, College Road, Singapore 169856, Singapore
| | - Inny Busmanis
- Department of Anatomical Pathology, Singapore General Hospital, Academia, College Road, Singapore 169856, Singapore
| | - Sung Hock Chew
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Timothy Yong Kuei Lim
- Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Wai Loong Wong
- Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Qiu Ju Ng
- Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Junjie Wang
- Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore
| | - Sun Kuie Tay
- Department of Obstetrics & Gynaecology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Chit Fang Cheok
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
| | - Darren Wan-Teck Lim
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore 168583, Singapore
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Office of Academic and Clinical Development, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Elaine Hsuen Lim
- Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore 168583, Singapore
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Martin Perez C, Liang X, Gupta D, Haughton ER, Conceição M, Mäger I, EL Andaloussi S, Wood MJ, Roberts TC. An extracellular vesicle delivery platform based on the PTTG1IP protein. EXTRACELLULAR VESICLE 2024; 4:None. [PMID: 39712388 PMCID: PMC11655445 DOI: 10.1016/j.vesic.2024.100054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/05/2024] [Accepted: 10/16/2024] [Indexed: 12/24/2024]
Abstract
Extracellular vesicles (EVs) are promising therapeutic delivery vehicles, although their potential is limited by a lack of efficient engineering strategies to enhance loading and functional cargo delivery. Using an in-house bioinformatics analysis, we identified N-glycosylation as a putative EV-sorting feature. PTTG1IP (a small, N-glycosylated, single-spanning transmembrane protein) was found to be a suitable scaffold for EV loading of therapeutic cargoes, with loading dependent on its N-glycosylation at two arginine residues. Chimeric proteins consisting of PTTG1IP fused with various cargo proteins, and separated by self-cleaving sequences (to promote cargo release), were shown to enable highly efficient functional delivery of Cre protein to recipient cell cultures and mouse xenograft tumors, and delivery of Cas9-sgRNA complexes to recipient reporter cells. The favorable membrane topology of PTTG1IP enabled facile engineering of further variants with improved properties, highlighting its versatility and potential as a platform for EV-based therapeutics.
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Affiliation(s)
- Carla Martin Perez
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK
| | - Xiuming Liang
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Dhanu Gupta
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford, OX3 7TY, UK
| | - Emily R. Haughton
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford, OX3 7TY, UK
| | - Mariana Conceição
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford, OX3 7TY, UK
- MDUK Oxford Neuromuscular Centre, Oxford, OX3 7TY, UK
| | - Imre Mäger
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
| | - Samir EL Andaloussi
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matthew J.A. Wood
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford, OX3 7TY, UK
- MDUK Oxford Neuromuscular Centre, Oxford, OX3 7TY, UK
| | - Thomas C. Roberts
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
- Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford, OX3 7TY, UK
- MDUK Oxford Neuromuscular Centre, Oxford, OX3 7TY, UK
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Sarabia-Sánchez MA, Tinajero-Rodríguez JM, Ortiz-Sánchez E, Alvarado-Ortiz E. Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion. Life Sci 2024; 355:123015. [PMID: 39182567 DOI: 10.1016/j.lfs.2024.123015] [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: 04/21/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024]
Abstract
Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
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Affiliation(s)
- Miguel Angel Sarabia-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México
| | - José Manuel Tinajero-Rodríguez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México; Tecnológico Nacional de México, Tecnológico de Estudios Superiores de Huixquilucan, México
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, México
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, México; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México.
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5
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Sun M, Zhao B, Chen T, Yao L, Li X, Hu S, Chen C, Gao X, Tang C. Novel molecular typing reveals the risk of recurrence in patients with early-stage papillary thyroid cancer. Thyroid Res 2024; 17:7. [PMID: 38556856 PMCID: PMC10983671 DOI: 10.1186/s13044-024-00193-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/06/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Papillary thyroid cancer (PTC) is an indolent disease with a favorable prognosis but characterized by a high recurrence rate. We aimed to improve precise stratification of recurrence risk in PTC patients with early stage using multi-gene signatures. PATIENTS AND METHODS The present study was performed using data from The Cancer Genome Atlas (TCGA) and multi-center datasets. Unsupervised consensus clustering was used to obtain the optimal molecular subtypes and least absolute shrinkage and selection operator (LASSO) analysis was performed to identify potential genes for the construction of recurrence signature. Kaplan-Meier survival analysis and the log-rank test was used to detect survival differences. Harrells concordance index (C-index) was used to assess the performance of the DNA damage repair (DDR) recurrence signature. RESULTS Through screening 8 candidate gene sets, the entire cohort was successfully stratified into two recurrence-related molecular subtypes based on DDR genes: DDR-high subtype and DDR-low subtype. The recurrence rate of DDR-high subtype was significantly lower than DDR-low subtype [HR = 0.288 (95%CI, 0.084-0.986), P = 0.047]. Further, a two-gene DDR recurrence signature was constructed, including PER1 and EME2. The high-risk group showed a significantly worse recurrence-free survival (RFS) than the low-risk group [HR = 10.647 (95%CI, 1.363-83.197), P = 0.024]. The multi-center data demonstrated that proportion of patients with low expression of PER1 and EME2 was higher in the recurrence group than those in the non-recurrence group. CONCLUSIONS These findings could help accurately and reliably identify PTC patients with high risk of recurrence so that they could receive more radical and aggressive treatment strategies and more rigorous surveillance practices.
