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Broso F, Gatto P, Sidarovich V, Ambrosini C, De Sanctis V, Bertorelli R, Zaccheroni E, Ricci B, Destefanis E, Longhi S, Sebastiani E, Tebaldi T, Adami V, Quattrone A. Alpha-1 Adrenergic Antagonists Sensitize Neuroblastoma to Therapeutic Differentiation. Cancer Res 2023; 83:2733-2749. [PMID: 37289021 DOI: 10.1158/0008-5472.can-22-1913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 03/28/2023] [Accepted: 06/02/2023] [Indexed: 06/09/2023]
Abstract
Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using α1/α1B adrenergic antagonists led to selective sensitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activity. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the α1B adrenergic receptor as a pharmacologic target in NB, supporting the evaluation of adding α1-antagonists to the post-consolidation therapy of NB to more efficiently control residual disease. SIGNIFICANCE Targeting α-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse.
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Affiliation(s)
- Francesca Broso
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Pamela Gatto
- High-Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Viktoryia Sidarovich
- High-Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Chiara Ambrosini
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Veronica De Sanctis
- Next Generation Sequencing (NGS) Core Facility LaBSSAH, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Roberto Bertorelli
- Next Generation Sequencing (NGS) Core Facility LaBSSAH, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Elena Zaccheroni
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Benedetta Ricci
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Eliana Destefanis
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Sara Longhi
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Enrico Sebastiani
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Toma Tebaldi
- Laboratory of RNA and Disease Data Science, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
- Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Valentina Adami
- High-Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Alessandro Quattrone
- Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
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Abstract
"De novo" genes evolve from previously non-genic DNA. This strikes many of us as remarkable, because it seems extraordinarily unlikely that random sequence would produce a functional gene. How is this possible? In this two-part review, I first summarize what is known about the origins and molecular functions of the small number of de novo genes for which such information is available. I then speculate on what these examples may tell us about how de novo genes manage to emerge despite what seem like enormous opposing odds.
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Affiliation(s)
- Caroline M Weisman
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
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3
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Segura-Bautista D, Maya-Nunez G, Aguilar-Rojas A, Huerta-Reyes M, Pérez-Solis MA. Contribution of Stemness-linked Transcription Regulators to the Progression of Breast Cancer. Curr Mol Med 2021; 22:766-778. [PMID: 34819003 DOI: 10.2174/1566524021666211124154803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 05/05/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022]
Abstract
Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial-Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.
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Affiliation(s)
- David Segura-Bautista
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Guadalupe Maya-Nunez
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Arturo Aguilar-Rojas
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Maira Huerta-Reyes
- Medical Research Unit in Nephrological Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Marco Allan Pérez-Solis
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
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4
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Liang E, Lu Y, Shi Y, Zhou Q, Zhi F. MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity. Oncogene 2020; 39:6437-6450. [PMID: 32879444 DOI: 10.1038/s41388-020-01443-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 08/05/2020] [Accepted: 08/21/2020] [Indexed: 01/07/2023]
Abstract
Emerging evidence indicates that myeloma overexpressed (MYEOV) is an oncogene and plays crucial roles in multiple human cancers. However, its roles in the development of pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we provide evidence of essential roles of MYEOV in the development and progression of PDAC. In tumor specimens derived from pancreatic cancer patients, MYEOV was overexpressed and associated with poor prognosis. In addition, MYEOV expression in PDAC was upregulated through promoter hypomethylation. MYEOV depletion impaired metastatic ability and proliferation of PDAC cells both in vitro and in vivo, whereas its overexpression had the opposite effect. Mechanistic investigations revealed that MYEOV interacted with SRY-Box Transcription Factor 9 (SOX9), a well-known oncogenic transcription factor in PDAC. This interaction occurred mainly in the nuclei of PDAC cells and increased transcriptional activity of SOX9. Furthermore, MYEOV promoted the expression of Hairy and enhancer of split homolog-1 (HES1), a SOX9 target gene, by enhancing SOX9 DNA-binding ability to the HES1 enhancer without affecting the protein level and subcellular localization of SOX9. HES1 knockdown partly abrogated the oncogenic effect of MYEOV. Our findings suggest that MYEOV could be a potential prognostic biomarker and therapeutic target for PDAC.
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Affiliation(s)
- Erbo Liang
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Yishi Lu
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Yanqiang Shi
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Qian Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
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5
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Jana S, Madhu Krishna B, Singhal J, Horne D, Awasthi S, Salgia R, Singhal SS. SOX9: The master regulator of cell fate in breast cancer. Biochem Pharmacol 2020; 174:113789. [PMID: 31911091 PMCID: PMC9048250 DOI: 10.1016/j.bcp.2019.113789] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes. Of note, the molecular mechanisms and functional regulation underlying SOX9 upregulation during BC progression are still being uncovered. The focus of this review is to appraise recent advances regarding the involvement of SOX9 in BC pathogenesis. First, we provide a general overview of SOX9 structure and function, as well as its involvement in various kinds of cancer. Next, we discuss pathways of SOX9 regulation, particularly its miRNA-mediated regulation, in BC. Finally, we describe the involvement of SOX9 in BC pathogenesis via its regulation of pathways involved in regulating cancer hallmarks, as well as its clinical and therapeutic importance. In general, this review article aims to serve as an ample source of knowledge on the involvement of SOX9 in BC progression. Targeting SOX9 activity may improve therapeutic strategies to treat BC, but precisely inhibiting SOX9 using drugs and/or small peptides remains a huge challenge for forthcoming cancer research.
