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Valle ABCDS, da Silva FFA, Carneiro MÂP, Espuche B, Tavares GD, Bernardes ES, Moya SE, Pittella F. In Vivo HOXB7 Gene Silencing and Cotreatment with Tamoxifen for Luminal A Breast Cancer Therapy. Pharmaceuticals (Basel) 2024; 17:1325. [PMID: 39458966 PMCID: PMC11509954 DOI: 10.3390/ph17101325] [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: 09/11/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Acquired resistance and adverse effects are some of the challenges faced by thousands of Luminal A breast cancer patients under tamoxifen (TMX) treatment. Some authors associate the overexpression of HOXB7 with TMX resistance in this molecular subtype, and the knockdown of this gene could be an effective strategy to regain TMX sensitivity. Therefore, we used calcium phosphate hybrid nanoparticles (HNP) for the delivery of short interfering RNA molecule (siRNA) complementary to the HOXB7 gene and evaluated the RNA interference (RNAi) effects associated with TMX treatment in breast cancer in vivo. METHODS HNP were prepared by the self-assembly of a methoxy-poly (ethylene glycol)-block-poly (L-glutamic acid) copolymer (PEG-pGlu) and the coprecipitation of CaPO4 to incorporate siRNA. The in vitro cell viability and migration were evaluated prior to in vivo experiments. Further, animals bearing early-stage and advanced Luminal A breast cancer were treated with HNP-siHOXB7, HNP-siHOXB7 + TMX, and TMX. Antitumoral activity and gene expression were evaluated following histopathological, hematological, and biochemical analysis. RESULTS The HNP were efficient in delivering the siRNA in vitro and in vivo, whilst HOXB7 silencing associated with TMX administration promoted controlled tumor growth, as well as a higher survival rate and reduction in immuno- and hepatotoxicity. CONCLUSIONS Therefore, our findings suggest that HOXB7 can be an interesting molecular target for Luminal A breast cancer, especially associated with hormone therapy, aiming for adverse effect mitigation and higher therapeutic efficacy.
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Affiliation(s)
- Ana Beatriz Caribé dos Santos Valle
- Laboratório de Desenvolvimento de Sistemas Nanoestruturados, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Rua José Lourenço Kelmer, Juiz de Fora 36036-900, Brazil; (A.B.C.d.S.V.); (G.D.T.)
| | - Fábio Fernando Alves da Silva
- Instituto de Pesquisas Energéticas e Nucleares, Centro de Radiofarmácia (IPEN/CECRF), Comissão Nacional de Energia Nuclear, São Paulo 05508-000, Brazil; (F.F.A.d.S.); (M.Â.P.C.); (E.S.B.)
| | - Maria Ângela Pepe Carneiro
- Instituto de Pesquisas Energéticas e Nucleares, Centro de Radiofarmácia (IPEN/CECRF), Comissão Nacional de Energia Nuclear, São Paulo 05508-000, Brazil; (F.F.A.d.S.); (M.Â.P.C.); (E.S.B.)
| | - Bruno Espuche
- Soft Matter Laboratory, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramón 194, 20014 Donostia-San Sebastián, Spain; (B.E.); (S.E.M.)
| | - Guilherme Diniz Tavares
- Laboratório de Desenvolvimento de Sistemas Nanoestruturados, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Rua José Lourenço Kelmer, Juiz de Fora 36036-900, Brazil; (A.B.C.d.S.V.); (G.D.T.)
| | - Emerson Soares Bernardes
- Instituto de Pesquisas Energéticas e Nucleares, Centro de Radiofarmácia (IPEN/CECRF), Comissão Nacional de Energia Nuclear, São Paulo 05508-000, Brazil; (F.F.A.d.S.); (M.Â.P.C.); (E.S.B.)
| | - Sergio Enrique Moya
- Soft Matter Laboratory, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramón 194, 20014 Donostia-San Sebastián, Spain; (B.E.); (S.E.M.)
| | - Frederico Pittella
- Laboratório de Desenvolvimento de Sistemas Nanoestruturados, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Rua José Lourenço Kelmer, Juiz de Fora 36036-900, Brazil; (A.B.C.d.S.V.); (G.D.T.)
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Lu Y, Fu W, Xing W, Wu H, Zhang C, Xu D. Transcriptional regulation mechanism of PARP1 and its application in disease treatment. Epigenetics Chromatin 2024; 17:26. [PMID: 39118189 PMCID: PMC11308664 DOI: 10.1186/s13072-024-00550-w] [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: 04/08/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024] Open
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.
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Affiliation(s)
- Yu Lu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
- Hebei University, Baoding, Hebei, P.R. China
| | - Wenliang Fu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Weiwei Xing
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Haowei Wu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Chao Zhang
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China.
| | - Donggang Xu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China.
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Samarelli AV, Tonelli R, Raineri G, Mastrolia I, Costantini M, Fabbiani L, Catani V, Petrachi T, Bruzzi G, Andrisani D, Gozzi F, Marchioni A, Masciale V, Aramini B, Ruggieri V, Grisendi G, Dominici M, Cerri S, Clini E. Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study. Biomedicines 2024; 12:1321. [PMID: 38927528 PMCID: PMC11201217 DOI: 10.3390/biomedicines12061321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. METHODS Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. RESULTS The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50-75%)-measured with high-resolution computer tomography-compared to those with a lower extent (0-25%) (difference between means = 25.74 ± 6.72, p = 0.004). CONCLUSIONS The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF.
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Affiliation(s)
- Anna Valeria Samarelli
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Roberto Tonelli
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Giulia Raineri
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Ilenia Mastrolia
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.C.); (V.M.); (G.G.); (M.D.)
| | - Matteo Costantini
- Pathology Unit, University Hospital of Modena, 41124 Modena, Italy; (M.C.); (L.F.)
| | - Luca Fabbiani
- Pathology Unit, University Hospital of Modena, 41124 Modena, Italy; (M.C.); (L.F.)
| | - Virginia Catani
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.C.); (V.M.); (G.G.); (M.D.)
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41125 Modena, Italy
| | - Tiziana Petrachi
- Technopole “Mario Veronesi”, Via 29 Maggio 6, 41037 Mirandola, Italy;
| | - Giulia Bruzzi
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41125 Modena, Italy
| | - Dario Andrisani
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Filippo Gozzi
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41125 Modena, Italy
| | - Alessandro Marchioni
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Valentina Masciale
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.C.); (V.M.); (G.G.); (M.D.)
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, DIMEC of the Alma Mater Studiorum, University of Bologna, GB Morgagni-L Pierantoni Hospital, 47121 Forlì, Italy;
| | - Valentina Ruggieri
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.C.); (V.M.); (G.G.); (M.D.)
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.C.); (V.M.); (G.G.); (M.D.)
- Department of Oncology and Hematology, University Hospital of Modena, 41124 Modena, Italy
| | - Stefania Cerri
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Enrico Clini
- Respiratory Diseases Unit, University Hospital of Modena, 41124 Modena, Italy; (A.V.S.); (G.R.); (G.B.); (D.A.); (F.G.); (A.M.); (V.R.); (S.C.); (E.C.)
- Laboratory of Cellular Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
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Li C, Mao X, Song L, Sheng J, Yang L, Huang X, Wang L. Unveiling HOXB7 as a novel diagnostic and prognostic biomarker through pan-cancer computer screening. Comput Biol Med 2024; 176:108562. [PMID: 38728993 DOI: 10.1016/j.compbiomed.2024.108562] [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: 02/01/2024] [Revised: 04/11/2024] [Accepted: 05/05/2024] [Indexed: 05/12/2024]
Abstract
We attempted to investigate the role of HOXB7 in tumor progression and evolution by means of an extensive computer screening analysis of various cancer types. We performed univariate Cox regression and Kaplan-Meier survival analyses to assess the impact of HOXB7 on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in different types of cancer. Furthermore, we examined the relationship between HOXB7 and several clinical features: tumor microenvironment, immune regulatory genes, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). We performed gene set enrichment analysis to gain deeper insights into the potential molecular mechanisms of HOXB7, and validated our findings through functional assays in cells, including methyl thiazolyl tetrazolium cytotoxicity and Transwell invasion assays. HOXB7 expression was associated with different clinical characteristics in numerous malignancies. Higher HOXB7 expression was associated with worse OS, DSS, and PFI in some cancer types. In particular, HOXB7 expression was favorably associated with immune cell infiltration, immune regulatory genes, immunological checkpoints, TMB, and MSI in malignancies. Furthermore, we identified a strong link between copper death-associated gene expression and HOXB7 expression. According to the findings of this study, HOXB7 might serve as an appealing focus for tumor diagnosis and immunotherapy and a prospective indicator of prognosis.
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Affiliation(s)
- Cong Li
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China
| | - Xulong Mao
- Department of Cardiology, First School of Clinical Medicine College, Yangtze University, Jingzhou, 434000, China
| | - Lanlan Song
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China
| | - Jueqi Sheng
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China
| | - Lehe Yang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China.
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China.
| | - Liangxing Wang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, 325000, China.
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Schuhwerk H, Brabletz T. Mutual regulation of TGFβ-induced oncogenic EMT, cell cycle progression and the DDR. Semin Cancer Biol 2023; 97:86-103. [PMID: 38029866 DOI: 10.1016/j.semcancer.2023.11.009] [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: 06/27/2023] [Revised: 10/06/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023]
Abstract
TGFβ signaling and the DNA damage response (DDR) are two cellular toolboxes with a strong impact on cancer biology. While TGFβ as a pleiotropic cytokine affects essentially all hallmarks of cancer, the multifunctional DDR mostly orchestrates cell cycle progression, DNA repair, chromatin remodeling and cell death. One oncogenic effect of TGFβ is the partial activation of epithelial-to-mesenchymal transition (EMT), conferring invasiveness, cellular plasticity and resistance to various noxae. Several reports show that both individual networks as well as their interface affect chemo-/radiotherapies. However, the underlying mechanisms remain poorly resolved. EMT often correlates with TGFβ-induced slowing of proliferation, yet numerous studies demonstrate that particularly the co-activated EMT transcription factors counteract anti-proliferative signaling in a partially non-redundant manner. Collectively, evidence piled up over decades underscore a multifaceted, reciprocal inter-connection of TGFβ signaling / EMT with the DDR / cell cycle progression, which we will discuss here. Altogether, we conclude that full cell cycle arrest is barely compatible with the propagation of oncogenic EMT traits and further propose that 'EMT-linked DDR plasticity' is a crucial, yet intricate facet of malignancy, decisively affecting metastasis formation and therapy resistance.