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Affiliation(s)
- Mingyu Sun
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Bingqing Zhao
- Department of Plastic and Reconstructive Surgery, Tianjin Hospital of ITCWM Nankai Hospital, Tianjin, 300100, China
| | - Tao Chen
- The Xuzhou Clinical College of Xuzhou Medical University, Jiangsu, 221009, China
| | - Lijun Yao
- Department of Oncology, Suzhou Ninth People's Hospital, Suzhou, 215200, China
| | - Xiaoxin Li
- Department of Pathology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Shaojun Hu
- Department of Oncology, Suzhou Ninth People's Hospital, Suzhou, 215200, China
| | - Chengling Chen
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China.
| | - Xinbao Gao
- Department of Surgery for Vascular Thyroid and Hernia, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China.
| | - Chuangang Tang
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China.
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Martínez VS, Rodriguez K, McCubbin T, Tong J, Mahler S, Shave E, Baker K, Munro TP, Marcellin E. Amino acid degradation pathway inhibitory by-products trigger apoptosis in CHO cells. Biotechnol J 2024; 19:e2300338. [PMID: 38375561 DOI: 10.1002/biot.202300338] [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: 07/12/2023] [Revised: 11/25/2023] [Accepted: 12/13/2023] [Indexed: 02/21/2024]
Abstract
Chinese hamster ovary (CHO) cells are widely used to produce complex biopharmaceuticals. Improving their productivity is necessary to fulfill the growing demand for such products. One way to enhance productivity is by cultivating cells at high densities, but inhibitory by-products, such as metabolite derivatives from amino acid degradation, can hinder achieving high cell densities. This research examines the impact of these inhibitory by-products on high-density cultures. We cultured X1 and X2 CHO cell lines in a small-scale semi-perfusion system and introduced a mix of inhibitory by-products on day 10. The X1 and X2 cell lines were chosen for their varied responses to the by-products; X2 was susceptible, while X1 survived. Proteomics revealed that the X2 cell line presented changes in the proteins linked to apoptosis regulation, cell building block synthesis, cell growth, DNA repair, and energy metabolism. We later used the AB cell line, an apoptosis-resistant cell line, to validate the results. AB behaved similar to X1 under stress. We confirmed the activation of apoptosis in X2 using a caspase assay. This research provides insights into the mechanisms of cell death triggered by inhibitory by-products and can guide the optimization of CHO cell culture for biopharmaceutical manufacturing.
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Affiliation(s)
- Verónica S Martínez
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
| | - Karen Rodriguez
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
| | - Timothy McCubbin
- Queensland Metabolomics and Proteomics (Q-MAP), The University of Queensland, St Lucia, Queensland, Australia
| | - Junjie Tong
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
| | - Stephen Mahler
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
| | - Evan Shave
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- Patheon, by Thermo Fisher Scientific, Woolloongabba, Queensland, Australia
| | - Kym Baker
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- Patheon, by Thermo Fisher Scientific, Woolloongabba, Queensland, Australia
| | - Trent P Munro
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- National Biologics Facility, The University of Queensland, St Lucia, Queensland, Australia
| | - Esteban Marcellin
- ARC Training Centre for Biopharmaceutical Innovation (CBI), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- Queensland Metabolomics and Proteomics (Q-MAP), The University of Queensland, St Lucia, Queensland, Australia
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Christiani E, Naumann N, Weiss C, Spiess B, Kleiner H, Fabarius A, Hofmann WK, Saussele S, Seifarth W. Gene Expression Pattern of ESPL1, PTTG1 and PTTG1IP Can Potentially Predict Response to TKI First-Line Treatment of Patients with Newly Diagnosed CML. Cancers (Basel) 2023; 15:cancers15092652. [PMID: 37174118 PMCID: PMC10177117 DOI: 10.3390/cancers15092652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first = line treatment.
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Affiliation(s)
- Eva Christiani
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Nicole Naumann
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Christel Weiss
- Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Birgit Spiess
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Helga Kleiner
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Alice Fabarius
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Wolf-Karsten Hofmann
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Susanne Saussele
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Wolfgang Seifarth
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
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8
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Ma R, Tang Z, Wang J. PTTG1IP (PBF) is a prognostic marker and correlates with immune infiltrate in ovarian cancer. Am J Transl Res 2023; 15:27-46. [PMID: 36777854 PMCID: PMC9908464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 11/08/2022] [Indexed: 02/14/2023]
Abstract
OBJECTIVE An oncogenic protein, pituitary tumor transforming gene 1 binding factor (PTTG1IP, also called PBF), has been found to be expressed in various cancers. However, few studies have explored its prognostic significance and biologic function in epithelial ovarian cancer (EOC). METHODS Based on the Cancer Genome Atlas (TCGA) database, this study determined the differential expression of PBF at the mRNA level in EOC and normal tissues, which was then verified using real-time PCR and western blotting. Moreover, the Kaplan-Meier method and the Cox regression method were adopted to assess the clinical value of PBF in EOC. A nomogram model was constructed to evaluate the prognostic performance of PBF in EOC. Gene set enrichment analysis (GSEA) was employed to evaluate the signaling and pathway enrichment of PBF in EOC. The association between PBF expression and tumor-infiltrating immune cells (TIICs) in EOC was examined by single-sample GSEA and TIMER. RESULTS PBF was significantly higher in EOC than normal tissues as shown through TCGA database, and this result was verified by qRT-PCR and western blotting of EOC tissues and different cell lines. High PBF was associated with tumor size and lymphatic metastasis status. Kaplan-Meier (KM) analysis indicated that high PBF expression correlated with poor prognosis in patients with EOC (P < 0.0001). Moreover, multivariate Cox regression analysis was used to verify that PBF is an independent prognostic factor for EOC. The nomogram model exhibited moderate predictive accuracy and clinical utility in predicting EOC prognosis. The GSEA revealed that the expression of signaling pathways, such DNA damage replication, p53 pathway, Akt phosphorylation pathway, and estrogen-dependent nuclear pathway, were increased in the phenotype with high PBF expression. PBF expression was associated with neutrophil cells, iDC cells, NK cells, and Tem cells. CONCLUSION As a prognostic biomarker for EOC, PBF was found to be correlated with immune infiltration, and may therefore be a promising target for immunotherapy for EOC.