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Affiliation(s)
- Samir Jana
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - B Madhu Krishna
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Jyotsana Singhal
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sanjay Awasthi
- Department of Internal Medicine, Division of Hematology & Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ravi Salgia
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
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6
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MicroRNA-30e inhibits proliferation and invasion of non-small cell lung cancer via targeting SOX9. Hum Cell 2019; 32:326-333. [DOI: 10.1007/s13577-018-0223-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 11/07/2018] [Indexed: 12/24/2022]
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7
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Huang JQ, Wei FK, Xu XL, Ye SX, Song JW, Ding PK, Zhu J, Li HF, Luo XP, Gong H, Su L, Yang L, Gong LY. SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/β-catenin pathway. J Transl Med 2019; 17:143. [PMID: 31060551 PMCID: PMC6501400 DOI: 10.1186/s12967-019-1895-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
Background The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown. Methods The relationship between SOX9 expression and T, N, M classification was assessed using the χ2 test and Spearman’s analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/β-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect β-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines. Results We found that SOX9 overexpression correlates with the T, N and M stage significantly (p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/β-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of β-catenin and increase the phosphorylation of GSK3β at Ser9. Further, inhibition of β-catenin suppressed the metastasis-promoting effects of SOX9 overexpression. Conclusions This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/β-catenin pathway.
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Affiliation(s)
- Jing-Qiang Huang
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China.,School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Fa-Kai Wei
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Xiu-Li Xu
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Shi-Xing Ye
- Department of Equipment, Shenzhen Longhua People's Hospital, Shenzhen, 518109, People's Republic of China
| | - Jun-Wei Song
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Pei-Kun Ding
- Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, 518020, People's Republic of China
| | - Jing Zhu
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - He-Feng Li
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China.,School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Xin-Ping Luo
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China
| | - Hui Gong
- Central Laboratory, Shenzhen Nanshan People's Hospital, Shenzhen University, Shenzhen, 518052, People's Republic of China
| | - Li Su
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.,Institute of Huazhong, University of Science and Technology in Shenzhen, Shenzhen, 518063, China
| | - Lin Yang
- Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, 518020, People's Republic of China.
| | - Li-Yun Gong
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, Shenzhen, 518060, People's Republic of China.
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8
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Zhao Y, Pang W, Yang N, Hao L, Wang L. MicroRNA-511 inhibits malignant behaviors of breast cancer by directly targeting SOX9 and regulating the PI3K/Akt pathway. Int J Oncol 2018; 53:2715-2726. [PMID: 30272349 DOI: 10.3892/ijo.2018.4576] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 09/14/2018] [Indexed: 11/06/2022] Open
Abstract
Numerous studies have revealed that a subset of microRNAs (miRNAs) is aberrantly expressed in breast cancer. The dysregulation of miRNAs is involved in the tumorigenesis and progression of breast cancer due to their negative regulation of downstream target genes. Therefore, the identification of deregulated miRNAs in breast cancer may provide important insights into the diagnosis and treatment of patients with this disease. miRNA‑511 (miR‑511) has been identified to be deregulated in diverse human cancer types; however, neither the expression status nor the detailed roles of miR‑511 in breast cancer have been clarified. Thus, it was aimed to determine the expression of miR‑511 in breast cancer, examine the role in malignant progression and explore its downstream targets. The results of the present study revealed that the expression of miR‑511 was downregulated in breast cancer tissues and cell lines. Decreased expression of miR‑511 was significantly associated with lymph node metastasis and tumor stage in patients with breast cancer. Functional analyses revealed that restoring miR‑511 expression suppressed breast cancer cell proliferation and colony formation, promoted apoptosis and reduced metastasis in vitro, while it attenuated tumor growth in vivo. Additionally, it was revealed that SRY‑box 9 (SOX9) was a direct target gene of miR‑511 in breast cancer cells. SOX9 was upregulated in breast cancer tissues and its expression was inversely correlated with that of miR‑511. Furthermore, SOX9 inhibition simulated the tumor‑suppressive roles of miR‑511 overexpression in breast cancer cells, while SOX9 reintroduction partially rescued these effects of miR‑511. Notably, the upregulation of miR‑511 targeted SOX9 to deactivate the PI3K/Akt signaling in breast cancer in vitro and in vivo. In conclusion, miR‑511 was downregulated in breast cancer, and impeded its malignant progression by directly targeting SOX9 and regulating the PI3K/Akt pathway. Thus, miR‑511 is a potential therapeutic target in breast cancer.
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Affiliation(s)
- Yuying Zhao
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weifeng Pang
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Ning Yang
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Ling Hao
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Lei Wang
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Liu S, Dong H, Dai H, Liu D, Wang Z. MicroRNA-216b regulated proliferation and invasion of non-small cell lung cancer by targeting SOX9. Oncol Lett 2018; 15:10077-10083. [PMID: 29928377 DOI: 10.3892/ol.2018.8573] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 12/21/2016] [Indexed: 12/21/2022] Open
Abstract
Micro (mi)RNAs are small, evolutionarily conserved and endogenous noncoding RNA molecules between 19 and 24 nucleotides in length. The potential roles of miRNAs in the carcinogenesis and progression of non-small cell lung cancer (NSCLC) have been studied previously. In the present study, it was revealed that miRNA-216b (miR-216b) expression was lower in NSCLC tissue and cell lines compared with that in adjacent healthy lung tissue samples and the normal bronchial epithelial 16HBE cell line, respectively. The ectopic expression of miR-216b inhibited the proliferation and invasion of NSCLC cells in vitro. SRY-Box 9 (SOX9) was identified as a direct target of miR-216b in NSCLC. In addition, SOX9 small interfering RNA was able to mimic the effects of miR-216b overexpression on cell proliferation and invasion in NSCLC. Therefore, the data reported in the present study demonstrate that miR-216b is an important tumor suppressor in NSCLC. These data may contribute to the understanding of the molecular mechanism underlying the carcinogenesis and progression of NSCLC, and provide novel therapies for patients with NSCLC.