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Affiliation(s)
- Harald Schuhwerk
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
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Chin FW, Chan SC, Veerakumarasivam A. Homeobox Gene Expression Dysregulation as Potential Diagnostic and Prognostic Biomarkers in Bladder Cancer. Diagnostics (Basel) 2023; 13:2641. [PMID: 37627900 PMCID: PMC10453580 DOI: 10.3390/diagnostics13162641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 08/27/2023] Open
Abstract
Homeobox genes serve as master regulatory transcription factors that regulate gene expression during embryogenesis. A homeobox gene may have either tumor-promoting or tumor-suppressive properties depending on the specific organ or cell lineage where it is expressed. The dysregulation of homeobox genes has been reported in various human cancers, including bladder cancer. The dysregulated expression of homeobox genes has been associated with bladder cancer clinical outcomes. Although bladder cancer has high risk of tumor recurrence and progression, it is highly challenging for clinicians to accurately predict the risk of tumor recurrence and progression at the initial point of diagnosis. Cystoscopy is the routine surveillance method used to detect tumor recurrence. However, the procedure causes significant discomfort and pain that results in poor surveillance follow-up amongst patients. Therefore, the development of reliable non-invasive biomarkers for the early detection and monitoring of bladder cancer is crucial. This review provides a comprehensive overview of the diagnostic and prognostic potential of homeobox gene expression dysregulation in bladder cancer.
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Affiliation(s)
- Fee-Wai Chin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia;
| | - Soon-Choy Chan
- School of Liberal Arts, Science and Technology, Perdana University, Kuala Lumpur 50490, Malaysia
| | - Abhi Veerakumarasivam
- School of Medical and Life Sciences, Sunway University, Bandar Sunway 47500, Selangor, Malaysia
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Hayashi T, Kobayashi N, Ushida K, Asai N, Nakano S, Fujii K, Ando T, Utsumi T. Effect of eribulin on epithelial-mesenchymal transition plasticity in metastatic breast cancer: An exploratory, prospective study. Genes Cells 2023; 28:364-373. [PMID: 36849792 DOI: 10.1111/gtc.13019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 02/01/2023] [Accepted: 02/20/2023] [Indexed: 03/01/2023]
Abstract
Epithelial-mesenchymal transition (EMT) plays a pivotal role in cancer metastasis and treatment resistance, which worsens prognosis. In phase III trials, eribulin improved overall survival in metastatic breast cancer (MBC) patients. In preclinical studies, eribulin suppressed EMT. However, clinical data on the use of eribulin for MBC patients are limited. In this exploratory, prospective study, we examined the effect of eribulin on EMT in MBC patients. Twenty-two patients aged 44-82 years with recurrent breast cancer or MBC were treated with eribulin. Breast cancer tissue samples were obtained before treatment and on Day 15 ± 5 of the first cycle of eribulin treatment. EMT markers (E-cadherin, claudin-3, vimentin, and N-cadherin) were analyzed using western blotting. EMT changes were evaluated based on the ratio of epithelial to mesenchymal markers before and after treatment in individual tumors. E-cadherin/vimentin, claudin-3/vimentin, E-cadherin/N-cadherin, and claudin-3/N-cadherin ratios were significantly higher after treatment (p = .007, p = .005, p = .006, and p = .011, respectively). Based on E-cadherin/vimentin, 65.0% of tumors shifted to an epithelial phenotype, as compared to 66.7% based on claudin-3/vimentin, 84.6% based on E-cadherin/N-cadherin, and 71.4% based on claudin-3/N-cadherin ratios. Thus, our results showed that eribulin suppressed EMT in breast cancer tissues.
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Affiliation(s)
- Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Naomi Kobayashi
- Department of Breast Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Aichi, Japan
| | - Kaori Ushida
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Shogo Nakano
- Division of Breast and Endocrine Surgery, Department of Surgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kimihito Fujii
- Division of Breast and Endocrine Surgery, Department of Surgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Takahito Ando
- Division of Breast and Endocrine Surgery, Department of Surgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Toshiaki Utsumi
- Department of Surgery, Fujita Health University School of Medicine, Nagoya, Aichi, Japan
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Wang T, Liu M, Jia M. Integrated Bioinformatic Analysis of the Correlation of HOXA10 Expression with Survival and Immune Cell Infiltration in Lower Grade Glioma. Biochem Genet 2023; 61:238-257. [PMID: 35836029 DOI: 10.1007/s10528-022-10258-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 06/22/2022] [Indexed: 01/24/2023]
Abstract
Homeobox A10 (HOXA10) encodes a transcription factor that regulates developmental processes. Whether HOXA10 mRNA levels in lower grade glioma (LGG) correlate with survival and immune cell infiltration has not been evaluated. The differential expression of HOXA10 in different tumors and their corresponding normal tissues was evaluated by exploring public datasets. The correlations between HOXA10 and survival, tumor immune cell infiltration, diverse gene mutation characteristics, and tumor mutation burden in LGG were also investigated using several independent datasets. Pathway enrichment analysis was conducted to identify HOXA10-associated signaling pathways. We found that HOXA10 expression levels did not significantly differ between LGG tumors and normal tissues. Upon assessing the association between HOXA10 expression and immune cell infiltration in LGG, as expected, HOXA10 gene mRNA levels were positively associated with B-cell and dendritic cell infiltration levels in public online datasets. Different HOXA10 expression groups showed diverse gene mutation characteristics and TMB, and low HOXA10 expression was closely related to improved LGG patient survival. Pathway enrichment analysis of HOXA10-associated genes indicated that the cell cycle signaling pathway may participate in affecting the outcomes of LGG patients. Our findings showed that HOXA10 expression was associated with LGG prognosis and tumor immunity.
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Affiliation(s)
- Ting Wang
- Department of Radiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Abdominal Medical Imaging, Shandong Lung Cancer Institute, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Mingqian Liu
- Department of Hematology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Ming Jia
- Department of Cancer Center, The Secondary Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, China.
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Cell Cycle-Related Gene SPC24: A Novel Potential Diagnostic and Prognostic Biomarker for Laryngeal Squamous Cell Cancer. BIOMED RESEARCH INTERNATIONAL 2023; 2023:1733100. [PMID: 36718148 PMCID: PMC9884166 DOI: 10.1155/2023/1733100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 10/02/2022] [Accepted: 12/27/2022] [Indexed: 01/22/2023]
Abstract
Laryngeal squamous cell cancer (LSCC) is a common malignant tumor with a high degree of malignancy, and its etiology remains unclear. Therefore, screening potential biomarkers is necessary to facilitate the treatment and diagnosis of LSCC. Robust rank aggregation (RRA) analysis was used to integrate two gene expression datasets of LSCC patients from the Gene Expression Omnibus (GEO) database and identify differentially expressed genes (DEGs) between LSCC and nonneoplastic tissues. A gene coexpression network was constructed using weighted gene correlation network analysis (WGCNA) to explore potential associations between the module genes and clinical features of LSCC. Combining differential gene expression analysis and survival analysis, we screened potential hub genes, including CDK1, SPC24, HOXB7, and SELENBP1. Subsequently, western blotting and immunohistochemistry were used to test the protein levels in clinical specimens to verify our findings. Finally, four candidate diagnostic and prognostic biomarkers (CDK1, SPC24, HOXB7, and SELENBP1) were identified. We propose, for the first time, that SPC24 is a gene that may associate with LSCC malignancy and is a novel therapeutic target. These findings may provide important mechanistic insight of LSCC.
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10
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Azuma K, Sakamoto M, Katayama S, Matsui A, Nakamichi K, Goshima N, Watanabe S, Nakayama J, Semba K. HOXB7 induces STAT3-mediated transformation and lung metastasis in immortalized mammary gland NMuMG cells. Genes Cells 2023; 28:277-287. [PMID: 36659836 DOI: 10.1111/gtc.13009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 12/30/2022] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
The homeobox family genes are often dysregulated in various cancer types. Particularly HOXB7 amplification and overexpression correlate with poor prognosis in various cancer such as gastric, pancreatic, and lung cancers. Moreover, HOXB7 is known to contribute to cancer progression by promoting epithelial to mesenchymal transition, anticancer drug resistance, and angiogenesis. In this study, we show that HOXB7 is coamplified with ERBB2 in a subset of breast cancer patients and HOXB7 expression correlates with poor prognosis in HER2-positive breast cancer patients. This clinical observation is supported by the following results-HOXB7 overexpression in an immortalized murine mammary gland epithelial cell line NMuMG induces cellular transformation in vitro, tumorigenesis, and lung metastasis through the activation of JAK-STAT signaling.
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Affiliation(s)
- Kazushi Azuma
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Mai Sakamoto
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.,Computational Bio-Big Data Open Innovation Lab (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Shota Katayama
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Atsuka Matsui
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Kazuya Nakamichi
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Naoki Goshima
- Division of Transcriptome Analysis, Translational Research Center, Fukushima Medical University, Fukushima, Japan.,Functional Proteomics Team, Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.,Department of Human Sciences, Musashino University, Tokyo, Japan
| | - Shinya Watanabe
- Translational Research Center, Fukushima Medical University, Fukushima, Japan
| | - Jun Nakayama
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.,Computational Bio-Big Data Open Innovation Lab (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.,Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kentaro Semba
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.,Translational Research Center, Fukushima Medical University, Fukushima, Japan
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11
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Howard AGA, Uribe RA. Hox proteins as regulators of extracellular matrix interactions during neural crest migration. Differentiation 2022; 128:26-32. [PMID: 36228422 PMCID: PMC10802151 DOI: 10.1016/j.diff.2022.09.003] [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: 08/02/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 01/19/2023]
Abstract
Emerging during embryogenesis, the neural crest are a migratory, transient population of multipotent stem cell that differentiates into various cell types in vertebrates. Neural crest cells arise along the anterior-posterior extent of the neural tube, delaminate and migrate along routes to their final destinations. The factors that orchestrate how neural crest cells undergo delamination and their subsequent sustained migration is not fully understood. This review provides a primer about neural crest epithelial-to-mesenchymal transition (EMT), with a special emphasis on the role of the Extracellular matrix (ECM), cellular effector proteins of EMT, and subsequent migration. We also summarize published findings that link the expression of Hox transcription factors to EMT and ECM modification, thereby implicating Hox factors in regulation of EMT and ECM remodeling during neural crest cell ontogenesis.
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Affiliation(s)
- Aubrey G A Howard
- BioSciences Department, Rice University, Houston, TX, 77005, USA; Biochemistry and Cell Biology Program, Rice University, Houston, TX, 77005, USA
| | - Rosa A Uribe
- BioSciences Department, Rice University, Houston, TX, 77005, USA; Biochemistry and Cell Biology Program, Rice University, Houston, TX, 77005, USA.