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Gong M, Wang J, Gao W, Liu Q, Chen J, Wang G, Zhang Q. Establishment of an endoplasmic reticulum stress-related signature predicting outcomes of gastric adenocarcinoma patients. Front Genet 2022; 13:944105. [PMID: 36147499 PMCID: PMC9486073 DOI: 10.3389/fgene.2022.944105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/11/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Gastric adenocarcinoma (GAC) is a common clinical malignancy with a poor prognosis. Endoplasmic reticulum (ER) stress plays important roles in the progression, immune filtration, and chemoresistance of cancers. However, whether ER stress-related gene signatures can predict the prognosis of GAC patients remains unknown. Methods: GAC patient RNA-seq data downloaded from The Cancer Genome Atlas and gastric cancer patient microarray data from Gene Expression Omnibus datasets were analyzed using LASSO regression to construct an ER stress-related signature. Survival analysis, time-dependent receiver operating characteristic (ROC) curves, and Cox regression analysis were used to verify the efficacy of the signature. Immune infiltration, somatic mutation, immune checkpoint, and copy number variation analyses were utilized to explore the potential biological significance of the signature. Results: In the present study, eight ER stress-related gene signatures were constructed. Survival analysis showed that patients in the high-risk group had a significantly worse prognosis. The area under the time-dependent ROC curves was 0.65, 0.70, and 0.63 at 1, 3, and 5 years, respectively, in the training cohort. Cox regression analysis showed that the signature is an independent prognostic factor. To predict GAC patients’ prognosis meeting individual needs, a nomogram was constructed with good accuracy. In addition, gene set enrichment and immune infiltration analyses showed that the ER stress-related signature is associated with cancer-related pathway activation and an immunosuppressive tumor microenvironment in GAC. Conclusion: In the current study, we established an ER stress-related signature. This prognostic signature has good predictive power and could facilitate the development of novel strategies for the clinical treatment of GAC.
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Affiliation(s)
- Meiyuan Gong
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jingtao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenfang Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Qian Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jiaxing Chen
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Guojun Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Guojun Wang, ; Qi Zhang,
| | - Qi Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
- *Correspondence: Guojun Wang, ; Qi Zhang,
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10
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Ibrahiem AT, Makhdoom AK, Alanazi KS, Alanazi AM, Mukhlef AM, Elshafey SH, Toraih EA, Fawzy MS. Analysis of anti-apoptotic PVT1 oncogene and apoptosis-related proteins (p53, Bcl2, PD-1, and PD-L1) expression in thyroid carcinoma. J Clin Lab Anal 2022; 36:e24390. [PMID: 35388548 PMCID: PMC9102754 DOI: 10.1002/jcla.24390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/10/2022] [Accepted: 03/21/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND An aberrant expression of long non-coding RNA PVT1 has been associated with apoptosis in various cancer types. We aimed to explore the PVT1 and four apoptosis-related proteins (p53, Bcl2, and PD-1/PD-L1) signature in thyroid cancer (TC). METHODS The PVT1 expression level was measured in 64 FFPE TC paired samples by real-time quantitative PCR. Overall and stratified analyses by different clinicopathological features were done. The apoptotic proteins were evaluated by immunohistochemistry staining. RESULTS Overall analysis showed significant PVT1upregulation in TC tissues (p < 0.001). Similarly, subgroup analysis by BRAFV600E mutation showed consistent results. Lower expression of p53 was associated with mortality (p = 0.001). Bcl2 overexpression was associated with greater tumor size (p = 0.005). At the same time, HCV-positive cases were associated with repressed Bcl2 expression levels (54.3% in HCV-negative vs. 6.9% in HCV-positive cases, p = 0.011). PD-1 expression was associated with lymph node metastasis (p = 0.004). Enhanced PD-L1 expression in the tumor was associated with a higher tumor stage, lymphovascular invasion, and mortality risk. Kaplan-Meier curves for overall survival showed that low p53 and high PD-L1 expressions were associated with lower survival time. The p53-positive staining is associated with a 90% decreased mortality risk (HR = 0.10, 95%CI = 0.02-0.47, p = 0.001), while patients with high PD-L1 were five times more likely to die (HR = 4.74, 95%CI = 1.2-18.7, p = 0.027). CONCLUSION Our results confirm the upregulation of PVT1 in TC. The apoptosis-related proteins (p53, Bcl2, and PD-1/PD-L1) showed different prognostic utility in TC patients; in particular, low p53 and high PD-L1 expressions associated with low survival times. Further large-scale and mechanistic studies are warranted.