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Affiliation(s)
- Sida Liu
- Department of Thoracic Surgery, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Han Dong
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hui Dai
- Department of Tumor and Blood Disease, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
| | - Danwei Liu
- Department of Infections, People's Hospital of Jilin Province, Changchun, Jilin 130021, P.R. China
| | - Zhihao Wang
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Wu Y, Gong L, Xu J, Mou Y, Xu X, Qian Z. The clinicopathological significance of HES1 promoter hypomethylation in patients with colorectal cancer. Onco Targets Ther 2017; 10:5827-5834. [PMID: 29263679 PMCID: PMC5726367 DOI: 10.2147/ott.s151857] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hairy/enhancer of split 1 (HES1) is a basic helix-loop-helix transcriptional repressor. Aberrant demethylation has been considered a common mechanism of tumor promoter gene activation. In the current study, we aimed to investigate the methylation status of the HES1 promoter and correlations with clinicopathological parameters and prognosis in colorectal cancer (CRC). The expression of HES1 in 50 paired CRC specimens and adjacent normal tissues was determined by using quantitative real-time polymerase chain reaction and immunohistochemical analysis. Moreover, DNA methylation status was evaluated through methylation-specific polymerase chain reaction and bisulfite sequencing. The correlation of methylation status with HES1 expression level and clinicopathological parameters was statistically analyzed in CRC patients. Our data showed that the methylation level of HES1 was significantly decreased and negatively correlated with HES1 expression in CRC tissues. Moreover, HES1 hypomethylation was associated with a poor histological grade, Dukes' classification, lymph node metastasis, and clinical stages (P<0.05). Furthermore, survival analyses revealed that a decreased methylation status of HES1 was linked to poor prognosis of CRC patients. In conclusion, promoter hypomethylation upregulates HES1 expression and plays a critical role in the progression and prognosis of CRC patients.
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Affiliation(s)
- Yinfang Wu
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
| | - Lijie Gong
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
| | - Ji Xu
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China
| | - Yiping Mou
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China
| | - Xiaowu Xu
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China
| | - Zhenyuan Qian
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China
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11
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Shi J, Guo J, Li X. Role of LASP-1, a novel SOX9 transcriptional target, in the progression of lung cancer. Int J Oncol 2017; 52:179-188. [PMID: 29138807 DOI: 10.3892/ijo.2017.4201] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 08/07/2017] [Indexed: 11/06/2022] Open
Abstract
Lung cancer accounts for most cancer-related deaths worldwide. However, the underlying mechanism by which it mediates the progression of lung cancer remains unclear. Expression of LASP-1 (LIM and SH3 protein 1) was evaluated in lung cancer tissues and tumor-adjacent normal tissues using immunohistochemistry and western blotting. Functional studies have shown that siRNA-mediated silencing of LASP-1 in human lung cancer cells and reduced cell proliferation, migration, and invasion. Flow cytometry and immunofluorescence staining also revealed that rate of cell apoptosis was increased after knockdown of expression of LASP-1, thereby suggesting that LASP-1 may function as an oncogene during lung cancer progression. SOX9 is an important transcription factor, which is involved in the development of several types of human cancer. Further analysis has showed the presence of a consensus-binding site of SOX9 in the promoter region of LASP-1. Mechanistic investigations showed that LASP-1 was transcriptionally activated by SOX9. Through luciferase reporter and ChIP assays, we demonstrated that LASP-1 was a direct target gene of sex determining region Y-box 9 (SOX9). Knockdown of SOX9 expression by RNA interference reduces cell proliferation and induces apoptosis of lung cancer cells, which was consistent with the results obtained from silencing the expression of LASP-1 in NCI‑H1650 cells. Together, these findings indicated that LASP-1, as a downstream target of SOX9, may act as a novel biomarker for lung cancer and plays an important role in cell proliferation, migration, and invasion.
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Affiliation(s)
- Jianguang Shi
- Department of Thoracic Surgery, Ningbo First Hospital, Haishu, Ningbo, Zhejiang 315010, P.R. China
| | - Jing Guo
- Department of Thoracic Surgery, Ningbo First Hospital, Haishu, Ningbo, Zhejiang 315010, P.R. China
| | - Xinjian Li
- Department of Thoracic Surgery, Ningbo First Hospital, Haishu, Ningbo, Zhejiang 315010, P.R. China
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Prévostel C, Blache P. The dose-dependent effect of SOX9 and its incidence in colorectal cancer. Eur J Cancer 2017; 86:150-157. [DOI: 10.1016/j.ejca.2017.08.037] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 08/24/2017] [Accepted: 08/30/2017] [Indexed: 10/18/2022]
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13
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Zhang S, Che D, Yang F, Chi C, Meng H, Shen J, Qi L, Liu F, Lv L, Li Y, Meng Q, Liu J, Shang L, Yu Y. Tumor-associated macrophages promote tumor metastasis via the TGF-β/SOX9 axis in non-small cell lung cancer. Oncotarget 2017; 8:99801-99815. [PMID: 29245941 PMCID: PMC5725132 DOI: 10.18632/oncotarget.21068] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/25/2017] [Indexed: 01/13/2023] Open
Abstract
Tumor-associated macrophages (TAMs), most of which display the immunosuppressive M2 phenotype, affect the tumor microenvironment and promote progression and metastasis in lung carcinoma. In this study, we analyzed clinical non-small cell lung cancer (NSCLC) samples and found that high densities of TAMs were associated with a poor prognosis in NSCLC patients. Moreover, the number of TAMs present correlated positively with expression of sex determining region Y (SRY)-related high mobility group box 9 (SOX9) in NSCLC tissues. TAMs secreted TGF-β, which increased SOX9 expression and promoted epithelial-to-mesenchymal transition (EMT) in lung cancer cells, thereby promoting tumor proliferation, migration, and invasion. SOX9 knockdown inhibited EMT, indicating that TGF-β-mediated EMT is SOX9-dependent. TGF-β induced SOX9 expression by upregulating the C-jun/SMAD3 pathway. These results indicate that TGF-β secreted by TAMs promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis. The TGF-β/SOX9 axis may therefore be an effective target for the treatment of lung cancer.