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12
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Erfanparast L, Taghizadieh M, Shekarchi AA. Non-Coding RNAs and Oral Cancer: Small Molecules With Big Functions. Front Oncol 2022; 12:914593. [PMID: 35898889 PMCID: PMC9309727 DOI: 10.3389/fonc.2022.914593] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/16/2022] [Indexed: 12/24/2022] Open
Abstract
Oral cancer remains a major public concern with considerable socioeconomic impact in the world. Despite substantial advancements have been made in treating oral cancer, the five-year survival rate for oral cancer remained undesirable, and the molecular mechanisms underlying OSCC carcinogenesis have not been fully understood. Noncoding RNAs (ncRNAs) include transfer RNAs (tRNAs), as well as small RNAs such as microRNAs, and the long ncRNAs such as HOTAIR are a large segment of the transcriptome that do not have apparent protein-coding roles, but they have been verified to play important roles in diverse biological processes, including cancer cell development. Cell death, such as apoptosis, necrosis, and autophagy, plays a vital role in the progression of cancer. A better understanding of the regulatory relationships between ncRNAs and these various types of cancer cell death is therefore urgently required. The occurrence and development of oral cancer can be controlled by increasing or decreasing the expression of ncRNAs, a method which confers broad prospects for oral cancer treatment. Therefore, it is urgent for us to understand the influence of ncRNAs on the development of different modes of oral tumor death, and to evaluate whether ncRNAs have the potential to be used as biological targets for inducing cell death and recurrence of chemotherapy. The purpose of this review is to describe the impact of ncRNAs on cell apoptosis and autophagy in oral cancer in order to explore potential targets for oral cancer therapy.
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Affiliation(s)
- Leila Erfanparast
- Department of Pediatric Dentistry, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Mohammad Taghizadieh,
| | - Ali Akbar Shekarchi
- Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
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13
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Lee MY. Embryonic Programs in Cancer and Metastasis—Insights From the Mammary Gland. Front Cell Dev Biol 2022; 10:938625. [PMID: 35846378 PMCID: PMC9277484 DOI: 10.3389/fcell.2022.938625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/07/2022] [Indexed: 11/24/2022] Open
Abstract
Cancer is characterized as a reversion of a differentiated cell to a primitive cell state that recapitulates, in many aspects, features of embryonic cells. This review explores the current knowledge of developmental mechanisms that are essential for embryonic mouse mammary gland development, with a particular focus on genes and signaling pathway components that are essential for the induction, morphogenesis, and lineage specification of the mammary gland. The roles of these same genes and signaling pathways in mammary gland or breast tumorigenesis and metastasis are then summarized. Strikingly, key embryonic developmental pathways are often reactivated or dysregulated during tumorigenesis and metastasis in processes such as aberrant proliferation, epithelial-to-mesenchymal transition (EMT), and stem cell potency which affects cellular lineage hierarchy. These observations are in line with findings from recent studies using lineage tracing as well as bulk- and single-cell transcriptomics that have uncovered features of embryonic cells in cancer and metastasis through the identification of cell types, cell states and characterisation of their dynamic changes. Given the many overlapping features and similarities of the molecular signatures of normal development and cancer, embryonic molecular signatures could be useful prognostic markers for cancer. In this way, the study of embryonic development will continue to complement the understanding of the mechanisms of cancer and aid in the discovery of novel therapeutic targets and strategies.
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14
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Belpaire M, Taminiau A, Geerts D, Rezsohazy R. HOXA1, a breast cancer oncogene. Biochim Biophys Acta Rev Cancer 2022; 1877:188747. [PMID: 35675857 DOI: 10.1016/j.bbcan.2022.188747] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022]
Abstract
More than 25 years ago, the first literature records mentioned HOXA1 expression in human breast cancer. A few years later, HOXA1 was confirmed as a proper oncogene in mammary tissue. In the following two decades, molecular data about the mode of action of the HOXA1 protein, the factors contributing to activate and maintain HOXA1 gene expression and the identity of its target genes have accumulated and provide a wider view on the association of this transcription factor to breast oncogenesis. Large-scale transcriptomic data gathered from wide cohorts of patients further allowed refining the relationship between breast cancer type and HOXA1 expression. Several recent reports have reviewed the connection between cancer hallmarks and the biology of HOX genes in general. Here we take HOXA1 as a paradigm and propose an extensive overview of the molecular data centered on this oncoprotein, from what its expression modulators, to the interactors contributing to its oncogenic activities, and to the pathways and genes it controls. The data converge to an intricate picture that answers questions on the multi-modality of its oncogene activities, point towards better understanding of breast cancer aetiology and thereby provides an appraisal for treatment opportunities.
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Affiliation(s)
- Magali Belpaire
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Arnaud Taminiau
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Dirk Geerts
- Heart Failure Research Center, Amsterdam University Medical Center (AMC), Universiteit van Amsterdam, Amsterdam, the Netherlands.
| | - René Rezsohazy
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium.
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15
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Sheng J, Zhou M, Wang C, Jia J, Chu J, Ju C, Wan J, He J, He F. Long non-coding RNA BBOX1-AS1 exacerbates esophageal squamous cell carcinoma development by regulating HOXB7/β-catenin axis. Exp Cell Res 2022; 415:113117. [PMID: 35351402 DOI: 10.1016/j.yexcr.2022.113117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023]
Abstract
Mounting evidence suggests that long non-coding RNAs play a critical role in the occurrence and development of human malignancies. Nonetheless, it remains unknown whether Gamma-Butyrobetaine Hydroxylase 1-Antisense RNA 1 (BBOX1-AS1) participates in the regulation of esophageal squamous cell carcinoma (ESCC) carcinogenesis. Herein, we validated that BBOX1-AS1 was notably overexpressed in ESCC tissues compared to the adjacent non-tumor tissues and significantly correlated with tumor sizes. BBOX1-AS1 enhanced the malignant behavior of ESCC cells in vitro, such as cell proliferation, migration, and invasion. In addition, knockdown of BBOX1-AS1 augmented the proportion of apoptotic cells in ESCC cells. Mechanistically, BBOX1-AS1 regulated HOXB7 expression, and rescue experiments indicated that silencing of HOXB7 could abolish the malignant phenotypes mediated by BBOX1-AS1 to a certain extent. Moreover, HOXB7 participated in the activation of the Wnt/β-catenin signaling pathway. In summary, our findings substantiated that BBOX1-AS1 could activate the Wnt/β-catenin pathway by upregulating HOXB7 expression to promote ESCC progression, providing a rationale to develop novel therapeutic approaches.
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Affiliation(s)
- Jinxiu Sheng
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China
| | - Mingxia Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chang Wang
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China
| | - Jinlin Jia
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China
| | - Jie Chu
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China
| | - Chenxi Ju
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China
| | - Junhu Wan
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China.
| | - Jing He
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Fucheng He
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China.
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16
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Barker CG, Petsalaki E, Giudice G, Sero J, Ekpenyong EN, Bakal C, Petsalaki E. Identification of phenotype-specific networks from paired gene expression-cell shape imaging data. Genome Res 2022; 32:750-765. [PMID: 35197309 PMCID: PMC8997347 DOI: 10.1101/gr.276059.121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 02/17/2022] [Indexed: 11/24/2022]
Abstract
The morphology of breast cancer cells is often used as an indicator of tumor severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes in order to undergo epithelial-to-mesenchymal transition and consequently metastasize. However, the exact regulatory systems that define these changes remain poorly characterized. In this study, we used a network-systems approach to integrate imaging data and RNA-seq expression data. Our workflow allowed the discovery of unbiased and context-specific gene expression signatures and cell signaling subnetworks relevant to the regulation of cell shape, rather than focusing on the identification of previously known, but not always representative, pathways. By constructing a cell-shape signaling network from shape-correlated gene expression modules and their upstream regulators, we found central roles for developmental pathways such as WNT and Notch, as well as evidence for the fine control of NF-kB signaling by numerous kinase and transcriptional regulators. Further analysis of our network implicates a gene expression module enriched in the RAP1 signaling pathway as a mediator between the sensing of mechanical stimuli and regulation of NF-kB activity, with specific relevance to cell shape in breast cancer.
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Affiliation(s)
- Charlie George Barker
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, United Kingdom
| | - Eirini Petsalaki
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, United Kingdom
| | - Girolamo Giudice
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, United Kingdom
| | - Julia Sero
- University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom
| | - Emmanuel Nsa Ekpenyong
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, United Kingdom
| | - Chris Bakal
- Institute of Cancer Research, London SW3 6JB, United Kingdom
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, United Kingdom
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17
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Morgan R, Hunter K, Pandha HS. Downstream of the HOX genes: explaining conflicting tumour suppressor and oncogenic functions in cancer. Int J Cancer 2022; 150:1919-1932. [PMID: 35080776 PMCID: PMC9304284 DOI: 10.1002/ijc.33949] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/24/2021] [Accepted: 01/07/2022] [Indexed: 11/07/2022]
Abstract
The HOX genes are a highly conserved group of transcription factors that have key roles in early development, but which are also highly expressed in most cancers. Many studies have found strong associative relationships between the expression of individual HOX genes in tumours and clinical parameters including survival. For the majority of HOX genes, high tumour expression levels seem to be associated with a worse outcome for patients, and in some cases this has been shown to result from the activation of pro-oncogenic genes and pathways. However, there are also many studies that indicate a tumour suppressor role for some HOX genes, sometimes with conclusions that contradict earlier work. In this review, we have attempted to clarify the role of HOX genes in cancer by focusing on their downstream targets as identified in studies that provide experimental evidence for their activation or repression. On this basis, the majority of HOX genes would appear to have a pro-oncogenic function, with the notable exception of HOXD10, which acts exclusively as a tumour suppressor. HOX proteins regulate a wide range of target genes involved in metastasis, cell death, proliferation, and angiogenesis, and activate key cell signalling pathways. Furthermore, for some functionally related targets, this regulation is achieved by a relatively small subgroup of HOX genes.