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Affiliation(s)
- Afaf T. Ibrahiem
- Department of PathologyFaculty of MedicineNorthern Border UniversityArarSaudi Arabia
- Department of PathologyFaculty of MedicineMansoura UniversityMansouraEgypt
| | | | | | | | | | - Saad H. Elshafey
- Department of AnatomyFaculty of MedicineNorthern Border UniversityArarSaudi Arabia
| | - Eman A. Toraih
- Division of Endocrine and Oncologic Surgery, Department of Surgery, School of MedicineTulane UniversityNew OrleansLouisianaUSA
- Genetics UnitHistology and Cell Biology DepartmentFaculty of MedicineSuez Canal UniversityIsmailiaEgypt
| | - Manal S. Fawzy
- Department of BiochemistryFaculty of MedicineNorthern Border UniversityArarSaudi Arabia
- Department of Medical Biochemistry and Molecular BiologyFaculty of MedicineSuez Canal UniversityIsmailiaEgypt
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Ding H, Wang X, Liu H, Na L. Higher circular RNA_0015278 correlates with absence of extrathyroidal invasion, lower pathological tumor stages, and prolonged disease-free survival in papillary thyroid carcinoma patients. J Clin Lab Anal 2021; 35:e23819. [PMID: 33969549 PMCID: PMC8275007 DOI: 10.1002/jcla.23819] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/16/2021] [Accepted: 04/23/2021] [Indexed: 02/03/2023] Open
Abstract
Background Circular RNA_0015278 (circ_0015278) inhibits the progression of several cancers and is greatly reduced in papillary thyroid carcinoma (PTC) tissues compared with benign thyroid lesions by microarray profiling. This study aimed to further investigate the correlation of circ_0015278 with tumor characteristics and prognosis in PTC patients. Methods Totally, 206 PTC patients who underwent tumor resection were retrospectively enrolled; subsequently, circ_0015278 expression in their tumor and adjacent tissues was detected by reverse transcriptional‐quantitative polymerase chain reaction. Besides, disease‐free survival (DFS) and overall survival (OS) were calculated. Results Circ_0015278 was reduced in tumor tissues compared with adjacent tissues (p < 0.001), and receiver operating characteristic analysis showed that it well discriminated tumor tissues from adjacent tissues (area under curve: 0.903, 95% confidence interval: 0.874–0.932). Besides, higher tumor circ_0015278 expression was correlated with absence of extrathyroidal invasion (p = 0.036), lower pathological tumor (pT) stage (p = 0.05), pathological node (pN) stage (p = 0.002), and pathological tumor‐node‐metastasis (pTNM) stage (p = 0.001). Moreover, higher tumor circ_0015278 expression was associated with a reduced relapse rate (p = 0.011), but not mortality rate (p = 0.110); meanwhile, it was also correlated with prolonged DFS (p = 0.017), but not OS (p = 0.136). Additionally, multivariate Cox's regression analyses showed that higher tumor circ_0015278 expression independently associated with favorable DFS (p = 0.026, hazard ratio = 0.529). Conclusion Circ_0015278 is reduced in tumor tissues, while its’ higher expression in tumor correlates with absence of extrathyroidal invasion, lower pT, pN, and pTNM stage, as well as prolonged DFS in PTC patients.
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Affiliation(s)
- Huajie Ding
- Department of Ultrasound, Affiliated Hospital of Chengde Medical College, Chengde, China
| | - Xiaojie Wang
- Department of Laboratory, Cheng De Medical College, Chengde, China
| | - Huiling Liu
- Department of Ultrasound, Affiliated Hospital of Chengde Medical College, Chengde, China
| | - Lei Na
- Department of Emergency, Affiliated Hospital of Chengde Medical College, Chengde, China
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12
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Zhang Y, Yang F, Peng X, Li X, Luo N, Zhu W, Fu M, Li Q, Hu G. Hypoxia Constructing the Prognostic Model of Colorectal Adenocarcinoma and Related to the Immune Microenvironment. Front Cell Dev Biol 2021; 9:665364. [PMID: 33959617 PMCID: PMC8093637 DOI: 10.3389/fcell.2021.665364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/26/2021] [Indexed: 01/05/2023] Open
Abstract
Background: Hypoxia is a common phenomenon in solid tumors, which plays an important role in tumor proliferation, apoptosis, angiogenesis, invasion and metastasis, energy metabolism and chemoradiotherapy resistance. However, comprehensive analysis of hypoxia markers in colorectal adenocarcinoma (COAD) is still lacking. And there is a need for mechanism exploration and clinical application. Methods: The gene expression, mutation and clinical data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. Tumor samples from TCGA were randomly divided into the training and internal validation groups, while tumor samples from GEO were used as the external validation group. Univariate COX—LASSO—multivariate COX method was applied to construct the prognostic model. We clustered all TCGA tumor samples into high, medium and low hypoxia groups, evaluated the correlation between hypoxia degree and immunoactivity, and explored the combined effect of mutation for common target genes and model riskscore on survival in COAD patients. Finally, we developed a dynamic nomograph App online for direct clinical application and carried out multiple validations of the prognostic model. Results: Our hypoxia-related prognostic model for COAD patients is accurate and has been successfully validated internally and externally. Single Sample Gene Set Enrichment Analysis (ssGSEA) and Gene Set Enrichment Analysis (GSEA) results suggest that for COAD patients with higher hypoxia, the stronger the associated immunosuppressive activity, providing a possible mechanism for the lower survival rate. Finally, the dynamic nomograph App online enhances the clinical translational significance of the study. Conclusion: In this study, an accurate prognostic model for COAD patients was established and validated. In addition, our innovative findings include correlations between hypoxia levels and immune activity, as well as an in-depth exploration of common target gene mutations.
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Affiliation(s)
- Yuanyuan Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohong Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Luo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjun Zhu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Fu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianxia Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangyuan Hu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Wang X, Zhang R, Wu S, Shen L, Ke M, Ouyang Y, Lin M, Lyu Y, Sun B, Zheng Z, Yang J, Yang J, Lu W, Yang Y, Li D, Zou Y, Huang H, Nan A. Super-Enhancer LncRNA LINC00162 Promotes Progression of Bladder Cancer. iScience 2020; 23:101857. [PMID: 33344916 PMCID: PMC7736918 DOI: 10.1016/j.isci.2020.101857] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/21/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023] Open
Abstract
Due to the lack of effective early diagnostic measures and treatment methods, bladder cancer has become a malignant tumor that seriously threatens people's lives and health. Here, we reported that LINC00162, a super-enhancer long noncoding RNA, was highly expressed in bladder cancer cells and tissues. And LINC00162 was negatively correlated with neighboring PTTG1IP expression. Knocking down LINC00162 expression can inhibit the proliferative activity of bladder cancer cells and the growth of transplanted tumors in vivo, while knocking down the expression of PTTG1IP could restore the proliferative activity of bladder cancer cells. In addition, both LINC00162 and PTTG1IP were found to be able to bind to THRAP3, a transcription-related protein. And THRAP3 can regulate PTTG1IP expression. Finally, we demonstrated a mechanism that LINC00162 could regulate PTTG1IP expression through binding THRAP3. This study provided a potential target molecule for clinical treatment of bladder cancer.