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Affiliation(s)
- Shuai Zhang
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dehai Che
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Fang Yang
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunling Chi
- 2 Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongxue Meng
- 3 Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jing Shen
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Li Qi
- 4 Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fang Liu
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Liyan Lv
- 5 Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Li
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qingwei Meng
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Junning Liu
- 6 Department of Oncology, The First Affiliated Hospital of Qiqihar Medical College, Qiqihar, China
| | - Lihua Shang
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yan Yu
- 1 The Sixth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Li Z, Li B, Niu L, Ge L. miR-592 functions as a tumor suppressor in human non-small cell lung cancer by targeting SOX9. Oncol Rep 2016; 37:297-304. [DOI: 10.3892/or.2016.5275] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 11/08/2016] [Indexed: 11/05/2022] Open
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Huang W, Beer RL, Delaspre F, Wang G, Edelman HE, Park H, Azuma M, Parsons MJ. Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation. Dev Biol 2016; 418:28-39. [PMID: 27565026 DOI: 10.1016/j.ydbio.2016.08.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 08/16/2016] [Accepted: 08/17/2016] [Indexed: 10/21/2022]
Abstract
Centroacinar cells (CACs) are ductal Notch-responsive progenitors that in the larval zebrafish pancreas differentiate to form new islets and ultimately contribute to the majority of the adult endocrine mass. Uncovering the mechanisms regulating CAC differentiation will facilitate understanding how insulin-producing β cells are formed. Previously we reported retinoic acid (RA) signaling and Notch signaling both regulate larval CAC differentiation, suggesting a shared downstream intermediate. Sox9b is a transcription factor important for islet formation whose expression is upregulated by Notch signaling in larval CACs. Here we report that sox9b expression in larval CACs is also regulated by RA signaling. Therefore, we hypothesized that Sox9b is an intermediate between both RA- and Notch-signaling pathways. In order to study the role of Sox9b in larval CACs, we generated two cre/lox based transgenic tools, which allowed us to express full-length or truncated Sox9b in larval CACs. In this way we were able to perform spatiotemporal-controlled Sox9b gain- and loss-of-function studies and observe the subsequent effect on progenitor differentiation. Our results are consistent with Sox9b regulating CAC differentiation by being a downstream intermediate of both RA- and Notch-signaling pathways. We also demonstrate that adult zebrafish with only one functional allele of sox9b undergo accelerated β-cell regeneration, an observation consistent with sox9b regulating CAC differentiation in adults.
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Affiliation(s)
- Wei Huang
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Rebecca L Beer
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Fabien Delaspre
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Guangliang Wang
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Hannah E Edelman
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Hyewon Park
- Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
| | - Mizuki Azuma
- Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
| | - Michael J Parsons
- McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA; Department of Surgery, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
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WANG XIAOYING, LIU YANLI, LIU XIAOLI, YANG JINGYAN, TENG GUOXIN, ZHANG LULU, ZHOU CHENGJUN. miR-124 inhibits cell proliferation, migration and invasion by directly targeting SOX9 in lung adenocarcinoma. Oncol Rep 2016; 35:3115-21. [DOI: 10.3892/or.2016.4648] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 01/05/2016] [Indexed: 11/06/2022] Open
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Zhu D, Chen H, Yang X, Chen W, Wang L, Xu J, Yu L. miR-32 functions as a tumor suppressor and directly targets SOX9 in human non-small cell lung cancer. Onco Targets Ther 2015; 8:1773-83. [PMID: 26229485 PMCID: PMC4516199 DOI: 10.2147/ott.s72457] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Purpose MicroRNA-32 (miR-32) is dysregulated in certain human malignancies and correlates with tumor progression. However, its expression and function in non-small cell lung cancer (NSCLC) remain unclear. Thus, the aim of this study was to explore the effects of miR-32 expression on NSCLC tumorigenesis and development. Methods Using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), we detected miR-32 expression in NSCLC cell lines and primary tumor tissues. The association of miR-32 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-32 expression on the biological behavior of NSCLC cells were investigated. Finally, the potential regulatory effect of miR-32 on SOX9 expression was confirmed. Results miR-32 expression levels were significantly downregulated in NSCLC compared with the corresponding noncancerous lung tissues (P<0.001). In addition, decreased miR-32 expression was significantly associated with lymph node metastasis (P=0.002), advanced tumor/nodes/metastasis (TNM) classification stages (P<0.001), and shorter overall survival (P<0.001). Multivariate regression analysis corroborated that downregulated miR-32 expression was an independent unfavorable prognostic factor for NSCLC patients. In vitro studies demonstrated that miR-32 overexpression reduced A549 cell proliferation, migration, and invasion, and promoted apoptosis. Furthermore, SOX9 was confirmed as a direct target of miR-32, using a luciferase reporter assay. Conclusion These findings indicate that miR-32 may act as a tumor suppressor in NSCLC and could serve as a novel therapeutic agent for miR-based therapy.