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Affiliation(s)
- Richard Morgan
- School of Biomedical SciencesUniversity of West LondonLondonUK
| | - Keith Hunter
- Unit of Oral and Maxillofacial Pathology, School of Clinical DentistryUniversity of SheffieldSheffieldUK
| | - Hardev S. Pandha
- Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
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18
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Zhou T, Feng Z, Yang F, Zhu W, Cao J, Hou X, Zhao Y, Chen D. High expression of HOXB7 is an unfavorable prognostic factor for solid malignancies: A meta-analysis. Medicine (Baltimore) 2022; 101:e28564. [PMID: 35060516 PMCID: PMC8772762 DOI: 10.1097/md.0000000000028564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 12/20/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND HOXB7 is abnormally expressed in a variety of tumors, but its prognostic value remains unclear due to sample size limitation and outcome inconsistency in previous studies. This meta-analysis was performed to explore the effect of HOXB7 expression on prognoses and clinicopathological factors in range of the whole solid tumors. METHODS PubMed, EMBASE, and Web of Science databases were searched to identify included studies. Hazard ratios (HR) with its 95% confidence interval (CI) and clinicopathological factors were extracted. Subgroup analyses were performed according to histopathological type, tumor occurrence systems, and HOXB7 detection methods. RESULTS A total of 3430 solid tumors patients from 20 studies (21 cohorts) were included in the meta-analysis. The results showed that high HOXB7 expression was significantly associated with worse survival (overall survival: HR = 1.98, 95%CI: 1.74-2.26, P < .001 and disease-free survival: HR = 1.59, 95%CI: 1.21-2.09, P = .001), more advanced tumor-node-metastasis (TNM) stage (odds ratio [OR] = 2.14, 95%CI: 1.68-2.73, P < .001), positive lymph node metastasis (OR = 2.16, 95%CI: 1.74-2.70, P < .001), more distant metastasis (OR = 1.63, 95%CI: 1.01-2.63, P = .048), poorer differentiation (OR = 1.48, 95%CI: 1.14-1.91, P = .003), and higher Ki-67 expression (OR = 2.53, 95%CI: 1.68-3.84, P < .001). Subgroup analysis showed that survival of patients with HOXB7 high expression was worse in either squamous cell carcinomas or non-squamous cell carcinomas, digestive tumors or non-digestive tumors, and protein level or mRNA level. CONCLUSION High HOXB7 expression might be a valuable biomarker of poor prognosis for solid tumors. HOXB7 promotes tumor proliferation and metastasis, and is associated with poorer differentiation, more advanced stage, even the chemotherapy resistance, suggesting that HOXB7 is a potential therapeutic target for solid tumors.
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Affiliation(s)
- Ting Zhou
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Zonghao Feng
- Department of Obstetrics and Gynecology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Fan Yang
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Weipeng Zhu
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Jiashun Cao
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Xianming Hou
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
| | - Yue Zhao
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, China
| | - Donghong Chen
- Department of Thoracic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, China
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19
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Paço A, Leitão-Castro J, Freitas R. Epigenetic Regulation of CDH1 Is Altered after HOXB7-Silencing in MDA-MB-468 Triple-Negative Breast Cancer Cells. Genes (Basel) 2021; 12:1575. [PMID: 34680970 PMCID: PMC8535730 DOI: 10.3390/genes12101575] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/25/2021] [Accepted: 10/02/2021] [Indexed: 12/14/2022] Open
Abstract
HOXB7 is often overexpressed in breast cancer cells and found to relate to poor prognosis. The search for the HOXB7 targets, as a transcription factor, has led to molecules involved in regulating cell proliferation, migration, invasion, and processes such as angiogenesis and therapy resistance. However, the specific targets affected by the deregulation of HOXB7 in breast cancer remain largely unknown in most molecular sub-types, such as triple-negative breast cancers (TNBC). To unveil the molecular basis behind these aggressive and often untreatable cancers, here we explored the contribution of HOXB7 deregulation for their aggressiveness. To this end, HOXB7 was silenced in TNBC Basal A cells MDA-MB-468, and the phenotype, gene/protein expression, and methylation profile of putative targets were analyzed. Lower migration and invasion rates were detected in HOXB7-silenced cells in comparison with the controls. In addition, these cells expressed more CDH1 and less DNMT3B, and the promoter methylation status of CDH1 diminished. Our data suggest that the HOXB7 transcription factor may act on TNBC Basal A cells by controlling CDH1 epigenetic regulation. This may occur indirectly through the up-regulation of DNMT3B, which then controls DNA methylation of the CDH1 promoter. Thus, future approaches interfering with HOXB7 regulation may be promising therapeutic strategies in TNBC treatment.
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Affiliation(s)
- Ana Paço
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (A.P.); (J.L.-C.)
| | - Joana Leitão-Castro
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (A.P.); (J.L.-C.)
| | - Renata Freitas
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (A.P.); (J.L.-C.)
- ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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20
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Wu X, Li J, Yan T, Ke X, Li X, Zhu Y, Yang J, Li Z. HOXB7 acts as an oncogenic biomarker in head and neck squamous cell carcinoma. Cancer Cell Int 2021; 21:393. [PMID: 34303375 PMCID: PMC8306226 DOI: 10.1186/s12935-021-02093-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/14/2021] [Indexed: 01/01/2023] Open
Abstract
Background The homeobox gene Homeobox B7 (HOXB7) is overexpressed across a range of cancers and promotes tumorigenesis through varying effects on proliferation, survival, migration and invasion. However, its expression pattern and oncogenic role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we aimed to explore the expression pattern of HOXB7, its clinical significance as well as functional roles in HNSCC. Methods HOXB7 mRNA expression in HNSCC was determined by data mining and analyses from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The protein abundance of HOXB7 was measured by immunohistochemistry in 119 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The pro-tumorigenic roles of HOXB7 in HNSCC were further delineated in vitro by loss-of-function assay. And a xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for HOXB7. Results Bioinformatics analyses showed that HOXB7 mRNA was significantly overexpressed in 8 independent HNSCC datasets from TCGA and GEO databases. HOXB7 protein was markedly upregulated in HNSCC samples as compared to normal counterparts and its overexpression significantly associated with high pathological grade, advanced clinical stage, cervical node metastasis (P = 0.0195, 0.0152, 0.0300) and reduced overall and disease-free survival (P = 0.0014, 0.0007). Univariate and multivariate Cox regression analyses further revealed HOXB7 as an independent prognostic factor for patients’ overall survival. Moreover, HOXB7 knockdown significantly inhibited cell proliferation, migration and invasion and induced cell apoptosis in HNSCC cells, and resulted in compromised tumour growth in vivo. Furthermore, CMap (Connectivity map) analysis has identified three potential bioactive small molecule inhibitors (NU-1025, thiamine, vinburnine) for HOXB7 targeted therapy in HNSCC. Conclusions Our findings revealed that overexpression of HOXB7 was associates with tumour aggressiveness and unfavourable prognosis by serving a novel prognostic biomarker in HNSCC. Moreover, HOXB7 might be involved in the development and progression of HNSCC as an oncogene, and thereby might be a potential therapeutic target for HNSCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02093-6.
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Affiliation(s)
- Xiang Wu
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jin Li
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Tingyuan Yan
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xueping Ke
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xin Li
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Yumin Zhu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jianrong Yang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Zhongwu Li
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. .,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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21
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Gong D, Zhu H, Zeng L, Hu R, Hu J, Ding J. Overexpression of HOXA10 promotes the growth and metastasis of nasopharyngeal carcinoma. Exp Biol Med (Maywood) 2021; 246:2454-2462. [PMID: 34293937 DOI: 10.1177/15353702211030854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Deregulation of HOX transcription factor family has frequently been observed in multiple human cancers; however, their role in nasopharyngeal carcinoma remains largely unclear. In the present study, we found that HOX gene family is consistently upregulated in nasopharyngeal carcinoma and identified HOXA10 as one of the mostly upregulated HOX genes. Importantly, we show that HOXA10 overexpression is associated with transcriptional activation of multiple oncogenes essential for nasopharyngeal carcinoma carcinogenesis, including S-phase kinase-associated protein 2 (SKP2), calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), and matrix metalloproteinase 1 (MMP1). Mechanistically, the overexpression of SKP2 induces the degradation of cell cycle inhibitor p27, leading to rapid cell cycle progression and cell proliferation. The overexpression of CAMKK2 is associated with enhanced mTOR signaling activity to meet the increased demand for proteins synthesis in rapid growing nasopharyngeal carcinoma cells. Moreover, MMP1 overexpression facilitates nasopharyngeal carcinoma cell migration and invasion and contributes to cancer metastasis and progression. We thus concluded that HOXA10 overexpression promotes the growth and metastasis of nasopharyngeal carcinoma by transcriptionally activating various oncogenic pathways.
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Affiliation(s)
- Dan Gong
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang 330006, China
| | - Hui Zhu
- Department of Breast Cancer Surgery, Jiangxi Provincial Cancer Hospital, Nanchang 330029, China
| | - Lei Zeng
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang 330006, China
| | - Ronghuan Hu
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang 330006, China
| | - Jiali Hu
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang 330006, China
| | - Jianwu Ding
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang 330006, China
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22
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Kim CY, Kim YC, Oh JH, Kim MH. HOXA5 confers tamoxifen resistance via the PI3K/AKT signaling pathway in ER-positive breast cancer. J Cancer 2021; 12:4626-4637. [PMID: 34149926 PMCID: PMC8210559 DOI: 10.7150/jca.59740] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/19/2021] [Indexed: 12/19/2022] Open
Abstract
Tamoxifen is a commonly used drug to treat estrogen receptor-positive patients with breast cancer. Despite the outstanding efficacy of tamoxifen, approximately one-third of patients develop resistance toward it, thereby presenting a therapeutic challenge. HOX genes may be involved in the acquisition of tamoxifen resistance. In this study, we identified HOXA5, a member of the HOX gene family, as a marker of tamoxifen resistance. Using ChIP assay, we found that HOXA5 expression was significantly overexpressed in tamoxifen-resistant MCF7 (TAMR) breast cancer cells because of reduced H3K27me3 binding. HOXA5 upregulation resulted in activation of the PI3K/AKT signaling cascade, which in turn, led to p53 and p21 reduction, ultimately making the TAMR cells less apoptotic. Furthermore, elevated HOXA5 expression resulted in breast cancer cells acquiring more mesenchymal-like and stem cell traits associated with aggressive breast cancer phenotypes. In conclusion, our results delineate a mechanism by which HOXA5 promotes tumorigenesis, cancer progression, and tamoxifen resistance in breast cancer cells.
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Affiliation(s)
- Clara Yuri Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yu Cheon Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul 03722, Korea
- Department of Anatomy, Graduate School of Medical Science, Bain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Ji Hoon Oh
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Myoung Hee Kim
- Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul 03722, Korea
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23
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de Bessa Garcia SA, Araújo M, Pereira T, Freitas R. HOXB7 Overexpression Leads Triple-Negative Breast Cancer Cells to a Less Aggressive Phenotype. Biomedicines 2021; 9:515. [PMID: 34063128 PMCID: PMC8148148 DOI: 10.3390/biomedicines9050515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 12/14/2022] Open
Abstract
HOX genes appear to play a role in breast cancer progression in a molecular subtype-dependent way. The altered expression of HOXB7, for example, was reported to promote breast cancer progression in specific subtypes. Here we induced HOXB7 overexpression in MDA-MB-231 cells, a cellular model of the Triple-Negative breast cancer molecular subtype, and evaluated the phenotypic changes in cell viability, morphogenesis, migration, invasion, and colony formation. During the phenotypic characterization of the HOXB7-overexpressing cells, we consistently found less aggressive behavior represented by lower cell viability, inhibition of cell migration, invasion, and attachment-independent colony formation capacities added to the more compact and organized spheroid growth in 3D cultures. We then evaluated the expression of putative downstream targets and their direct binding to HOXB7 comparing ChIP-qPCR data generated from HOXB7-overexpressing cells and controls. In the manipulated cells, we found enriched biding of HOXB7 to CTNNB1, EGFR, FGF2, CDH1, DNMT3B, TGFB2, and COMMD7. Taken together, these results highlight the plasticity of the HOXB7 function in breast cancer, according to the cellular genetic background and expression levels, and provide evidence that in Triple-Negative breast cancer cells, HOXB7 overexpression has the potential to promote less aggressive phenotypes.