Expression of LINC00162 is increased in bladder cancer LINC00162 promotes bladder cancer progress in vitro and in vivo LINC00162 regulates neighboring PTTG1IP expression to promote bladder cancer LINC00162 inhibits PTTG1IP expression by interacting THRAP3
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Affiliation(s)
- Xin Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Ruirui Zhang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.,Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Shuilian Wu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Liping Shen
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Meixia Ke
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yan Ouyang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Mengqi Lin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yiting Lyu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Binuo Sun
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Zhijian Zheng
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Jialei Yang
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Jie Yang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Wenmin Lu
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Yiping Yang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Danni Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Yunfeng Zou
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
| | - Haishan Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Aruo Nan
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.,Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
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14
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Identification of GSN and LAMC2 as Key Prognostic Genes of Bladder Cancer by Integrated Bioinformatics Analysis. Cancers (Basel) 2020; 12:cancers12071809. [PMID: 32640634 PMCID: PMC7408759 DOI: 10.3390/cancers12071809] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/26/2020] [Accepted: 07/03/2020] [Indexed: 12/14/2022] Open
Abstract
Bladder cancer is a common malignancy with mechanisms of pathogenesis and progression. This study aimed to identify the prognostic hub genes, which are the central modulators to regulate the progression and proliferation in the specific subtype of bladder cancer. The identification of the candidate hub gene was performed by weighted gene co-expression network analysis to construct a free-scale gene co-expression network. The gene expression profile of GSE97768 from the Gene Expression Omnibus database was used. The association between prognosis and hub gene was evaluated by The Cancer Genome Atlas database. Four gene-expression modules were significantly related to bladder cancer disease: the red module (human adenocarcinoma lymph node metastasis), the darkturquioise module (grade 2 carcinoma), the lightgreen module (grade 3 carcinoma), and the royalblue module (transitional cell carcinoma lymphatic metastasis). Based on betweenness centrality and survival analysis, we identified laminin subunit gamma-2 (LAMC2) in the grade 2 carcinoma, gelsolin (GSN) in the grade 3 carcinoma, and homeodomain-interacting protein kinase 2 (HIPK2) in the transitional cell carcinoma lymphatic metastasis. Subsequently, the protein levels of LAMC2 and GSN were respectively down-regulated and up-regulated in tumor tissue with the Human Protein Atlas (HPA) database. Our results suggested that LAMC2 and GSN are the central modulators to transfer information in the specific subtype of the disease.
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'From Felix to the helix, and from the cradle to the grave - Semon's contribution to thyroid surgery', Royal Society of Medicine, 1 November 2019, London, UK. The Journal of Laryngology & Otology 2020; 134:381-386. [PMID: 32468965 DOI: 10.1017/s0022215120001000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Mr President, Mr President Elect, Fellows and Members, Ladies and Gentleman, it is a pleasure to address the Section of Laryngology this morning and deliver the 94th Semon Lecture. I would like to thank the Semon Committee for their kind invitation. My lecture will discuss Sir Felix Semon (the man himself), highlight the history of head and neck surgery, and then discuss the requirements of a modern-day thyroid surgeon. I have no conflict of interest and nothing to declare.
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Xiong Z, Li X, Yang Q. PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas. Protein Pept Lett 2019; 26:800-818. [PMID: 37020362 DOI: 10.2174/0929866526666190722145449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 06/12/2019] [Accepted: 06/14/2019] [Indexed: 11/22/2022]
Abstract
Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.
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Affiliation(s)
- Zujian Xiong
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qi Yang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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17
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Lian SH, Song JD, Huang Y. PBF, a Proto-oncogene in Esophageal Carcinoma. Open Med (Wars) 2019; 14:748-756. [PMID: 31637306 PMCID: PMC6795029 DOI: 10.1515/med-2019-0086] [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: 11/18/2018] [Accepted: 07/26/2019] [Indexed: 11/15/2022] Open
Abstract
Emerging evidence shows that the pituitary tumour-transforming gene (PTTG)-binding factor (PBF) functions as a proto-oncogene in some tumors. However, the precise functions of PBF in tumorigenesis and its action mechanisms remain largely unknown. Here for the first time we demonstrated that PBF was associated with a tumor-related cell phenotype in esophageal carcinoma (ESCA) and identified the involved signaling pathways. PBF was up-regulated in ESCA tissues (Data from GEPIA) and cells. Then we down-regulated PBF in ESCA cell lines, Eca-109 and TE-1, by using RNAi technology. Cell function analysis suggested that down-regulation of PBF could inhibit tumor-related cell phenotypes, including proliferation, motility, apoptosis and cell cycle, in Eca-109 and TE-1 cells. Mechanism investigation suggested that apoptosis induced by PBF knockdown may be mediated by the activation of the mitochondrial apoptosis pathway and cell cycle arrest. AKT/mTOR and Wnt3a/β-catenin, key pathways in regulating tumor proliferation and metastasis, were found to be inactivated by the down-regulation of PBF in ESCA cells. In conclusion, our study demonstrates that PBF functions as a proto-oncogene in ESCA in vitro, which may be mediated through AKT/mTOR and Wnt3a/β-catenin pathways.