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Affiliation(s)
- Dan Zhu
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Hui Chen
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Xiguang Yang
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Weisong Chen
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Linying Wang
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Jilin Xu
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
| | - Long Yu
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, People's Republic of China
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Wang X, Ju Y, Zhou MI, Liu X, Zhou C. Upregulation of SOX9 promotes cell proliferation, migration and invasion in lung adenocarcinoma. Oncol Lett 2015; 10:990-994. [PMID: 26622611 DOI: 10.3892/ol.2015.3303] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 04/24/2015] [Indexed: 12/17/2022] Open
Abstract
Sex determining region Y-box 9 (SOX9) is an important transcription factor in development and has been implicated in several types of cancer. Although the association between upregulation of SOX9 and lung adenocarcinoma (ADC) has been reported previously, the role of SOX9 in the proliferation, migration and invasion of cancer cells remains unclear. Therefore, in the present study, SOX9 expression was detected in 163 human lung adenocarcinoma tissues by immunohistochemistry and western blotting. It was found that the SOX9 protein was over-expressed in the majority of lung adenocarcinoma. The full-length human SOX9 plasmid was then transfected into the lung ADC A549 cell line. An MTT assay was used to investigate the role of SOX9 in cell proliferation. Scratch and extracellular matrix cell invasion assays were performed to investigate whether SOX9 promotes the migration and invasion of lung ADC cells. The results revealed that ectopic overexpression of SOX9 in the lung adenocarcinoma cell line resulted in a marked increase in cell proliferation, migration and invasion. Accordingly, knockdown of SOX9 by RNA interference resulted in the inhibition of cell growth, migration and invasion. The present data indicate that SOX9 may act as a novel marker for lung adenocarcinoma and perform an important role in cell proliferation, migration and invasion.
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Affiliation(s)
- Xiaoying Wang
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ying Ju
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - M I Zhou
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaoli Liu
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Su YX, Hou CC, Yang WX. Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5. Gene 2014; 558:6-24. [PMID: 25550047 DOI: 10.1016/j.gene.2014.12.054] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/23/2014] [Accepted: 12/25/2014] [Indexed: 01/14/2023]
Abstract
Atoh1, Hes1 and Hes5 are crucial for normal inner ear hair cell development. They regulate the expression of each other in a complex network, while they also interact with many other genes and pathways, such as Notch, FGF, SHH, WNT, BMP and RA. This paper summarized molecular pathways that involve Atoh1, Hes1, and Hes5. Some of the pathways and gene regulation mechanisms discussed here were studied in other tissues, yet they might inspire studies in inner ear hair cell development. Thereby, we presented a complex regulatory network involving these three genes, which might be crucial for proliferation and differentiation of inner ear hair cells.
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Affiliation(s)
- Yi-Xun Su
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Cong-Cong Hou
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
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20
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Huang W, Wang G, Delaspre F, Vitery MDC, Beer RL, Parsons MJ. Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development. Dev Biol 2014; 394:83-93. [PMID: 25127993 PMCID: PMC4623430 DOI: 10.1016/j.ydbio.2014.07.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 07/22/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023]
Abstract
As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs.
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Affiliation(s)
- Wei Huang
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Guangliang Wang
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Fabien Delaspre
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Maria Del Carmen Vitery
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Rebecca L Beer
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
| | - Michael J Parsons
- Department of Surgery, and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA
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21
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Inhibitory effects of fucoxanthinol on the viability of human breast cancer cell lines MCF-7 and MDA-MB-231 are correlated with modulation of the NF-kappaB pathway. Cell Biol Toxicol 2014; 30:157-67. [PMID: 24760606 DOI: 10.1007/s10565-014-9277-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 04/10/2014] [Indexed: 02/07/2023]
Abstract
Fucoxanthin is a carotenoid present in the chloroplasts of brown seaweeds. When ingested, it is metabolized mainly to fucoxanthinol in the gastrointestinal tract by digestive enzymes. These compounds have been shown to have many beneficial health effects. The present study was designed to evaluate the molecular mechanisms of action of fucoxanthin and/or of its metabolite fucoxanthinol against viability of estrogen-sensitive MCF-7 and estrogen-resistant MDA-MB-231 breast cancer cell lines. Fucoxanthin and fucoxanthinol reduced the viability of MCF-7 and MDA-MB-231 cells in dose- and time-dependent manners as a result of increased apoptosis. Furthermore, fucoxanthinol-induced apoptosis was more potent than that of fucoxanthin and correlated, for MDA-MB-231 cells, with inhibitory actions on members of the NF-κB pathway p65, p50, RelB, and p52. Being overexpressed and regulated by NF-κB in different types of cancers, the transcription factor SOX9 was also decreased at the nuclear level by fucoxanthin and fucoxanthinol in MDA-MB-231. Taken together, the current results suggest that fucoxanthinol and fucoxanthin could be potentially effective for the treatment and/or prevention of different types of cancers, including breast cancer.