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Affiliation(s)
| | - Mafalda Araújo
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (M.A.); (T.P.)
| | - Tiago Pereira
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (M.A.); (T.P.)
| | - Renata Freitas
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (M.A.); (T.P.)
- ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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24
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Demény MA, Virág L. The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions. Cancers (Basel) 2021; 13:2057. [PMID: 33923319 PMCID: PMC8123211 DOI: 10.3390/cancers13092057] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/07/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1-3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds.
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Affiliation(s)
- Máté A. Demény
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
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Abstract
Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins.
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26
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Hussain I, Deb P, Chini A, Obaid M, Bhan A, Ansari KI, Mishra BP, Bobzean SA, Udden SMN, Alluri PG, Das HK, Brothers RM, Perrotti LI, Mandal SS. HOXA5 Expression Is Elevated in Breast Cancer and Is Transcriptionally Regulated by Estradiol. Front Genet 2021; 11:592436. [PMID: 33384715 PMCID: PMC7770181 DOI: 10.3389/fgene.2020.592436] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022] Open
Abstract
HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. HOXA5 expression is critical for breast cancer cell viability. Biochemical studies show that estradiol (E2) regulates HOXA5 gene expression in cultured breast cancer cells in vitro. HOXA5 expression is also upregulated in vivo in the mammary tissues of ovariectomized female rats. E2-induced HOXA5 expression is coordinated by ERs. Knockdown of either ERα or ERβ downregulated E2-induced HOXA5 expression. Additionally, ER co-regulators, including CBP/p300 (histone acetylases) and MLL-histone methylases (MLL2, MLL3), histone acetylation-, and H3K4 trimethylation levels are enriched at the HOXA5 promoter in present E2. In summary, our studies demonstrate that HOXA5 is overexpressed in breast cancer and is transcriptionally regulated via estradiol in breast cancer cells.
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Affiliation(s)
- Imran Hussain
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Paromita Deb
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Avisankar Chini
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Monira Obaid
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Arunoday Bhan
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Khairul I Ansari
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Bibhu P Mishra
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
| | - Samara A Bobzean
- Department of Psychology, The University of Texas at Arlington, Arlington, TX, United States
| | - S M Nashir Udden
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Prasanna G Alluri
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Hriday K Das
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Institute for Healthy Aging, Fort Worth, TX, United States
| | - Robert Matthew Brothers
- Department of Kinesiology, The University of Texas at Arlington, Arlington, TX, United States
| | - Linda I Perrotti
- Department of Psychology, The University of Texas at Arlington, Arlington, TX, United States
| | - Subhrangsu S Mandal
- Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States
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Paço A, Aparecida de Bessa Garcia S, Leitão Castro J, Costa-Pinto AR, Freitas R. Roles of the HOX Proteins in Cancer Invasion and Metastasis. Cancers (Basel) 2020; 13:E10. [PMID: 33375038 PMCID: PMC7792759 DOI: 10.3390/cancers13010010] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Invasion and metastasis correspond to the foremost cause of cancer-related death, and the molecular networks behind these two processes are extremely complex and dependent on the intra- and extracellular conditions along with the prime of the premetastatic niche. Currently, several studies suggest an association between the levels of HOX genes expression and cancer cell invasion and metastasis, which favour the formation of novel tumour masses. The deregulation of HOX genes by HMGA2/TET1 signalling and the regulatory effect of noncoding RNAs generated by the HOX loci can also promote invasion and metastasis, interfering with the expression of HOX genes or other genes relevant to these processes. In this review, we present five molecular mechanisms of HOX deregulation by which the HOX clusters products may affect invasion and metastatic processes in solid tumours.
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Affiliation(s)
- Ana Paço
- BLC3—Biomassa Lenho-Celulósica de 3ª Geração, Campus of Technology and Innovation, 3405-169 Oliveira do Hospital, Portugal
| | - Simone Aparecida de Bessa Garcia
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Joana Leitão Castro
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Ana Rita Costa-Pinto
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Renata Freitas
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
- ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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Francis JC, Gardiner JR, Renaud Y, Chauhan R, Weinstein Y, Gomez-Sanchez C, Lefrançois-Martinez AM, Bertherat J, Val P, Swain A. HOX genes promote cell proliferation and are potential therapeutic targets in adrenocortical tumours. Br J Cancer 2020; 124:805-816. [PMID: 33214683 PMCID: PMC7884796 DOI: 10.1038/s41416-020-01166-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 09/23/2020] [Accepted: 10/29/2020] [Indexed: 12/27/2022] Open
Abstract
Background Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment. Methods We used transgenic mouse models to determine the role of Hoxb9 in adrenal tumour development. Patient transcriptomic data was analysed for the expression of HOX genes and their association with disease. Drug response studies on various adrenocortical models were done to establish novel therapeutic options. Results Our human ACC dataset analyses showed high expression of HOXB9, and other HOX factors, are associated with poorer prognosis. Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours. This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne1. Adrenal tumour cells were found to be dependent on HOX function for survival and were sensitive to a specific peptide inhibitor. Conclusions These studies show Hoxb9 can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC.
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Affiliation(s)
- Jeffrey C Francis
- Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK
| | - Jennifer R Gardiner
- Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK
| | - Yoan Renaud
- Genétique Reproduction & Développement, CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 63001, Clermont-Ferrand, France
| | - Ritika Chauhan
- Tumour Profiling Unit, The Institute of Cancer Research, 237 Fulham Road, London, UK
| | - Yacob Weinstein
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel
| | - Celso Gomez-Sanchez
- Division of Endocrinology, Medical Service, G.V. (Sonny) Montgomery VA Medical Center, 1500 E. Woodrow Wilson Dr, Jackson, MS, 39216, USA
| | - Anne-Marie Lefrançois-Martinez
- Genétique Reproduction & Développement, CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 63001, Clermont-Ferrand, France
| | - Jérôme Bertherat
- Institut Cochin, Inserm U1016, CNRS UMR 8104, Université Paris Descartes, UMR-S1016, 75014, Paris, France
| | - Pierre Val
- Genétique Reproduction & Développement, CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 63001, Clermont-Ferrand, France
| | - Amanda Swain
- Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK.
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Bondos SE, Geraldo Mendes G, Jons A. Context-dependent HOX transcription factor function in health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 174:225-262. [PMID: 32828467 DOI: 10.1016/bs.pmbts.2020.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational modifications to regulate cell proliferation, cell death, cell migration, cell differentiation, and angiogenesis. Although mutation and/or mis-expression of HOX proteins during development can be lethal, changes in HOX proteins that do not pattern vital organs can result in survivable malformations. In adults, mutation and/or mis-expression of HOX proteins disrupts their gene regulatory networks, deregulating cell behaviors and leading to arthritis and cancer. On the molecular level, HOX proteins are composed of DNA binding homeodomain, and large regions of unstructured, or intrinsically disordered, protein sequence. The primary roles of HOX proteins in arthritis and cancer suggest that mutations associated with these diseases in both the structured and disordered regions of HOX proteins can have substantial functional effects. These insights lead to new questions critical for understanding and manipulating HOX function in physiological and pathological conditions.
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Affiliation(s)
- Sarah E Bondos
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States.
| | - Gabriela Geraldo Mendes
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States
| | - Amanda Jons
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States
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Garcia SADB, Araújo M, Freitas R. Dataset of HOXB7, HOXB8 and HOXB9 expression profiles in cell lines representative of the breast cancer molecular subtypes Luminal a (MCF7), Luminal b (BT474), HER2+ (SKBR3) and triple-negative (MDA231, MDA468), compared to a model of normal cells (MCF10A). Data Brief 2020; 30:105572. [PMID: 32346580 PMCID: PMC7182708 DOI: 10.1016/j.dib.2020.105572] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 11/22/2022] Open
Abstract
Alterations in HOXB genes expression in breast cancer have been described and related to therapy response and disease progression. However, due to breast cancer complexity and heterogeneity, added to the use of different technical approaches, the observed expression profiles are sometimes contradictory. Here, we provided the analyses of HOXB7, HOXB8 and HOXB9 expression profiles in cell lines extensively used in the literature addressing the putative role of HOXB genes in breast cancer (MCF7, BT474, SKBR3, MDA231 and MDA468) and representative of the clinical breast cancer molecular subtypes (Luminal A, Luminal B, HER2+ and Triple-negatives Claudin-low/Basal), compared to a normal breast model (MCF10A), using quantitative-PCR (qPCR). This technique allows a very sensitive quantification of gene expression and was performed using the fluorophore SYBR Green in order to obtain the expression levels relative to a reference gene, GAPDH in this case. We showed that HOXB7 is upregulated in all breast cancer cells analyzed, while HOXB8 and HOXB9 are significantly upregulated in MCF7 (Luminal A), BT474 (Luminal B) and MDA231 cells (Triple-negative Claudin-low). In addition, we found that the magnitude of the upregulation is highly subtype-specific, being the HER2+ cells the model with lowest HOXB7 upregulation, presenting very low or even null expression for HOXB8 and HOXB9, respectively. These results are analyzed in more detail in "HOX genes function in Breast Cancer development" [1] and are potentially relevant for a better understanding of the molecular heterogeneity of breast cancer, in addition to be a valuable tool assisting researchers in the choice of the most suitable cell models to perform functional assays concerning HOXB7, HOXB8 and HOXB9 genes.
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Affiliation(s)
- Simone Aparecida de Bessa Garcia
- IBMC – Institute for Molecular and Cellular Biology, i3S – Institute for Innovation and Health Research, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Mafalda Araújo
- IBMC – Institute for Molecular and Cellular Biology, i3S – Institute for Innovation and Health Research, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Renata Freitas
- IBMC – Institute for Molecular and Cellular Biology, i3S – Institute for Innovation and Health Research, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- ICBAS – Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
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de Bessa Garcia SA, Araújo M, Pereira T, Mouta J, Freitas R. HOX genes function in Breast Cancer development. Biochim Biophys Acta Rev Cancer 2020; 1873:188358. [PMID: 32147544 DOI: 10.1016/j.bbcan.2020.188358] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 03/03/2020] [Accepted: 03/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer develops in the mammary glands during mammalian adulthood and is considered the second most common type of human carcinoma and the most incident and mortal in the female population. In contrast to other human structures, the female mammary glands continue to develop after birth, undergoing various modifications during pregnancy, lactation and involution under the regulation of hormones and transcription factors, including those encoded by the HOX clusters (A, B, C, and D). Interestingly, HOX gene deregulation is often associated to breast cancer development. Within the HOXB cluster, 8 out of the 10 genes present altered expression levels in breast cancer with an impact in its aggressiveness and resistance to hormone therapy, which highlights the importance of HOXB genes as potential therapeutic targets used to overcome the limitations of tamoxifen-resistant cancer treatments. Here, we review the current state of knowledge on the role of HOX genes in breast cancer, specially focus on HOXB, discussing the causes and consequences of HOXB gene deregulation and their relevance as prognostic factors and therapeutic targets.