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Affiliation(s)
- Shi-hai Lian
- Department of Cardiothoracic surgery, Zaozhuang Municipal Hospital, Zaozhuang 277000, Shandong Province, China
| | - Jun-ding Song
- Department of Cardiothoracic surgery, Zaozhuang Municipal Hospital, Zaozhuang 277000, Shandong Province, China
| | - Yi Huang
- Department of Cardiothoracic surgery, Zaozhuang Municipal Hospital, 41# Longtou Rd, Zaozhuang 277100, Shandong Province, China
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18
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Tan X, Zhang S, Gao H, He W, Xu M, Wu Q, Ni X, Jiang H. Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer. Oncol Lett 2019; 18:1278-1286. [PMID: 31423188 PMCID: PMC6607221 DOI: 10.3892/ol.2019.10400] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 04/15/2019] [Indexed: 12/25/2022] Open
Abstract
Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood. Pituitary tumor transforming gene 1 binding factor (PTTG1IP) is a tumor-associated gene; however, to the best of our knowledge, its association with lung cancer has not been reported. The present study analyzed PTTG1IP expression in early-stage non-small cell lung cancer (NSCLC) samples and investigated its epigenetic regulatory mechanisms. The results revealed that the mRNA level of PTTG1IP in NSCLC tissues was significantly downregulated by 43% compared with that in adjacent tissues. In addition, overexpression of this gene significantly inhibited cell proliferation. According to data from The Cancer Genome Atlas, a significant negative correlation was identified between the PTTG1IP gene methylation level and expression level in lung adenocarcinoma and lung squamous cell carcinoma cases. Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing. Following treatment with 5-aza-2′-deoxycytidine to reduce DNA methylation in the promoter region, the PTTG1IP mRNA level increased, indicating that the PTTG1IP promoter DNA methylation level negatively regulates PTTG1IP transcription. In conclusion, in early-stage NSCLC, the PTTG1IP gene is regulated by DNA methylation in its promoter region, which may participate in the development and progression of lung cancer.
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Affiliation(s)
- Xiaoming Tan
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China
| | - Sufen Zhang
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Huifang Gao
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Wanhong He
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Minjie Xu
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Qihan Wu
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Xiaohua Ni
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, P.R. China
| | - Handong Jiang
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P.R. China
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19
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Read ML, Modasia B, Fletcher A, Thompson RJ, Brookes K, Rae PC, Nieto HR, Poole VL, Roberts S, Campbell MJ, Boelaert K, Turnell AS, Smith VE, Mehanna H, McCabe CJ. PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer. Cancer Res 2018; 78:5863-5876. [PMID: 30154144 DOI: 10.1158/0008-5472.can-18-0855] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 07/05/2018] [Accepted: 08/21/2018] [Indexed: 12/12/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild-type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. Patients with HNSCC with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signaling.Significance: These findings reveal a complex and novel interrelationship between the expression and function of PTTG, PBF, and p53 in human HNSCC that significantly influences patient outcome. Cancer Res; 78(20); 5863-76. ©2018 AACR.
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Affiliation(s)
- Martin L Read
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
| | - Bhavika Modasia
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Alice Fletcher
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Rebecca J Thompson
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Katie Brookes
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Peter C Rae
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Hannah R Nieto
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Vikki L Poole
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Sally Roberts
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Moray J Campbell
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Kristien Boelaert
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Andrew S Turnell
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Vicki E Smith
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Hisham Mehanna
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Christopher J McCabe
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
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20
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Li Z, Xu Y, Lin Y. Transcriptome analyses reveal genes of alternative splicing associated with muscle development in chickens. Gene 2018; 676:146-155. [PMID: 30010040 DOI: 10.1016/j.gene.2018.07.027] [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] [Received: 04/15/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 01/18/2023]
Abstract
Alternative splicing (AS) of pre-mRNA is a central mode of genetic regulation in higher eukaryotes. High-throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. However, little information is available on the transcriptome-wide changes during different ages in different chicken breeds. In this study, the sequencing reads of chicken muscle tissues collected from White feather broiler (day 42) and Luning Chicken (day 70, 120, 150) were mapped to the chicken genome. Results showed that a total of 16,958 genes were annotated, with 2230 differentially expressed genes (DEGs) when comparing White feather broiler and Luning Chicken, and an average of 700 DEGs when comparing different ages in Luning Chicken. Functional classification by Gene Ontology (GO) and pathways analysis for selecting the genes showed most DEGs were related to muscle development and immune response. Of the 16,958 genes, a total of 6249 genes (36.85%) underwent AS events, and over 40% were specifically expressed in each library. Additionally, 6 DEGs (SRPK3, ENSGALG00000022884, CCL4, GATM, SESN1, PTTG1IP) involved in muscle development and immunity response were found to be alternatively spliced among all the four muscle tissues. In conclusion, we present a complete dataset involving the spatial and temporal transcriptome of chicken muscle tissue using RNA -seq. These data will facilitate the understanding of the effects of breed and age on the development of muscle and uncover that AS events of candidate genes may have important functional roles in regulation of muscle development in chicken.
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Affiliation(s)
- Zhixiong Li
- College of Life Science and Technology, Southwest Minzu University, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, Sichuan 610041, PR China.