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Riemenschnitter C, Teleki I, Tischler V, Guo W, Varga Z. Stability and prognostic value of Slug, Sox9 and Sox10 expression in breast cancers treated with neoadjuvant chemotherapy. SPRINGERPLUS 2013; 2:695. [PMID: 24404438 PMCID: PMC3879394 DOI: 10.1186/2193-1801-2-695] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 12/10/2013] [Indexed: 01/20/2023]
Abstract
BACKGROUND Expression of transcription-factors as Slug and Sox9 was recently described to determine mammary stem-cell state. Sox10 was previously shown to be present also in breast cancer. Protein overexpression of Slug, Sox9 and Sox10 were associated with poor overall survival and with triple-negative phenotype in breast cancer. In this study we tested the stability of Slug, Sox9 and Sox10 expression during chemotherapy and addressed their prognostic role of in neoadjuvant treated primary breast-cancer and their correlation to pathological-response and overall survival. METHODS We analyzed immunohistochemical expression of Slug, Sox9 and Sox10 in tissue microarrays of 96 breast cancers prior to and after neoadjuvant chemotherapy. Expression was evaluated in invasive tumor cells and in tumor stroma and scored as 0, 1+, 2+ 3+. Expression-profile prior to and after chemotherapy was correlated to overall survival (Kaplan Meier) and with established clinico-pathological parameter. RESULTS Sox9, Sox10 and Slug were expressed in 82-96% of the tumor cells prior to chemotherapy. Slug was expressed in 97% of the cases in tumor stroma before therapy. Change in expression-profile after chemotherapy occurred only in Slug expression in tumor-cells (decreased from 82 to 51%, p = 0.0001, Fisher's exact test). The other markers showed no significant change after chemotherapy. Stromal Sox9 expression (0 to 2+) correlated to better overall survival after chemotherapy (p = 0.004) and reached almost statistical significance prior to chemotherapy (p = 0.065). There was no correlation between Sox9 and hormone-receptor expression. In multivariate-analysis, the stromal Sox9 expression after chemotherapy proved to be an independent and better prognostic marker than hormone-receptor status. Other clinico-pathological parameter (as HER2-status or pathological-stage) showed no correlation to the analyzed markers. CONCLUSION Strong stromal Sox9 expression in breast cancer after chemotherapy was found to bear negative prognostic information and was associated with shortened overall survival. Slug expression was significantly changed (reduced) in samples after neoadjuvant chemotherapy.
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Affiliation(s)
- Cosima Riemenschnitter
- Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH 8091 Zurich, Switzerland
| | - Ivett Teleki
- 1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Verena Tischler
- Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH 8091 Zurich, Switzerland
| | - Wenjun Guo
- Ruth L and Davis S Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY USA
| | - Zsuzsanna Varga
- Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH 8091 Zurich, Switzerland ; Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH 8091 Zurich, Switzerland
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Candy PA, Phillips MR, Redfern AD, Colley SM, Davidson JA, Stuart LM, Wood BA, Zeps N, Leedman PJ. Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients. Br J Cancer 2013; 109:1023-30. [PMID: 23900217 PMCID: PMC3749585 DOI: 10.1038/bjc.2013.431] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 06/29/2013] [Accepted: 07/04/2013] [Indexed: 12/15/2022] Open
Abstract
Background: The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance. Methods: Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables. Results: The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19). Conclusion: The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.
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Affiliation(s)
- P A Candy
- Laboratory for Cancer Medicine, University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia 6000, Australia
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Wang H, He L, Ma F, Regan MM, Balk SP, Richardson AL, Yuan X. SOX9 regulates low density lipoprotein receptor-related protein 6 (LRP6) and T-cell factor 4 (TCF4) expression and Wnt/β-catenin activation in breast cancer. J Biol Chem 2013; 288:6478-87. [PMID: 23306204 DOI: 10.1074/jbc.m112.419184] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Gene expression profiling has identified breast cancer (BCa) subtypes, including an aggressive basal-like (BL) subtype. The molecular signals underlying the behavior observed in BL-BCa group are largely unknown, although recent results indicate a prevalent increase in Wnt/β-catenin activity. Our immunohistochemistry study confirmed that SOX9, one of the BL-BCa signature genes, was expressed by most BL-BCa, and its expression correlated with indicators of poor prognosis. Importantly, BCa gene expression profiling strongly associated SOX9 with the expression of Wnt/β-catenin pathway components, LRP6 and TCF4. In cancer cell lines, SOX9 silencing reduced cell proliferation and invasion, LRP6 and TCF4 transcription, and decreased Wnt/β-catenin activation. SOX9 expression was also increased by Wnt, indicating that SOX9 is at the center of a positive feedback loop that enhances Wnt/β-catenin signaling. Consistently, SOX9 overexpression in BCa cell lines and transgenic SOX9 expression in breast epithelium caused increased LRP6 and TCF4 expression and Wnt/β-catenin activation. These results identify SOX9-mediated Wnt/β-catenin activation as one of the molecular mechanisms underlying aberrant Wnt/β-catenin activity in BCa, especially in the BL-BCa subgroup.
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Affiliation(s)
- Hongyun Wang
- Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Zhao ZK, Yu HF, Wang DR, Dong P, Chen L, Wu WG, Ding WJ, Liu YB. Overexpression of lysine specific demethylase 1 predicts worse prognosis in primary hepatocellular carcinoma patients. World J Gastroenterol 2012; 18:6651-6. [PMID: 23236241 PMCID: PMC3516205 DOI: 10.3748/wjg.v18.i45.6651] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 08/10/2012] [Accepted: 08/25/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinicopathological features and prognostic value of lysine specific demethylase 1 (LSD1) in hepatocellular carcinoma (HCC).