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Affiliation(s)
- Simone Aparecida de Bessa Garcia
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Mafalda Araújo
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Tiago Pereira
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - João Mouta
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Renata Freitas
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal.; ICBAS- Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, Portugal..
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Paço A, Freitas R. HOX genes as transcriptional and epigenetic regulators during tumorigenesis and their value as therapeutic targets. Epigenomics 2019; 11:1539-1552. [PMID: 31556724 DOI: 10.2217/epi-2019-0090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Several HOX genes are aberrantly expressed in a wide range of cancers interfering with their development and resistance to treatment. This seems to be often caused by alterations in the methylation profiles of their promoters. The role of HOX gene products in cancer is highly 'tissue specific', relying ultimately on their ability to regulate oncogenes or tumor-suppressor genes, directly as transcriptional regulators or indirectly interfering with the levels of epigenetic regulators. Nowadays, different strategies have been tested the use of HOX genes as therapeutic targets for cancer diagnosis and treatment. Here, we trace the history of the research concerning the involvement of HOX genes in cancer, their connection with epigenetic regulation and their potential use as therapeutic targets.
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Affiliation(s)
- Ana Paço
- Laboratório de Microbiologia do Solo, Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICAAM), Instituto de Investigação e Formação Avançada (IIFA), Universidade de Évora, 7006-554 Évora, Portugal
| | - Renata Freitas
- I3S - Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal.,IBMC - Institute for Molecular & Cell Biology, University of Porto, 4200-135 Porto, Portugal.,ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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Dai L, Hu W, Yang Z, Chen D, He B, Chen Y, Zhou L, Xie H, Wu J, Zheng S. Upregulated expression of HOXB7 in intrahepatic cholangiocarcinoma is associated with tumor cell metastasis and poor prognosis. J Transl Med 2019; 99:736-748. [PMID: 30664713 PMCID: PMC6760572 DOI: 10.1038/s41374-018-0150-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 10/04/2018] [Accepted: 10/08/2018] [Indexed: 02/08/2023] Open
Abstract
Homeobox B7 (HOXB7) protein is reported to be aberrantly expressed in a variety of cancers and to play an important role in multiple cellular processes. However, the specific mechanism by which HOXB7 promotes the malignant progression of intrahepatic cholangiocarcinoma (ICC) remains unclear. Therefore, we used quantitative real-time polymerase chain reaction (PCR) to detect the expression level of HOXB7 in 38 paired ICC tissue samples. Additionally, to assess correlation between HOXB7 and ICC prognosis, we performed immunohistochemistry (IHC) using 122 ICC tissues to detect HOXB7 expression. Cell Counting Kit-8 (CCK-8) and colony formation assays were employed to assess ICC cell proliferation, and Transwell assays were performed to estimate the invasion and migration abilities of ICC cells. The capillary tube formation assay was applied to explore the angiogenic effects of HOXB7. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth and lung metastasis. The results showed higher expression of HOXB7 in ICC tissues than in noncancerous tissues, and this increased expression was significantly associated with a poor prognosis. In addition, HOXB7 overexpression enhanced capillary tube formation, invasion and migration of ICC cells in vitro, whereas HOXB7 knockdown produced the opposite results in vitro. Moreover, the role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that the expression levels of MMP2, MMP9, VEGFa, and IL8 were elevated by HOXB7 and that the ERK pathway was activated. Our results demonstrate the prognostic value of HOXB7 and its role in metastasis and angiogenesis in ICC. HOXB7 upregulated MMP2, MMP9, VEGFa, and IL8 expression via the ERK pathway to accelerate the malignant progression of ICC.
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Affiliation(s)
- Longfei Dai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Wendi Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Zhenjie Yang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Diyu Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Bin He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Yunhao Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, 310000, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, 310000, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China.
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, 310000, China.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, 310000, China.
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China.
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, 310000, China.
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Kuo TL, Cheng KH, Chen LT, Hung WC. Deciphering The Potential Role of Hox Genes in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11050734. [PMID: 31137902 PMCID: PMC6562939 DOI: 10.3390/cancers11050734] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/23/2019] [Accepted: 05/23/2019] [Indexed: 02/06/2023] Open
Abstract
The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. However, the expression of Hox genes in pancreatic tumor tissues has been investigated in only a few studies. In addition, whether specific Hox genes can promote or suppress cancer metastasis is not clear. In this article, we first review the recent progress in studies on the role of Hox genes in pancreatic cancer. By comparing the expression profiles of pancreatic cancer cells isolated from genetically engineered mice established in our laboratory with three different proliferative and metastatic abilities, we identified novel Hox genes that exhibited tumor-promoting activity in pancreatic cancer. Finally, a potential oncogenic mechanism of the Hox genes was hypothesized.
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Affiliation(s)
- Tzu-Lei Kuo
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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Huang L, Ying H, Chen Z, Zhu YL, Gu Y, Hu L, Chen D, Zhong N. Down-regulation of DKK1 and Wnt1/β-catenin pathway by increased homeobox B7 resulted in cell differentiation suppression of intrauterine fetal growth retardation in human placenta. Placenta 2019; 80:27-35. [PMID: 31103063 DOI: 10.1016/j.placenta.2019.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/05/2019] [Accepted: 03/04/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVE This study aimed to test the influence of homeobox B7 (HoxB7) on the proliferation, invasion, and migration of human trophoblast cells and to reveal the down-regulation of HoxB7 on the transcriptional suppression of Dick Kopf-related protein1 (DKK1) and of Cysteine-rich glycosylated wingless protein 1 (Wnt1)/β-catenin in intrauterine fetal growth retardation (FGR). METHODS Quantitative measurement of HoxB7, DKK1, Wnt1, and β-catenin was performed in human placentas collected from normal pregnancies and from FGR with quantitative real time PCR (qRT-PCR). Cultured HTR-8/SVneo cells, transfected with a lentiviral plasmid that in-frame expresses human HoxB7 gene, were applied to functional assessment to study the biological impact of HoxB7 gene on DKK1, Wnt1, and β-catenin. Counting Kit-8, Transwell invasion assays, and flow cytometry were applied for the functional measurements. RESULTS The expression of HoxB7 was significantly increased, and of DKK1, Wnt1, and β-catenin was decreased, in FGR placenta tissues and in HTR-8/SVneo cells. Function studies revealed that overexpression of HoxB7 inhibited proliferation, migration, and invasion in HTR-8/SVneo cells. DKK1, Wnt1, and β-catenin were down-regulated in HTR-8/SVneo cells, inversely correlated with HoxB7 expression. Overexpression of HoxB7 showed a suppressive effect on proliferation, migration, and invasion in the HTR-8/SVneo cells. CONCLUSIONS Our results indicate that HoxB7 inhibited human trophoblast cell differentiation by down-regulating DKK1 expression and that it may affect transcription of Wnt1/β-catenin. The activation of HoxB7 might suppress the cell differentiation in HTR-8/SVneo cell cultures. The Wnt/β-catenin signaling pathway may play a significant role in the pathogenesis of FGR by regulating the invasion and proliferation of trophoblasts.
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Affiliation(s)
- Lu Huang
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China
| | - Hao Ying
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 536 Changle Road, Shanghai, 200040, China
| | - Zhong Chen
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China
| | - Yun Long Zhu
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China
| | - Ying Gu
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China
| | - Lingqing Hu
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China
| | - Daozhen Chen
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China.
| | - Nanbert Zhong
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Huaishuxiang Road, Chong an Street, Wuxi, 214002, China; New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
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Li B, Huang Q, Wei GH. The Role of HOX Transcription Factors in Cancer Predisposition and Progression. Cancers (Basel) 2019; 11:cancers11040528. [PMID: 31013831 PMCID: PMC6520925 DOI: 10.3390/cancers11040528] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 12/12/2022] Open
Abstract
Homeobox (HOX) transcription factors, encoded by a subset of homeodomain superfamily genes, play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Findings over the past decade have revealed that mutations in HOX genes can lead to increased cancer predisposition, and HOX genes might mediate the effect of many other cancer susceptibility factors by recognizing or executing altered genetic information. Remarkably, several lines of evidence highlight the interplays between HOX transcription factors and cancer risk loci discovered by genome-wide association studies, thereby gaining molecular and biological insight into cancer etiology. In addition, deregulated HOX gene expression impacts various aspects of cancer progression, including tumor angiogenesis, cell autophagy, proliferation, apoptosis, tumor cell migration, and metabolism. In this review, we will discuss the fundamental roles of HOX genes in cancer susceptibility and progression, highlighting multiple molecular mechanisms of HOX involved gene misregulation, as well as their potential implications in clinical practice.
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Affiliation(s)
- Bo Li
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China.
| | - Qilai Huang
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China.
| | - Gong-Hong Wei
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland.
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A Case of Identity: HOX Genes in Normal and Cancer Stem Cells. Cancers (Basel) 2019; 11:cancers11040512. [PMID: 30974862 PMCID: PMC6521190 DOI: 10.3390/cancers11040512] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/08/2019] [Accepted: 04/09/2019] [Indexed: 12/14/2022] Open
Abstract
Stem cells are undifferentiated cells that have the unique ability to self-renew and differentiate into many different cell types. Their function is controlled by core gene networks whose misregulation can result in aberrant stem cell function and defects of regeneration or neoplasia. HOX genes are master regulators of cell identity and cell fate during embryonic development. They play a crucial role in embryonic stem cell differentiation into specific lineages and their expression is maintained in adult stem cells along differentiation hierarchies. Aberrant HOX gene expression is found in several cancers where they can function as either oncogenes by sustaining cell proliferation or tumor-suppressor genes by controlling cell differentiation. Emerging evidence shows that abnormal expression of HOX genes is involved in the transformation of adult stem cells into cancer stem cells. Cancer stem cells have been identified in most malignancies and proved to be responsible for cancer initiation, recurrence, and metastasis. In this review, we consider the role of HOX genes in normal and cancer stem cells and discuss how the modulation of HOX gene function could lead to the development of novel therapeutic strategies that target cancer stem cells to halt tumor initiation, progression, and resistance to treatment.