| | - Yaou Xu
- College of Life Science and Technology, Southwest Minzu University, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, Sichuan 610041, PR China
| | - Yaqiu Lin
- College of Life Science and Technology, Southwest Minzu University, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, Sichuan 610041, PR China
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21
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Repo H, Gurvits N, Löyttyniemi E, Nykänen M, Lintunen M, Karra H, Kurki S, Kuopio T, Talvinen K, Söderström M, Kronqvist P. PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival. BMC Cancer 2017; 17:705. [PMID: 29078751 PMCID: PMC5658989 DOI: 10.1186/s12885-017-3694-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 10/19/2017] [Indexed: 12/11/2022] Open
Abstract
Background PTTG1-interacting protein (PTTG1IP) is an oncogenic protein, which participates in metaphase-anaphase transition of the cell cycle through activation of securin (PTTG1). PTTG1IP promotes the shift of securin from the cell cytoplasm to the nucleus, allowing the interaction between separase and securin. PTTG1IP overexpression has been previously observed in malignant disease, e.g. in breast carcinoma. However, the prognostic value of PTTG1IP in breast carcinoma patients has not previously been revealed. Methods A total of 497 breast carcinoma patients with up to 22-year follow-up were analysed for PTTG1IP and securin immunoexpression. The results were evaluated for correlations with the clinical prognosticators and patient survival. Results In our material, negative PTTG1IP immunoexpression predicted a 1.5-fold risk of breast cancer death (p = 0.02). However, adding securin immunoexpression to the analysis indicated an even stronger and independent prognostic power in the patient material (HR = 2.5, p < 0.0001). The subcellular location of securin was found with potential prognostic value also among the triple-negative breast carcinomas (n = 96, p = 0.052). Conclusions PTTG1IP-negativity alone and in combination with high securin immunoexpression indicates a high risk of breast cancer death, resulting in up to 14-year survival difference in our material.
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Affiliation(s)
- Heli Repo
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland.
| | - Natalia Gurvits
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
| | - Eliisa Löyttyniemi
- Department of Medical Statistics, Medical Faculty, University of Turku, Lemminkäisenkatu 1, 20510, Turku, Finland
| | - Marjukka Nykänen
- Biological and Environmental Science, University of Jyväskylä and Department of Pathology, Central Finland Health Care District, Keskussairaalantie 19, 40620, Jyväskylä, Finland
| | - Minnamaija Lintunen
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
| | - Henna Karra
- Department of Pathology, Pori Central Hospital, Sairaalantie 3, 28500, Pori, Finland
| | - Samu Kurki
- Auria Biobank, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
| | - Teijo Kuopio
- Biological and Environmental Science, University of Jyväskylä and Department of Pathology, Central Finland Health Care District, Keskussairaalantie 19, 40620, Jyväskylä, Finland
| | - Kati Talvinen
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
| | - Mirva Söderström
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
| | - Pauliina Kronqvist
- Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland
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22
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Imruetaicharoenchoke W, Fletcher A, Lu W, Watkins RJ, Modasia B, Poole VL, Nieto HR, Thompson RJ, Boelaert K, Read ML, Smith VE, McCabe CJ. Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF. Endocr Relat Cancer 2017; 24:459-474. [PMID: 28676500 PMCID: PMC5551380 DOI: 10.1530/erc-16-0340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 07/03/2017] [Indexed: 12/25/2022]
Abstract
Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent report of mutations in PBF within the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We therefore sought to determine whether the first 10 PBF missense substitutions in human cancer might be oncogenic. Anisomycin half-life studies revealed that most mutations were associated with reduced protein stability compared to wild-type (WT) PBF. Proliferation assays narrowed our interest to two mutational events which significantly altered cell turnover: C51R and R140W. C51R was mainly confined to the endoplasmic reticulum while R140W was apparent in the Golgi apparatus. Both C51R and R140W lost the capacity to induce cellular migration and significantly reduced cell invasion. Colony formation and soft agar assays demonstrated that, in contrast to WT PBF, both mutants were unable to elicit significant colony formation or anchorage-independent growth. However, C51R and R140W retained the ability to repress radioiodide uptake, a functional hallmark of PBF. Our data reveal new insight into PBF function and confirm that, rather than being oncogenic, mutations in PBF are likely to be passenger effects, with overexpression of PBF the more important aetiological event in human cancer.
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Affiliation(s)
- W Imruetaicharoenchoke
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
- Department of SurgeryFaculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - A Fletcher
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - W Lu
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - R J Watkins
- Institute of Cancer and Genomic SciencesUniversity of Birmingham, Birmingham, UK
| | - B Modasia
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - V L Poole
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - H R Nieto
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - R J Thompson
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - K Boelaert
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - M L Read
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - V E Smith
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - C J McCabe
- Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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23
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Manzella L, Stella S, Pennisi MS, Tirrò E, Massimino M, Romano C, Puma A, Tavarelli M, Vigneri P. New Insights in Thyroid Cancer and p53 Family Proteins. Int J Mol Sci 2017. [PMID: 28635633 PMCID: PMC5486146 DOI: 10.3390/ijms18061325] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease.
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Affiliation(s)
- Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Stefania Stella
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Maria Stella Pennisi
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Elena Tirrò
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Chiara Romano
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Adriana Puma
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
| | - Martina Tavarelli
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi Nesima Medical Center, University of Catania, 95122 Catania, Italy.
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
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24
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Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer. Oncogene 2017; 36:5296-5308. [PMID: 28504713 PMCID: PMC5563453 DOI: 10.1038/onc.2017.154] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 04/06/2017] [Accepted: 04/17/2017] [Indexed: 01/15/2023]
Abstract
The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10-4) compared with either PBF- (P=1.5 × 10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10-5) and disease-free survival (P=4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.
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25
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An H, Yang L, Wang C, Gan Z, Gu H, Zhang T, Huang X, Liu Y, Li Y, Chang SJ, Lai J, Li YB, Chen S, Sun FL. Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage. Mol Cell Biol 2017; 37:e00419-16. [PMID: 28031328 PMCID: PMC5335506 DOI: 10.1128/mcb.00419-16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 09/01/2016] [Accepted: 12/04/2016] [Indexed: 01/25/2023] Open
Abstract
RAD6, an E2 ubiquitin-conjugating enzyme, is a key node for determining different DNA damage repair pathways, controlling both the error-prone and the error-free DNA damage repair pathways through differential regulation of the ubiquitination of the proliferating cell nuclear antigen (PCNA) protein. However, whether other pathways are involved in the RAD6-mediated regulation of DNA damage repair is still unclear. To deeply understand the molecular mechanisms of RAD6 in DNA damage repair, we performed a proteomic analysis and identified the changes of the protein-protein interaction (PPI) networks of RAD6 before and after X-ray irradiation. Furthermore, our study indicated that a proteasome-related event is likely involved in the DNA damage repair process. Moreover, we found that RAD6 promotes proteasome activity and nuclear translocation by enhancing the degradation of PSMF1 and the lamin B receptor (LBR). Therefore, we provide a novel pathway that is employed by RAD6 in response to DNA damage.