METHODS: We examined LSD1 expression in 60 paired liver cancer tissues and adjacent noncancerous tissues by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting. In addition, we analyzed LSD1 expression in 198 HCC samples by immunohistochemistry. The relationship between LSD1 expression, clinicopathological features and patient survival was investigated.
RESULTS: Immunohistochemistry, Western blotting, and qRT-PCR consistently confirmed LSD1 overexpression in HCC tissues compared to adjacent non-neoplastic tissues (P < 0.01). Additionally, immunostaining showed more LSD1-positive cells in the higher tumor stage (T3-4) and tumor grade (G3) than in the lower tumor stage (T1-2, P < 0.001) and tumor grade (G1-2, P < 0.001), respectively. Moreover, HCC patients with high LSD1 expression had significantly lower 5-year overall survival rates (P < 0.001) and lower 5-year disease-free survival rates (P < 0.001), respectively. A Cox proportional hazards model further demonstrated that LSD1 over-expression was an independent predictor of poor prognosis for both 5-year disease-free survival [hazards ratio (HR) = 1.426, 95%CI: 0.672-2.146, P < 0.001] and 5-year overall survival (HR = 2.456, 95%CI: 1.234-3.932, P < 0.001) in HCC.
CONCLUSION: Our data suggest for the first time that the overexpression of LSD1 protein in HCC tissues indicates tumor progression and predicts poor prognosis.
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Zhao ZK, Dong P, Gu J, Chen L, Zhuang M, Lu WJ, Wang DR, Liu YB. Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. Tumour Biol 2012; 34:173-80. [PMID: 23015317 DOI: 10.1007/s13277-012-0525-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Accepted: 09/13/2012] [Indexed: 02/06/2023] Open
Abstract
The aim of this study was to investigate the expression of LSD1 in human hepatocellular carcinoma (HCC) cell lines and HCC samples. In this study, we examined LSD1 expression in 60 paired liver cancer tissues and adjacent noncancerous tissues by Western blot. In addition, we analyzed LSD1 expression in 198 HCC samples by immunohistochemistry. The relationship between LSD1 expression and clinicopathological features was investigated. The HCC cell line SMMC-7721 was transfected with LSD1 siRNA expressing plasmids. We subsequently examined in vitro cell growth using the MTT assay and anchorage-independent growth through a soft-agar colony-formation assay. In addition, the expression levels of Bcl-2 and c-Myc were also examined. Immunohistochemistry and Western blotting consistently confirmed LSD1 overexpression in HCC tissues compared with adjacent non-neoplastic tissues (P < 0.01). Additionally, immunostaining showed more LSD1-positive cells in the higher tumor stage (T3-4) and tumor grade (G3) than in the lower tumor stage (T1-2, P < 0.001) and tumor grade (G1-2, P < 0.001). Knockdown of LSD1 expression in HCC cells led to decreased cell proliferation. The expression of Bcl-2 and c-Myc were down-regulated after transfection of LSD1 siRNA into HCC cell line SMMC-7721. In conclusion, because LSD1 was overexpressed in HCC and has an important role in the development of HCC, LSD1 could be a latent target in the diagnosis and therapy of HCC.
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Affiliation(s)
- Ze-Kun Zhao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University, No. 1165, Kongjiang Rd, Shanghai, 200092, China
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Castillo SD, Sanchez-Cespedes M. The SOX family of genes in cancer development: biological relevance and opportunities for therapy. Expert Opin Ther Targets 2012; 16:903-19. [DOI: 10.1517/14728222.2012.709239] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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GATA-1 utilizes Ikaros and polycomb repressive complex 2 to suppress Hes1 and to promote erythropoiesis. Mol Cell Biol 2012; 32:3624-38. [PMID: 22778136 DOI: 10.1128/mcb.00163-12] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The transcription factor Hairy Enhancer of Split 1 (HES1), a downstream effector of the Notch signaling pathway, is an important regulator of hematopoiesis. Here, we demonstrate that in primary erythroid cells, Hes1 gene expression is transiently repressed around proerythroblast stage of differentiation. Using mouse erythroleukemia cells, we found that the RNA interference (RNAi)-mediated depletion of HES1 enhances erythroid cell differentiation, suggesting that this protein opposes terminal erythroid differentiation. This is also supported by the decreased primary erythroid cell differentiation upon HES1 upregulation in Ikaros-deficient mice. A comprehensive analysis led us to determine that Ikaros favors Hes1 repression in erythroid cells by facilitating recruitment of the master regulator of erythropoiesis GATA-1 alongside FOG-1, which mediates Hes1 repression. GATA-1 is then necessary for the chromatin binding of the NuRD remodeling complex ATPase MI-2, the transcription factor GFI1B, and the histone H3K27 methyltransferase EZH2 along with Polycomb repressive complex 2. We show that EZH2 is required for the transient repression of Hes1 in erythroid cells. In aggregate, our results describe a mechanism whereby GATA-1 utilizes Ikaros and Polycomb repressive complex 2 to promote Hes1 repression as an important step in erythroid cell differentiation.