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Hatanaka Y, de Velasco MA, Oki T, Shimizu N, Nozawa M, Yoshimura K, Yoshikawa K, Nishio K, Uemura H. HOXA10 expression profiling in prostate cancer. Prostate 2019; 79:554-563. [PMID: 30614022 DOI: 10.1002/pros.23761] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/13/2018] [Indexed: 01/29/2023]
Abstract
BACKGROUND HOX genes encode transcription factors that play key roles in modulating normal tissue morphogenesis, differentiation and homeostasis. Disruption of normal HOX gene expression occurs frequently in human cancers and is associated with both tumor promoting and suppressing activities. Among these is, HOXA10, a pleiotropic gene that is critical for normal prostate development. In this study we characterized HOXA10 expression in human and mouse PCa to gain insights into its clinical significance. METHODS A meta-analysis of HOXA10 mRNA expression was carried out across several publicly available data sets. Expression of HOXA10 protein expression was assessed by immunohistochemistry (IHC) using human radical prostatectomy (RP) cases. We correlated HOXA10 expression to clinicopathological features and investigated its relationship to biochemical recurrence (BCR) after RP by the Kaplan-Meier method. HOXA10 mRNA and IHC protein expression was also examined in a mouse model of Pten-null PCa. RESULTS A meta-analysis of HOXA10 gene expression indicated dysregulated expression of HOXA10 in human PCa. IHC profiling of HOXA10 revealed inverse correlations between HOXA10 expression and Gleason pattern, Gleason score, and pathological stage (P < 0.01). Patients with low expression profiles of HOXA10 were associated with a higher risk of BCR, (OR, 3.54; 95%CI, 1.21-16.14; P = 0.049) whereas patients with high HOXA10 expression experienced longer times to BCR (P = 0.045). However, HOXA10 was not an independent predictor of BCR (OR, 1.52; 95%CI, 0.42-5.54; P = 0.52). Evaluation of expression patterns of HOXA10 in mouse prostate tumors mimicked that of humans. CONCLUSIONS Our findings show that HOXA10 expression is inversely associated with tumor differentiation and high HOXA10 expression is associated with improved BCR-free survival. This study provides human and mouse evidence to suggest tumor suppressive roles for HOXA10 in the context of prostate cancer.
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Affiliation(s)
- Yuji Hatanaka
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Marco A de Velasco
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Takashi Oki
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Nobutaka Shimizu
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masahiro Nozawa
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kazuhiro Yoshimura
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kazuhiro Yoshikawa
- Promoting Center for Clinical Research, Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Song Z, Liao Z, Cui Y, Yang C. The relationship between homeobox B7 expression and the clinical characteristics of patient with prostate cancer. J Cell Biochem 2019; 120:6395-6401. [PMID: 30317675 DOI: 10.1002/jcb.27926] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/25/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND The prognosis of patients with prostate cancer (PCa) remains poor. METHODS GSE16560, GSE32448, GSE79957, GSE17951, and TCGA-PRAD were reanalyzed to evaluate the expression of homeobox B7 (HOXB7) between PCa tissues and normal prostate tissues and to characterize the correlation between the expression of HOXB7 and the clinicopathological features of patients with PCa. Gene set enrichment analysis was conducted to investigate the mechanisms. RESULTS HOXB7 was upregulated in PCa tissues (P = 0.0005). Both the univariate and multivariate analyses demonstrated that the expression of HOXB7 was correlated with the Gleason score and TNM staging of patients with PCa. The Gleason score and TNM staging were higher in the HOXB7 high expression group. The overall survival (hazard ratio [HR] = 0.632; 95% confidence interval [CI]: 0.4773-0.8369; P = 0.0014) and progression-free survival (HR = 0.544; 95% CI: 0.3157-0.9373; P = 0.0283) favored patients with PCa in HOXB7 low expression group over those in HOXB7 high expression group. PCa samples in HOXB7 low expression group were enriched in gene sets associated with the epithelial mesenchymal transition, apical junction, angiogenesis, ultraviolet response, and hypoxia. CONCLUSIONS HOXB7 might be an independent prognostic factor of patients with PCa.
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Affiliation(s)
- Zhangxing Song
- Department of Urology, The National Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei Province, China
| | - Zhaolin Liao
- Department of Urology, The National Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei Province, China
| | - Yingdong Cui
- Department of Urology, The National Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei Province, China
| | - Chao Yang
- Department of Urology, The National Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei Province, China
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Zhong Y, Zhang Y, Ma D, Ren X, Xu C, Wan D. Inhibition of HOXB7 suppresses p27-mediated acute lymphoblastic leukemia by regulating basic fibroblast growth factor and ERK1/2. Life Sci 2019; 218:1-7. [DOI: 10.1016/j.lfs.2018.12.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 01/30/2023]
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Gao D, Chen HQ. Specific knockdown of HOXB7 inhibits cutaneous squamous cell carcinoma cell migration and invasion while inducing apoptosis via the Wnt/β-catenin signaling pathway. Am J Physiol Cell Physiol 2018; 315:C675-C686. [PMID: 30067384 DOI: 10.1152/ajpcell.00291.2017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metastatic cutaneous squamous cell carcinoma (CSCC) is a major cause of death associated with nonmelanoma skin cancer. The involvement of homeobox B7 ( HOXB7) in cancers has been reported. Thus, the current study intends to explore the effect of HOXB7 on CSCC and its relationship with the Wnt/β-catenin signaling pathway. Initially, microarray-based gene expression profiling of CSCC was performed, and HOXB7 was identified as an upregulated gene based on the microarray data of GSE66359 . Following this, the experimental results indicated that HOXB7 and β-catenin formed a composite, demonstrating that endogenous HOXB7 binds to β-catenin. Subsequently, CSCC cells were treated with siRNA against HOXB7 or an inhibitor of the Wnt/β-catenin signaling pathway to analyze any underlying regulatory mechanism of HOXB7 on the CSCC cells. Tumor growth involving xenografts in nude mice was also observed so as to explore whether or not HOXB7 could regulate subcutaneous tumor growth through in vivo culturing. To investigate the potential effects of HOXB7 on the Wnt/β-catenin signaling pathway, we determined the expression of HOXB7 and downstream genes of the Wnt/β-catenin signaling pathway. Notably, siRNA-mediated knockdown of HOXB7 inhibited the activation of the Wnt/β-catenin signaling pathway, thereby impeding the progression of cell viability, migration, and invasion as well as of the tumor growth, although contrarily facilitating cell apoptosis. Taken together, silencing of the HOXB7 has the mechanism of inactivating the Wnt/β-catenin signaling pathway, thereby accelerating cell apoptosis and suppressing cell migration and invasion in CSCC, which could provide a candidate target for the CSCC treatment.
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Affiliation(s)
- Dong Gao
- Department of Dermatology, Yantai Yu Huang Ding Hospital, Yantai, People’s Republic of China
| | - Hong-Quan Chen
- Department of Dermatology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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Collord G, Tarpey P, Kurbatova N, Martincorena I, Moran S, Castro M, Nagy T, Bignell G, Maura F, Young MD, Berna J, Tubio JMC, McMurran CE, Young AMH, Sanders M, Noorani I, Price SJ, Watts C, Leipnitz E, Kirsch M, Schackert G, Pearson D, Devadass A, Ram Z, Collins VP, Allinson K, Jenkinson MD, Zakaria R, Syed K, Hanemann CO, Dunn J, McDermott MW, Kirollos RW, Vassiliou GS, Esteller M, Behjati S, Brazma A, Santarius T, McDermott U. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures. Sci Rep 2018; 8:13537. [PMID: 30202034 PMCID: PMC6131140 DOI: 10.1038/s41598-018-31659-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/16/2018] [Indexed: 12/21/2022] Open
Abstract
Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
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Affiliation(s)
- Grace Collord
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Patrick Tarpey
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Natalja Kurbatova
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
| | - Inigo Martincorena
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Sebastian Moran
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Manuel Castro
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Tibor Nagy
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Graham Bignell
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Francesco Maura
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Matthew D Young
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Jorge Berna
- Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, 15706, Spain
| | - Jose M C Tubio
- Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, 15706, Spain
| | - Chris E McMurran
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Adam M H Young
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Mathijs Sanders
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Erasmus University Medical Center, Department of Hematology, Rotterdam, The Netherlands
| | - Imran Noorani
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Stephen J Price
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Colin Watts
- Department of Neurosurgery, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Elke Leipnitz
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Matthias Kirsch
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Gabriele Schackert
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Danita Pearson
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Abel Devadass
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Zvi Ram
- Department of Neurosurgery, Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - V Peter Collins
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Kieren Allinson
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Michael D Jenkinson
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, L9 7LJ, UK
| | - Rasheed Zakaria
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Integrative Biology, University of Liverpool, Liverpool, L9 7LJ, UK
| | - Khaja Syed
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Integrative Biology, University of Liverpool, Liverpool, L9 7LJ, UK
| | - C Oliver Hanemann
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK
| | - Jemma Dunn
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK
| | - Michael W McDermott
- Department of Neurosurgery, UCSF Medical Center, San Francisco, CA, 94143-0112, USA
| | - Ramez W Kirollos
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - George S Vassiliou
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Sam Behjati
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Alvis Brazma
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
| | - Thomas Santarius
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
| | - Ultan McDermott
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
- Institute of Translational Medicine, University of Liverpool, Liverpool, L9 7LJ, UK.
- AstraZeneca, CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
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43
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Platais C, Radhakrishnan R, Ebensberger SN, Morgan R, Lambert DW, Hunter KD. Targeting HOX-PBX interactions causes death in oral potentially malignant and squamous carcinoma cells but not normal oral keratinocytes. BMC Cancer 2018; 18:723. [PMID: 29980182 PMCID: PMC6035449 DOI: 10.1186/s12885-018-4622-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 06/20/2018] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND High HOX gene expression has been described in many cancers, including oral squamous cell carcinoma and the functional roles of these genes are gradually being understood. The pattern of overexpression suggests that inhibition may be useful therapeutically. Inhibition of HOX protein binding to PBX cofactors by the use of synthetic peptides, such as HXR9, results in apoptosis in multiple cancers. METHODS Activity of the HOX-PBX inhibiting peptide HXR9 was tested in immortalised normal oral (NOK), potentially-malignant (PMOL) and squamous cell carcinoma (OSCC) cells, compared to the inactive peptide CXR9. Cytotoxicity was assessed by LDH assay. Expression of PBX1/2 and c-Fos was assessed by qPCR and western blotting. Apoptosis was assessed by Annexin-V assay. RESULTS PMOL and OSCC cells expressed PBX1/2. HOX-PBX inhibition by HXR9 caused death of PMOL and OSCC cells, but not NOKs. HXR9 treatment resulted in apoptosis and increased expression of c-Fos in some cells, whereas CXR9 did not. A correlation was observed between HOX expression and resistance to HXR9. CONCLUSION Inhibition of HOX-PBX interactions causes selective apoptosis of OSCC/PMOL, indicating selective toxicity that may be useful clinically.