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Affiliation(s)
- Hongli An
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Lu Yang
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Chen Wang
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, Shanghai, People's Republic of China
| | - Zhixue Gan
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, Shanghai, People's Republic of China
| | - Haihui Gu
- Department of Transfusion Medicine, Changhai Hospital, Second Military Medical University, Shanghai, Shanghai, People's Republic of China
| | - Tao Zhang
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Xin Huang
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Yan Liu
- People's Hospital of Zunhua, School of Life Sciences, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China
| | - Yufeng Li
- People's Hospital of Zunhua, School of Life Sciences, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China
| | - Shing-Jyh Chang
- Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan, Republic of China
| | - Jianghua Lai
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Ya-Bin Li
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, Shanghai, People's Republic of China
| | - Su Chen
- Center for Translational Medicine at The First Affiliated Hospital, School of Forensic Sciences, School of Pharmacy, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, Shanghai, People's Republic of China
- People's Hospital of Zunhua, School of Life Sciences, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China
| | - Fang-Lin Sun
- Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, Shanghai, People's Republic of China
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26
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Watkins RJ, Imruetaicharoenchoke W, Read ML, Sharma N, Poole VL, Gentilin E, Bansal S, Bosseboeuf E, Fletcher R, Nieto HR, Mallick U, Hackshaw A, Mehanna H, Boelaert K, Smith VE, McCabe CJ. Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin. J Clin Endocrinol Metab 2016; 101:4551-4563. [PMID: 27603901 PMCID: PMC5155689 DOI: 10.1210/jc.2016-1932] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. OBJECTIVE The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action. Design, Setting, Patients, and Interventions: Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data. PRIMARY OUTCOME MEASURE Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays. RESULTS Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells. CONCLUSION Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement.
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Affiliation(s)
- Rachel J Watkins
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Waraporn Imruetaicharoenchoke
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Martin L Read
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Neil Sharma
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Vikki L Poole
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Erica Gentilin
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Sukhchain Bansal
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Emy Bosseboeuf
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Rachel Fletcher
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Hannah R Nieto
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Ujjal Mallick
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Allan Hackshaw
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Hisham Mehanna
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Kristien Boelaert
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Vicki E Smith
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Christopher J McCabe
- Institute of Metabolism and Systems Research (R.J.W., W.I., M.L.R., N.S., V.L.P., S.B., R.F., H.R.N., K.B., V.E.S., C.J.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Surgery, Faculty of Medicine (W.I.), Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Section of Endocrinology and Internal Medicine (E.G.), University of Ferrara, 44121 Ferrara, Italy; STIM Laboratory (E.B.), University of Poitiers, 86073 Poitiers Cedex 9, France; Northern Centre for Cancer Care (U.M.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; Cancer Research United Kingdom & UCL Cancer Trials Centre (A.H.), University College London, London WC1E 6BT, United Kingdom; and Institute of Cancer and Genomic Sciences (H.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom
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27
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Prognostic implications of securin expression and sub-cellular localization in human breast cancer. Cell Oncol (Dordr) 2016; 39:319-31. [DOI: 10.1007/s13402-016-0277-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2016] [Indexed: 02/06/2023] Open
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28
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Tsai ST, Wang PJ, Liou NJ, Lin PS, Chen CH, Chang WC. ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma. PLoS One 2015; 10:e0142834. [PMID: 26571024 PMCID: PMC4646358 DOI: 10.1371/journal.pone.0142834] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 10/27/2015] [Indexed: 12/13/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC.
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Affiliation(s)
- Sheng-Ta Tsai
- Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Po-Jen Wang
- Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
| | - Nia-Jhen Liou
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Pei-Shan Lin
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chung-Hsuan Chen
- Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Department of Chemistry, National Taiwan University, Taipei, Taiwan
- Institute of Atomic & Molecular Sciences, Academia Sinica, Taipei, Taiwan
| | - Wei-Chao Chang
- Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
- * E-mail:
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29
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Read ML, Seed RI, Modasia B, Kwan PPK, Sharma N, Smith VE, Watkins RJ, Bansal S, Gagliano T, Stratford AL, Ismail T, Wakelam MJO, Kim DS, Ward ST, Boelaert K, Franklyn JA, Turnell AS, McCabe CJ. The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer. Mol Carcinog 2014; 55:15-26. [PMID: 25408419 DOI: 10.1002/mc.22254] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/08/2014] [Accepted: 10/22/2014] [Indexed: 12/20/2022]
Abstract
The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.
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Affiliation(s)
- Martin L Read
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Robert I Seed
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Bhavika Modasia
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Perkin P K Kwan
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Neil Sharma
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Vicki E Smith
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Rachel J Watkins
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Sukhchain Bansal
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | | | - Anna L Stratford
- Department of Pediatrics, University of British Columbia, Canada
| | - Tariq Ismail
- School of Cancer Sciences, University of Birmingham, UK
| | | | - Dae S Kim
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Stephen T Ward
- Centre for Liver Research and NIHR Centre for Biomedical Research Unit, University of Birmingham, UK
| | - Kristien Boelaert
- School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Jayne A Franklyn
- School of Clinical and Experimental Medicine, University of Birmingham, UK
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