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Guo X, Xiong L, Sun T, Peng R, Zou L, Zhu H, Zhang J, Li H, Zhao J. Expression features of SOX9 associate with tumor progression and poor prognosis of hepatocellular carcinoma. Diagn Pathol 2012; 7:44. [PMID: 22515642 PMCID: PMC3464896 DOI: 10.1186/1746-1596-7-44] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2012] [Accepted: 04/19/2012] [Indexed: 12/30/2022] Open
Abstract
UNLABELLED BACKGROUND SOX9 as a member of the SOX (SRY [sex determining region Y] box) gene superfamily has been previously demonstrated to be a proto-oncogene in a variety of malignancies. However, the clinical significance of SOX9 expression in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of SOX9 in HCC and determine its correlation with tumor progression and prognosis. METHODS One-hundred and thirty HCC patients who had undergone curative liver resection were selected and immunohistochemistry, Western blotting, and quantitative real time polymerase chain reaction (Q-PCR) were performed to analyze SOX9 expression in the respective tumors. RESULTS Immunohistochemistry, Western blotting, and Q-PCR consistently confirmed SOX9 overexpression in HCC tissues compared with their adjacent nonneoplastic tissues (P ≪ 0.01). Additionally, immunostaining showed more SOX9 positive cells in the higher tumor stage (T3 ~ 4) and tumor grade (G3) than in the lower tumor stage (T1 ~ 2, P = 0.03) and tumor grade (G1 ~ 2, P = 0.01), respectively. Moreover, HCC patients with high SOX9 expression were significantly associated with lower 5-year overall survival (P ≪ 0.01) and lower 5-year disease-free survival (P ≪ 0.01), respectively. The Cox proportional hazards model further showed that SOX9 over-expression was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR] = 2.621, 95% confidence interval[CI] = 1.548-5.829, P = 0.01) and 5-year overall survival (HR = 3.825, CI = 1.638-7.612, P = 0.003) in HCC. CONCLUSION Our data suggest for the first time that the overexpression of SOX9 protein in HCC tissues is of predictive value on tumor progression and poor prognosis. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9029740396926377.
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Affiliation(s)
- Xiaodong Guo
- Postgraduate Medical School of PLA, Beijing, China
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Zhou CH, Ye LP, Ye SX, Li Y, Zhang XY, Xu XY, Gong LY. Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:18. [PMID: 22385677 PMCID: PMC3313873 DOI: 10.1186/1756-9966-31-18] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 03/03/2012] [Indexed: 11/10/2022]
Abstract
BACKGROUND Sex determining region Y (SRY)-related high mobility groupbox 9 (SOX9) is an important transcription factor required for development, which regulates the expression of target genes in the associated pathway. The aim of this study was to describe the expression of SOX9 in human non-small cell lung cancer (NSCLC) and to investigate the association between SOX9 expression and progression of NSCLC. METHODS SOX9 protein and mRNA expression in normal human pneumonocytes, lung cancer cell lines, and eight pairs of matched lung cancer tissues and their adjacent normal lung tissues were detected by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry was used to determine SOX9 protein expression in 142 cases of histologically characterized NSCLC. Statistical analyses were applied to test for prognostic and diagnostic associations. RESULTS SOX9 in lung cancer cell lines was upregulated at both mRNA and protein levels, and SOX9 mRNA and protein were also elevated in NSCLC tissues compared with levels in corresponding adjacent non-cancerous lung tissues. Immunohistochemical analysis demonstrated a high expression of SOX9 in 74/142 (52.1%) paraffin-embedded archival lung cancer biopsies. Statistical analysis indicated that upregulation of SOX9 was significantly correlated with the histological stage of NSCLC (P=0.017) and that patients with a high SOX9 level exhibited a shorter survival time (P<0.001). Multivariate analysis illustrated that SOX9 upregulation might be an independent prognostic indicator for the survival of patients with NSCLC. CONCLUSIONS This work shows that SOX9 may serve as a novel and prognostic marker for NSCLC, and play a role during the development and progression of the disease.
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Affiliation(s)
- Chun-Hui Zhou
- Department of Biochemistry and Molecular Biology, School of medicine, ShenZhen University, Shen Zhen, China
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Pritchett J, Athwal V, Roberts N, Hanley NA, Hanley KP. Understanding the role of SOX9 in acquired diseases: lessons from development. Trends Mol Med 2011; 17:166-74. [DOI: 10.1016/j.molmed.2010.12.001] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 11/26/2010] [Accepted: 12/01/2010] [Indexed: 11/25/2022]
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Abstract
Retinoids are ubiquitous signaling molecules that influence nearly every cell type, exert profound effects on development, and complement cancer chemotherapeutic regimens. All-trans retinoic acid (RA) and other active retinoids are generated from vitamin A (retinol), but key aspects of the signaling pathways required to produce active retinoids remain unclear. Retinoids generated by one cell type can affect nearby cells, so retinoids also function in intercellular communication. RA induces differentiation primarily by binding to RARs, transcription factors that associate with RXRs and bind RAREs in the nucleus. Binding of RA: (1) initiates changes in interactions of RAR/RXRs with co-repressor and co-activator proteins, activating transcription of primary target genes; (2) alters interactions with proteins that induce epigenetic changes; (3) induces transcription of genes encoding transcription factors and signaling proteins that further modify gene expression (e.g., FOX03A, Hoxa1, Sox9, TRAIL, UBE2D3); and (4) results in alterations in estrogen receptor α signaling. Proteins that bind at or near RAREs include Sin3a, N-CoR1, PRAME, Trim24, NRIP1, Ajuba, Zfp423, and MN1/TEL. Interactions among retinoids, RARs/RXRs, and these proteins explain in part the powerful effects of retinoids on stem cell differentiation. Studies of this retinol signaling cascade enhance our ability to understand and regulate stem cell differentiation for therapeutic and scientific purposes. In cancer chemotherapeutic regimens retinoids can promote tumor cell differentiation and/or induce proteins that sensitize tumors to drug combinations. Mechanistic studies of retinoid signaling continue to suggest novel drug targets and will improve therapeutic strategies for cancer and other diseases, such as immune-mediated inflammatory diseases.
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Affiliation(s)
- Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA.
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