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Affiliation(s)
- Christopher Platais
- Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Raghu Radhakrishnan
- Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Sven Niklander Ebensberger
- Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
- Facultad de Odontologia, Universidad Andres Bello, av. Valparaiso, 1560 Viña del Mar, Chile
| | - Richard Morgan
- Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Daniel W. Lambert
- Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Keith D. Hunter
- Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
- Department of Oral Biology and Pathology, University of Pretoria, Pretoria, South Africa
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44
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Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers. Sci Rep 2018; 8:7326. [PMID: 29743718 PMCID: PMC5943339 DOI: 10.1038/s41598-018-25512-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 04/23/2018] [Indexed: 12/22/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC.
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45
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Lou Y, Fallah Y, Yamane K, Berg PE. BP1, a potential biomarker for breast cancer prognosis. Biomark Med 2018; 12:535-545. [DOI: 10.2217/bmm-2017-0212] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Homeobox genes are critical in tumor development. An isoform protein of DLX4 called BP1 is expressed in 80% of invasive ductal breast carcinomas. BP1 overexpression is implicated in an aggressive phenotype and poor prognosis. BP1 upregulation is associated with estrogen receptor negativity so those tumors do not respond to antiestrogens. Breast cancer is the second leading cause of death in women. BP1 could serve as both a novel prognostic biomarker for breast cancer and a therapeutic target. In this review, we address the role of BP1 protein in tumorigenesis of breast cancer and four other malignancies. A number of functions of BP1 in cancer are also discussed.
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Affiliation(s)
- Yaoxian Lou
- Department of Biochemistry & Molecular Medicine, George Washington University, Washington, DC 20037, USA
| | - Yassi Fallah
- Department of Oncology, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA
| | - Kellie Yamane
- NantOmics, Diagnostic Center in Montgomery County, Rockville, MD 20850, USA
| | - Patricia E Berg
- Department of Biochemistry & Molecular Medicine, George Washington University, Washington, DC 20037, USA
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46
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Monterisi S, Lo Riso P, Russo K, Bertalot G, Vecchi M, Testa G, Di Fiore PP, Bianchi F. HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype. Oncogene 2018; 37:3575-3588. [PMID: 29576613 DOI: 10.1038/s41388-018-0229-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/31/2018] [Accepted: 02/28/2018] [Indexed: 12/24/2022]
Abstract
HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.
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Affiliation(s)
- Simona Monterisi
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy.,IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy.,Humanitas Clinical and Research Center, 20089 Rozzano (MI), Italy
| | - Pietro Lo Riso
- Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy
| | - Karin Russo
- IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy
| | - Giovanni Bertalot
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy
| | - Manuela Vecchi
- IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy
| | - Giuseppe Testa
- Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy.,DIPO, Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
| | - Pier Paolo Di Fiore
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy.,IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy.,DIPO, Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy
| | - Fabrizio Bianchi
- Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy. .,ISBREMIT, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (FG), Italy.
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47
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He X, Liu Z, Xia Y, Xu J, Lv G, Wang L, Ma T, Jiang L, Mou Y, Jiang X, Ma J, Zhao Z, Ni H, Xu W, Ru G, Huang D, Tao H. HOXB7 overexpression promotes cell proliferation and correlates with poor prognosis in gastric cancer patients by inducing expression of both AKT and MARKs. Oncotarget 2018; 8:1247-1261. [PMID: 27901487 PMCID: PMC5352052 DOI: 10.18632/oncotarget.13604] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 11/11/2016] [Indexed: 12/23/2022] Open
Abstract
Increased expression of HOXB7 has been reported to correlate with the progression in many cancers. However, the specific mechanism by which it promotes the evolution of gastric cancer (GC) is poorly understood.In this study, we sought to investigate the role of HOXB7 in GC by assessing HOXB7 expression in patient tissue and its correlation to clinical characteristics. We found that GC tissues showed increased expression of HOXB7 and that the HOXB7 expression was significantly associated with Lauren classification, invasion depth, lymphatic metastasis and poor prognosis, and could serve as an independent prognostic factor. To further investigate the role of HOXB7 in GC, we generated stable GC cell lines and both over-expressed and knocked down HOXB7 expression. Over-expression of HOXB7 in GC cell lines enhanced cell proliferation, colony formation, migration and invasion ability, whereas the opposite trends were observed upon reduction of HOXB7 expression by knockdown. These findings were further supported by our in vivo studies which show that HOXB7 expression can affect the GC cells' subcutaneous growth and lung metastases. A Phospho-MAPK Array Kit was used to explore the possible mechanism of HOXB7-induced cell proliferation and invasion. We found that the AKT signaling pathway and the two members of the MAPK pathway, were involved in those promoting effects. In conclusion, our results showed that increased expression of HOXB7 might play an important role in promoting GC proliferation, migration and invasion by inducing both AKT and MAPK pathways, thus resulting in progression of, and poor prognosis in GC patients.
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Affiliation(s)
- Xujun He
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Zhengchuang Liu
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Yingjie Xia
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Ji Xu
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China.,Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Guocai Lv
- Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.,Key Laboratory of Clinical In vitro Diagnostic Techniques of Zhejiang Province, Hangzhou 310003, China
| | - Lu Wang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Tonghui Ma
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Liping Jiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Yiping Mou
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China.,Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Xiaoting Jiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China.,Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Zhongkuo Zhao
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China.,Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Haibin Ni
- Department of Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang, China
| | - Wenjuan Xu
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China.,Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Guoqing Ru
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China.,Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Dongsheng Huang
- Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
| | - Houquan Tao
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China.,Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China
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48
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Liu H, Zhang M, Xu S, Zhang J, Zou J, Yang C, Zhang Y, Gong C, Kai Y, Li Y. HOXC8 promotes proliferation and migration through transcriptional up-regulation of TGFβ1 in non-small cell lung cancer. Oncogenesis 2018; 7:1. [PMID: 29367650 PMCID: PMC5833702 DOI: 10.1038/s41389-017-0016-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 11/02/2017] [Accepted: 11/23/2017] [Indexed: 12/22/2022] Open
Abstract
Homeobox (HOX) genes encode a family of transcription factors, which play crucial roles in numerous processes, and their dysregulation is involved in the carcinogenesis of many human cancers. In the present study, we investigated the roles of HOXC8 in non-small cell lung cancer (NSCLC). We showed that HOXC8 was upregulated in clinical NSCLC specimens compared to normal lung tissues, and the high expression of HOXC8 correlated with tumor node metastasis (TNM) stage, tumor status, lymph nodal status and poor relapse-free survival for lung cancer patients. Functionally, HOXC8 expression significantly promoted the proliferation, anchorage-independent growth and migration of NSCLC, and HOXC8 functioned as a transcription activator to induce the expression of TGFβ1, leading to an increase in the proliferation, anchorage-independent growth and migration of NSCLC. Furthermore, we demonstrated that HOXC8 expression was associated with chemoresistance and anti-apoptosis in NSCLC, suggesting that HOXC8 is a promising therapeutic target for chemosensitization of NSCLC to cisplatin. Altogether, our study defined a critical role of HOXC8 in promoting transcription of TGFβ1 and NSCLC tumorigenesis.
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Affiliation(s)
- Houli Liu
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Mingsheng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shanshan Xu
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Jie Zhang
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Jin Zou
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Chenchen Yang
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Yang Zhang
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Chen Gong
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Yuanzhong Kai
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China
| | - Yong Li
- School of Life Sciences, Anhui University, Hefei, Anhui Province, China.
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49
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Bonfim-Silva R, Ferreira Melo FU, Thomé CH, Abraham KJ, De Souza FAL, Ramalho FS, Machado HR, De Oliveira RS, Cardoso AA, Covas DT, Fontes AM. Functional analysis of HOXA10 and HOXB4 in human medulloblastoma cell lines. Int J Oncol 2017; 51:1929-1940. [PMID: 29039487 DOI: 10.3892/ijo.2017.4151] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 09/28/2017] [Indexed: 11/06/2022] Open
Abstract
Medulloblastoma (MB) is a malignant childhood brain tumor which at molecular level is classified into at least four major subtypes: WNT, SHH, group C and group D differing in response to treatment. Previous studies have associated changes in expression levels and activation of certain HOX genes with MB development. In the present study, we investigate the role of HOX genes in two attributes acquired by tumor cells: migration and proliferation potential, as well as, in vivo tumorigenic potential. We analyzed UW402, UW473, DAOY and ONS-76 human pediatric MB cell lines and cerebellum primary cultures. Two-color microarray-based gene expression analysis was used to identify differentially expressed HOX genes. Among the various HOX genes significantly overexpressed in DAOY and ONS-76 cell lines compared to UW402 and UW473 cell lines, HOXA10 and HOXB4 were selected for further analysis. The expression levels of these HOX genes were validated by real-time PCR. A mouse model was used to study the effect of the HOXA10 and HOXB4 genes on the in vivo tumorigenic potential and the in vitro proliferative and migration potential of MB cell lines. Our results show that the inhibition of HOXA10 in DAOY cell line led to increased in vitro cell migration while in vitro cell proliferation or in vivo tumorigenic potential were unaffected. We also observed that induced expression of HOXB4 in the UW473 cell line significantly reduced in vitro cell proliferation and migration capability of UW473 cells with no effect on the in vivo tumorigenicity. This suggests that HOXA10 plays a role in migration events and the HOXB4 gene is involved in proliferation and migration processes of medulloblastoma cells, however, it appears that these genes are not essential for the tumorigenic process of these cells.
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Affiliation(s)
- Ricardo Bonfim-Silva
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Fernanda Ursoli Ferreira Melo
- Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Carolina Hassibe Thomé
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Kuruvilla Joseph Abraham
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Fábio Augusto Labre De Souza
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Fernando Silva Ramalho
- Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Hélio Rubens Machado
- Division of Pediatric Neurosurgery of the Department of Surgery and Anatomy, University Hospital of Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Ricardo Santos De Oliveira
- Division of Pediatric Neurosurgery of the Department of Surgery and Anatomy, University Hospital of Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Angelo A Cardoso
- Center for Gene Therapy, City of Hope Alpha Stem Cell Clinic, Duarte, CA 91010, USA
| | - Dimas Tadeu Covas
- Department of Internal Medicine, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
| | - Aparecida Maria Fontes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil
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Assessment of potential miRNA biomarkers of VERO-cell tumorigenicity in a new line (AGMK1-9T7) of African green monkey kidney cells. Vaccine 2017; 35:5503-5509. [DOI: 10.1016/j.vaccine.2017.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 03/30/2017] [Accepted: 04/04/2017] [Indexed: 11/18/2022]
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